Entrenamiento de los músculos respiratorios para la fibrosis quística
Resumen
Antecedentes
La fibrosis quística es la enfermedad autosómica recesiva más frecuente en las poblaciones blancas y causa disfunción respiratoria en la mayoría de personas. Se han descrito en la literatura numerosos tipos de entrenamiento muscular respiratorio para mejorar la función respiratoria y la calidad de vida relacionada con la salud en personas con fibrosis quística. Por tanto, se necesita una revisión sistemática de esta bibliografía para establecer la efectividad del entrenamiento muscular espiratorio (entrenamiento muscular inspiratorio o espiratorio) en los desenlaces clínicos en la fibrosis quística. Esta es una actualización de una revisión publicada anteriormente.
Objetivos
Determinar la efectividad del entrenamiento de los músculos respiratorios en los desenlaces clínicos de las personas con fibrosis quística.
Métodos de búsqueda
Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Fibrosis Quística (Cochrane Cystic Fibrosis and Genetic Disorders Group), que comprenden referencias identificadas por búsquedas exhaustivas en bases de datos electrónicas y por búsqueda manual en revistas pertinentes y en libros de resúmenes de congresos.
Fecha de la búsqueda más reciente: 11 de junio de 2020.
Se realizó una búsqueda manual en el Journal of Cystic Fibrosis and Pediatric Pulmonology, junto con una búsqueda electrónica en las bases de datos de ensayos en línea. Fecha de la búsqueda más reciente: 05 de octubre de 2020.
Criterios de selección
Ensayos controlados aleatorizados que compararan entrenamiento muscular respiratorio con un grupo control en los pacientes con fibrosis quística.
Obtención y análisis de los datos
Los autores de la revisión seleccionaron de forma independiente artículos para su inclusión, evaluaron la calidad metodológica de los estudios y extrajeron los datos. Cuando fue necesario, se buscó información adicional de los autores del ensayo. La calidad de la evidencia se evaluó mediante el sistema GRADE.
Resultados principales
Los autores identificaron 20 estudios, de los cuales diez con 238 participantes cumplieron los criterios de inclusión de la revisión. Hubo bastantes diferencias en la calidad metodológica y narrativa entre los estudios incluidos. Cuatro de los diez estudios incluidos estaban publicados sólo como resúmenes y les faltaban detalles concisos, lo cual limitaba la información disponible. Ocho estudios fueron estudios de grupos paralelos y dos tuvieron un diseño cruzado. Las intervenciones de entrenamiento de los músculos respiratorios variaron drásticamente, con una frecuencia, intensidad y duración que oscilaba entre tres veces por semana y dos veces al día, entre el 20% y el 80% del esfuerzo máximo, y entre 10 y 30 minutos, respectivamente. El número de participantes osciló entre 11 y 39 en los estudios incluidos; cinco estudios se realizaron en adultos solo, uno en niños y cuatro en una combinación de niños y adultos.
No se informaron diferencias entre el tratamiento y el control en el desenlace principal de función pulmonar (volumen espiratorio forzado en un segundo y capacidad vital forzada) (evidencia de calidad muy baja). Aunque no se informó de ningún cambio en la capacidad de ejercicio evaluada por la tasa máxima de uso de oxígeno y distancia completada en una prueba de seis minutos de marcha, se encontró una mejora del 10% en la duración del ejercicio cuando se trabajaba al 60% del esfuerzo máximo en un estudio (n = 20) (evidencia de muy baja calidad). En un estudio posterior (n = 18), al trabajar al 80% del esfuerzo máximo, la calidad de vida relacionada con la salud mejoró en los dominios de la maestría y las emociones (evidencia de muy baja calidad). En cuanto a los desenlaces secundarios de la revisión, un estudio (n = 11) encontró un cambio en la presión intramural, la capacidad residual funcional y la presión inspiratoria máxima después del entrenamiento (evidencia de calidad muy baja). Otro estudio (n=36) informó acerca de mejoras en la presión inspiratoria máxima después del entrenamiento (P < 0.001) (evidencia de calidad muy baja). Un estudio adicional (n = 22) informó que la resistencia de los músculos respiratorios fue mayor en el grupo de entrenamiento (P < 0,01). Ningún estudio incluido informó diferencias significativas ni ningún otro desenlace secundario. No se pudieron realizar metanálisis debido a la falta de consistencia y detalles en las medidas de desenlace informadas.
Conclusiones de los autores
No existe evidencia suficiente que indique si esta intervención es beneficiosa o no. Los profesionales de la salud deben considerar el uso del entrenamiento de los músculos respiratorios caso por caso. Se necesitan más estudios de calidad metodológica de confianza para determinar la efectividad del entrenamiento de los músculos respiratorios en las personas con fibrosis quística. Los investigadores deben tener en cuenta los siguientes desenlaces clínicos en futuros estudios: función muscular respiratoria, función pulmonar, capacidad de ejercicio, ingresos hospitalarios y calidad de vida relacionada con la salud. Los cambios sensorial‐perceptivos, como la sensación de esfuerzo respiratorio (por ejemplo, la calificación de la disnea percibida) y la sensación de esfuerzo periférico (por ejemplo, la calificación del esfuerzo percibido) también pueden ayudar a dilucidar los mecanismos que sustentan la eficacia del entrenamiento de los músculos respiratorios.
PICO
Resumen en términos sencillos
Entrenamiento de los músculos que provocan la expansión y contracción del tórax para las personas con fibrosis quística
Pregunta de la revisión
¿Cuáles son los efectos del entrenamiento de los músculos que influyen en la respiración (inspirar‐espirar) en las personas con fibrosis quística?
Antecedentes
La fibrosis quística es la enfermedad genética más frecuente en las poblaciones blancas y causa problemas con los pulmones en la mayoría de personas con esta enfermedad. El entrenamiento de los músculos que provocan la expansión y contracción del tórax podría ayudar a mejorar la función pulmonar y la calidad de vida de las personas con fibrosis quísticas.
Fecha de la búsqueda
La evidencia está actualizada hasta: 11 de junio de 2020.
Características de los estudios
Se buscaron estudios en los que las personas con fibrosis quística fueron asignadas al azar a un grupo de entrenamiento de los músculos respiratorios o a un grupo de control. Se incluyeron diez estudios con 238 personas que utilizaron una amplia variedad de métodos y niveles de entrenamiento. En ocho de los estudios, el grupo de tratamiento y el grupo de control sólo recibieron entrenamiento de los músculos respiratorios o un tratamiento de control (un estudio tenía tres grupos en total: uno que recibía tratamiento de control y dos que recibían diferentes niveles de entrenamiento). En un estudio los participantes recibieron ambos tipos de tratamientos, pero en un orden aleatoria. Por último, un estudio comparó el entrenamiento con la atención habitual. Los estudios duraron un máximo de 12 semanas y todos fueron bastante pequeños; el más grande sólo contó con la participación de 39 personas. Los estudios incluyeron a pacientes con un abanico de edades a partir de seis años pero la mayoría parecieron ser adultos. Los estudios informaron varios desenlaces. Todos informaron sobre alguna medida de fuerza muscular respiratoria, y la mayoría informó sobre al menos una medida de función pulmonar, sin embargo sólo tres estudios informaron sobre la calidad de vida.
Resultados clave
No se pudieron combinar los resultados para responder a la pregunta de la revisión, porque los estudios o no publicaron suficientes detalles o no usaron las mismas mediciones estándar. Ningún estudio encontró diferencias en la función pulmonar después del entrenamiento, pero uno de los estudios informó una mejoría en la duración del ejercicio cuando se entrenaba al 60% del esfuerzo máximo y un estudio adicional que entrenó a los participantes al 80% del esfuerzo máximo informó algunas mejoras en los juicios sobre la calidad de vida. Hubo cierta evidencia de una mejoría en la función muscular respiratoria en dos estudios.
Dada esta falta de información, no se puede hacer una recomendación a favor o en contra del entrenamiento de los músculos respiratorios. Los estudios futuros deben tratar de mejorar los métodos de los realizados anteriormente, y deben informar utilizando mediciones estandarizadas.
Calidad de la evidencia
En general, no estuvo claro cómo se dividía a las personas en grupos para el tratamiento y si esto habría afectado a los resultados. En tres estudios se afirmó que las personas que evaluaban los desenlaces no sabían qué tratamiento habían recibido los participantes, pero esto no estaba claro en otros estudios. Hubo personas que abandonaron tres de los estudios por razones que pueden estar directamente relacionadas con el tratamiento y, por lo tanto, pueden introducir un riesgo de sesgo en los resultados. Un estudio no tuvo abandonos y los otros seis no especificaron cuántas personas abandonaron los estudios. Se evaluó la calidad de la evidencia y se consideró que la evidencia de la función pulmonar, la capacidad de ejercicio, la estabilidad postural y la calidad de vida relacionada con la salud eran de muy baja calidad, pero la evidencia de la función muscular respiratoria de baja calidad.
Authors' conclusions
Summary of findings
| Respiratory muscle training compared with control for cystic fibrosis | ||||||
| Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: respiratory muscle traininga Comparison: controla | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Control | Respiratory muscle training | |||||
| FEV1 % predicted Follow‐up: 1 ‐ 3 months | No study reported any differences between the respiratory muscle training group and the control group. | NA | 83 (4) | ⊕⊝⊝⊝ | 1 study reported data for FEV1 % predicted at 40% of maximal capacity (de Jong 2001). 2 studies reported FEV1 % predicted at 30% of maximal capacity (Amelina 2006; Zeren 2019). 1 study reported FEV1 % predicted, but did not specify the resistance used (Asher 1983). 3 studies reported FEV1 measured in L and 1 measured z score; 1 study did not report the units of measurement. Results were similar to those for FEV1 % predicted. | |
| FVC: % predicted Follow‐up: 1 ‐ 3 months | No study reported any differences between the respiratory muscle training group and the control group. | NA | 72 (3) | ⊕⊝⊝⊝ | 1 study reported data for analysis for FVC (% predicted) at 40% of maximal capacity (de Jong 2001) and two studies at 30% of maximal capacity (Amelina 2006; Zeren 2019). 2 studies reported FVC in L and 1 measured z score; 1 study did not report the units of measurement. Results were similar to those for FVC % predicted. | |
| Exercise capacity: VO2max (mL/kg/min) Follow‐up: 1 ‐ 3 months | No study reported any differences between the respiratory muscle training group and the control group. | NA | 54 (3 studies including 1 cross‐over study) | ⊕⊝⊝⊝ | One study with an unspecified level of resistance reported an improvement within the respiratory muscle training group. | |
| HRQoL: total score Follow‐up: 1 ‐ 3 months | 2 studies reported no differences between the respiratory muscle training group and the control group. 1 study reported improvements in the parameters of mastery and emotion in the respiratory muscle training group compared to the control group. | NA | 69 (3 studies including 1 cross‐over study) | ⊕⊝⊝⊝ | 2 studies used the Chronic Respiratory Disease Questionnaire (CRDQ) and 1 study used the cystic fibrosis questionnaire (CFQ). | |
| Respiratory muscle function: maximal inspiratory pressure (PImax) Follow‐up: 1 ‐ 3 months | There was a greater improvement in the respiratory muscle training groups in 2 of the 4 studies measuring this outcome: MD 26.00 (95% CI 8.63 to 43.47) (Sawyer 1993); and MD 14.63 (95% CI 5.63 to 23.63) (Zeren 2019). The remaining 2 studies reported no differences between the respiratory muscle training group and the control group (Amelina 2006; Asher 1983). | NA | 87 (4 studies including 1 cross‐over study) | ⊕⊝⊝⊝ | Of the studies reporting a difference, the Sawyer study measured at 60% of maximal effort (Sawyer 1993) and the Zeren study measured at 30% resistance (Zeren 2019). 1 of the remaining studies reported at 30% of maximal effort (Amelina 2006) and 1 did not specify the level of resistance (Asher 1983). | |
| Respiratory muscle function: inspiratory capacity Follow‐up: 1 ‐ 3 months | No studies reported this outcome. | NA | ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a. The resistance level of the respiratory muscle training intervention was variable; three studies used 80% of maximal effort, one study used 60% of maximal effort, one study used 40% of maximal effort, one study used 30% of maximal effort and three studies did not specify the level of resistance. Control groups were also variable; cycle ergometer, H20, treatment as usual, standard chest physiotherapy, low resistance threshold loading device, no training or sham training. b. Downgraded twice due to serious risk of bias: the included studies lacked methodological detail relating to methods of randomisation, allocation concealment and blinding. Most of the studies were at high risk of bias due to lack of blinding, incomplete outcome data or selective reporting, or both. c. Downgraded due to imprecision: studies included a small number of participants and numerical results were not available for some of the studies. | ||||||
Background
Description of the condition
Cystic Fibrosis (CF) is caused by mutations of the CF transmembrane conductance regulator (CFTR) gene that disturbs the function of the CFTR channel (Elborn 2016). Over 2000 variants of CFTR mutations with a spectrum of effects on CFTR function, have been identified to date (Bell 2020). Dysfunction of the CFTR channel reduces chloride secretion resulting in dehydrated and viscous secretions that are difficult to clear (Wine 1999). The pathological consequences of this mutation can impact function of the respiratory, reproductive and digestive systems, as well as affecting temperature regulation and fluid balance (Wheatley 2011). At present the median predicted survival stands at 49.1 years in the UK and 44 years in the USA (CFF 2019; UK CF Trust 2019). Recently the management of CF has changed dramatically with the introduction of CFTR modulator medications, which correct the basic defect (Bell 2020), which in time may alter the presentation and complications of CF. However a large proportion of today’s CF population still have significant CF manifestations which cause morbidity and premature mortality.
Worldwide, respiratory or cardiorespiratory causes are the current primary cause of death from CF (CFF 2019; UK CF Trust 2019), accounting for 70.2% of all UK deaths from CF between 2017 and 2019 (UK CF Trust 2019). CFTR dysfunction creating viscous secretions leads to bacterial colonisation and chronic pulmonary infection which imposes structural lung damage, mostly bronchiectasis, and small airway obstruction (Cantin 2015). Recurrent pulmonary infection results in the progressive deterioration of pulmonary function and eventually respiratory failure (Grasemann 2013). Other physiological factors such as inflammation, gas trapping and mucous plugging contribute towards further airway obstruction, thus reducing forced expiratory volumes and causing excessive dyspnoea (Kozlowska 2008). Co‐morbidities such as thoracic kyphosis can exacerbate this, restricting lung expansion, decreasing lung volumes, and leading to an increased work of breathing (Aris 1998; Denton 1981).
Management of CF has evolved around preventing infections and deterioration of pulmonary function through individualised combinations of medications including antibiotics and mucoactive agents alongside airway clearance to optimise secretion mobilisation. This management strategy has led to a substantial increase in life expectancy for people with CF over the last 30 years (Ratjen 2015). With an increasingly well population, interventions such as exercise which focus on optimising health outcomes and preventing complications of CF are becoming key in CF care.
Description of the intervention
Respiratory muscle training (RMT) is a form of exercise training specifically targeting the muscles that drive expansion or contraction of the chest, or both. Training can stress the musculature of inspiration or expiration, or both, depending upon the type of training performed and the specification of the individual device. There are two main types of RMT, namely resistive training and normocapnic hyperpnoea. Resistive training can be performed using either flow‐resistive loading or pressure‐threshold loading, and requires the use of a portable hand‐held device. Both devices typically involve a one‐way valve mechanism, such that only the inspiratory or expiratory musculature can be trained at one given time. Flow‐resistive loading involves breathing through a hole of small diameter (resistor), thus limiting airflow, increasing the work of breathing and challenging the respiratory musculature. The resistance (load) applied to the respiratory musculature can be adjusted according to the diameter of the hole, whereby reducing the diameter increases airflow limitation. Pressure‐threshold training creates a similar physiological challenge, and involves breathing with sufficient force to overcome a spring‐loaded valve to enable airflow. The resistance (load) is set at a proportion of maximal static inspiratory mouth pressure (PImax). Resistive training regimens vary in terms of the intensity (load), duration (sets, repetitions and time) and frequency (sessions per week), depending upon the desired physiological outcome i.e. muscular strength or endurance. Overall training volume can be altered using a combination of intensity, duration and frequency, and training can be either continuous or interval in nature. While resistive training can be performed under the supervision of a suitably qualified therapist, users may perform this independently.
Normocapnic hyperpnoea is a type of RMT that requires the individual to ventilate at a high proportion of their maximum voluntary ventilation (MVV) for a predetermined period of time (around 10 to 15 minutes (Koppers 2006)). It is proposed that normocapnic hyperpnoea strengthens the respiratory muscles by accelerated deep breathing with controlled oxygen saturation of the blood. Complex rebreathing circuitry is required to perform this form of training and to minimise the risk of inducing hypercapnia. Unlike resistive training, normocapnic hyperpnoea trains both the inspiratory and expiratory musculature simultaneously. As the physiological challenge is derived from high ventilation, as opposed to high resistive load, the training load is determined by the rate of minute ventilation. For the same reason, normocapnic hyperpnoea is thought to target muscular endurance as opposed to muscular strength (Reid 1995).
How the intervention might work
It has been suggested that RMT may improve health‐related quality of life, pulmonary function and exercise capacity in people with CF (Padula 2007). Some studies have postulated that RMT may enhance the clearance of mucous from the lungs (Chatham 2004), which is a fundamental aspect in preventing pulmonary infection. Although RMT may be thought to improve pulmonary function, exercise tolerance and quality of life, the causal mechanisms remain unclear.
As there is some evidence that people with CF have similar respiratory muscle strength to healthy peers (Arikan 2015; Dunnink 2009), several potential mechanisms that have been postulated in a healthy population may also be comparable in those with CF. Perceptual changes have been found to occur following RMT, whereby a significant reduction in the perception of respiratory effort has been observed (Romer 2002). Numerous mechanisms have been hypothesised, including an improvement in the contractile and endurance properties of the inspiratory musculature, and a desensitising effect on the sensory input from the inspiratory muscles to the brain (El‐Manshawi 1986; Revelette 1987; Sales 2016; Wilson 1990). Significant reductions in the perception of peripheral effort have also been observed, attributed to a changes in acid‐base balance and respiratory muscle blood flow (Caine 2000). Reduced work of breathing and decreased rating of perceived breathlessness or exertion have also been reported (Shei 2018).
In CF, these mechanisms may also account for the improvements in health‐related quality of life, pulmonary function and exercise capacity that have been observed. As a combination of structural lung damage and physical deconditioning can increase the perception of respiratory (dyspnoea) and peripheral effort in people with CF, the need for this review is apparent.
Why it is important to do this review
Prior to the original version of this review (Houston 2008), there was no systematic review of the currently available evidence from randomised controlled trials (RCTs) or quasi‐randomised controlled trials as to whether RMT is beneficial, nor on the optimal regime (i.e. the nature of the training load and specifics of the training protocol), for people with CF. The effect of RMT on improving health outcomes in CF remains unclear. Previous versions of this Cochrane Review were unable to conclude if this treatment is either beneficial or not, due to the apparent lack of clinical trials, particularly those of a high‐quality; this version of the review is the latest update of the original review (Hilton 2018; Houston 2008; Houston 2009; Houston 2013).
Objectives
To determine the effectiveness of respiratory muscle training on clinical outcomes in people with cystic fibrosis.
Methods
Criteria for considering studies for this review
Types of studies
Any parallel or cross‐over randomised controlled trial (RCT) comparing RMT with a control group.
Types of participants
Any person with CF who has been diagnosed by sweat testing, genotyping or both. Participants were included irrespective of gender, age, or the presence of co‐morbidities.
Types of interventions
Trials were considered for inclusion if the author(s) had compared RMT with a control group, such as a placebo (e.g. sham‐training) or no intervention. RMT included either inspiratory or expiratory muscle training, or both, including resistive loading (flow‐resistive or pressure threshold, or both) and normocapnic hyperpnoea training. Singing training interventions were excluded from this review. Studies that performed RMT in combination with any other form of physical exercise training were excluded from the review. Combining these interventions is the subject of another Cochrane Review (Radtke 2015).
Types of outcome measures
We assessed the following outcome measures.
Primary outcomes
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Pulmonary function
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forced expiratory volume at one second (FEV1)
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forced vital capacity (FVC)
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peak expiratory flow (PEF)
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Exercise capacity (measured by e.g. maximal oxygen uptake (VO2max), exercise duration, etc.)
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Health‐related quality of life (measured by e.g. Chronic Respiratory Disease Questionnaire (CRDQ) (Chauvin 2008), Cystic Fibrosis Questionnaire (CFQ) (Wenninger 2003), etc.)
Secondary outcomes
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Respiratory muscle function
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maximal inspiratory pressure (PImax)
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inspiratory capacity (IC)
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maximal expiratory pressure (PEmax)
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Respiratory muscle strength and endurance (RME)
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Frequency and duration of respiratory infections, hospitalisations
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Adherence
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Death or survival
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Adverse effects (pneumothorax, musculoskeletal pains or injuries, others)
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Costs
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Oxygen saturations (post hoc change)
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Postural stability measured using the Biodex Balance System (post hoc change)
Search methods for identification of studies
The authors searched for all relevant published and unpublished trials without restrictions on language, year or publication status.
Electronic searches
We identified relevant studies from the Group's Cystic Fibrosis Trials Register using the term: inspiratory muscle training.
The Group's Cystic Fibrosis Trials Register, which is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library), weekly searches of MEDLINE, a search of Embase to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching the abstract books of four major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference, the North American Cystic Fibrosis Conference and the Australia and New Zealand Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group website.
Date of the last search of the Group's Cystic Fibrosis Trials Register: 11 June 2020.
We also performed separate searches of clinicaltrials.gov and the WHO ICTRP databases (Appendix 1; Appendix 2). Date of the last search: 05 October 2020.
We completed separate searches of the following databases: MEDLINE, PEDro (The Physiotherapy Evidence Database), Science Direct and SCOPUS between July and October 2020 (for the individual dates please see the relevant appendix), using both the Cochrane RCT and CF search filters and terms specific to the intervention (Appendix 3; Appendix 4; Appendix 5; Appendix 6).
For versions of the review up to and including 2014 the former author team also performed separate searches of the following databases: Embase, CINAHL, AMED (Allied and Complementary Medicine), BIOSIS Previews to 2013, using both the Cochrane RCT and Cystic Fibrosis search filters; and terms specific to the intervention (Appendix 3; Appendix 4; Appendix 5; Appendix 6). They also searched Current Controlled Trials and the UK National Research Registerfor ongoing and recently completed studies. These searches last run on the 01 August 2013 (Appendix 5; Appendix 6; Appendix 7).
Searching other resources
For this update and the original review, we also contacted manufacturers and study investigators and checked reference lists of relevant literature.
Data collection and analysis
Where the text below describes "the authors", up to the 2018 update the original three authors (BH, NM and ASM) are referred to; for the 2018 update "the authors" refers to NH and ASM and for the 2020 update "the authors" refers to GS, ASM and HR.
Selection of studies
To identify potentially eligible studies, authors screened the titles and abstracts of each record retrieved from the search. We then obtained the full‐text articles and inspected these independently for the review, including titles and abstracts that could not be rejected with certainty. If we could not reach an agreement we would have resolved these issues by discussion and the involvement of another person if necessary.
Data extraction and management
The review authors assessed the methodological quality of the selected studies and independently extracted data using a standardised data collection form based upon the recommendation in the Cochrane Handbook for Systematic Reviews of Interventions (Li 2020). We entered all eligible studies into the Review Manager software (RevMan Web 2020); we did not need to resolve any disagreements.
The data will be grouped at the following time points: up to one month; one month to three months; three to six months; six months to one year and annually thereafter.
Assessment of risk of bias in included studies
The review authors used the Cochrane risk of bias tool to independently assess the study quality according to the following criteria: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and any other identified sources of bias (Higgins 2017). We also considered the external validity of each study, particularly the description of study participants (e.g. mean FEV1) and the study intervention (e.g. controlling inspiratory flow rate), as well as the reliability of reported outcomes (e.g. familiarity).
Measures of treatment effect
The review authors graphically presented quantitative data for the outcomes listed in the inclusion criteria. Where we were able to obtain data for continuous outcomes (pulmonary function, exercise capacity, quality of life, respiratory muscle function, frequency and duration of respiratory infections, hospitalisations and costs), we calculated the mean differences (MD) and presented these with 95% confidence intervals (CIs). No analysable data were available for dichotomous outcomes; for future updates, if we are able to analyse dichotomous outcomes (adherence, survival and adverse effects), we plan to calculate the risk ratio (RR) and 95% CIs for dichotomous outcomes.
Unit of analysis issues
Ideally when conducting a meta‐analysis combining results from cross‐over studies, the review authors planned to use the inverse variance methods that are recommended by Elbourne (Elbourne 2002). However, if there were limited data available they planned to either use first‐arm data only or treat the cross‐over study as if it was of parallel design (assuming a correlation of zero as the most conservative estimate). Elbourne says that this approach produces conservative results as it does not take into account within‐patient correlation (Elbourne 2002). Also each participant appears in both the treatment and control group, so the two groups are not independent. Currently there are two cross‐over studies included in the review and we have reported the results narratively due to data limitations (Asher 1983; Bieli 2017).
Where studies measured data longitudinally, the authors based the analysis on the results from the final time point. Methods are not yet available to carry out a meta‐analysis of aggregate longitudinal data, where individual patient data (IPD) is not available.
Dealing with missing data
Where data were missing, the review authors attempted to contact the author(s) of the study to obtain the missing data. Where data are still missing, we catagorised these studies as 'awaiting classification'. We only analysed the available data (i.e. without imputing missing data).
Assessment of heterogeneity
We would have conducted a meta‐analysis and assessed heterogeneity if we had included and combined sufficient studies in the review. We planned to examine heterogeneity between comparable studies using a standard Chi² test with the alpha level of significance set at P < 0.05. We would have determined levels of heterogeneity using the I² statistic, whereby we considered I² greater than 50% to be substantial heterogeneity (Deeks 2020).
Assessment of reporting biases
If sufficient data were available, the review authors planned to explore potential publication bias by preparing a funnel plot. Where possible the authors compared the 'Methods' section of the full study report to the outcomes reported in the 'Results' section to identify any selective outcome reporting.
Data synthesis
The review authors planned to pool the results of comparable groups of studies using the fixed‐effect model and to calculate the relevant 95% CIs if sufficient data were available.
Subgroup analysis and investigation of heterogeneity
The review authors did not plan to perform any meta‐analyses if there had been substantial and statistically significant heterogeneity. If we had been able to combine a sufficient number of included studies and had identified substantial heterogeneity (as defined above), we planned to explore this using the following subgroup analyses:
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type of RMT (e.g. resistive loading or normocapnic hypopnea)
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regimen of RMT (e.g. daily versus three times per week)
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characteristics of study participants
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age (up to 16 years versus older than 16 years)
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gender
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participants with poor respiratory muscle strength compared to those with preserved strength (e.g. determined by PImax)
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participants with mild airflow obstruction compared to those with severe hyperinflation airflow obstruction (e.g. determined by FEV1)
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definition of outcome measures
Sensitivity analysis
If we had been able to include and combine a sufficient number of studies, we would have performed sensitivity analyses based upon the methodological quality of the included studies, including allocation concealment, blinding of outcome assessments, and analyses performed on an intention‐to‐treat basis.
Summary of findings and assessment of the certainty of the evidence
In a post hoc change at the 2018 update, and in accordance with current Cochrane guidance, we have included a summary of findings table presenting results comparing respiratory muscle training (all intensities) versus control comparison. We have included the six outcomes which we consider to be the most clinically relevant.
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FEV1 % predicted
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FVC % predicted
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VO2max (mL/kg/min)
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health‐related quality of life (overall score)
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PImax
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IC
We assessed the quality of the evidence for each outcome using the GRADE approach (Schünemann 2020a; Schünemann 2020b). This approach is based on the risk of bias within the studies, relevance to our population of interest (indirectness), unexplained heterogeneity or inconsistency, imprecision of the results or high risk of publication bias. We downgraded the evidence once if the risk was serious and twice if the risk was deemed to be very serious.
Results
Description of studies
Please see the tables for additional information (Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification).
Results of the search
The database searches identified 279 potentially eligible studies. The authors reviewed the abstracts of the studies and identified 10 studies with a total of 238 participants for inclusion (Albinni 2004; Amelina 2006; Asher 1983; Bieli 2017; Chatham 1997; de Jong 2001; Enright 2004; Heward 2000; Sawyer 1993; Zeren 2019). Of these 10 studies, four were published as abstracts only (Albinni 2004; Amelina 2006; Chatham 1997; Heward 2000). A further seven studies were excluded (Howard 2000; Irons 2012; Keens 1977; Patterson 2004; Santana‐Sosa 2014; Sartori 2008; Vivodtzev 2013). Five studies are currently listed as 'Awaiting classification' until further details are available (Emirza 2020; Giacomodonato 2015; NCT03190031; NCT03737630; Ozaydin 2010); three of these studies were identified from the study registry ClinicalTrials.gov and although now closed, have no results published to date (Emirza 2020; NCT03190031; NCT03737630).
Included studies
A full comparison of the included studies can be found in the table (Characteristics of included studies).
Study design
All studies were RCTs. Of these, eight were of a parallel design (Albinni 2004; Amelina 2006; Chatham 1997; de Jong 2001; Enright 2004; Heward 2000; Sawyer 1993; Zeren 2019) and two studies had a cross‐over design (Asher 1983; Bieli 2017). One study utilised a three‐way comparison between two different RMT interventions and control condition (Enright 2004). The duration of the intervention ranged from four (Asher 1983) to 12 weeks (Albinni 2004) and all outcomes were recorded at the end of the study period. All studies were relatively small with the number of participants ranging from 11 (Asher 1983) to 39 (Heward 2000). The studies were run in a number of different countries: USA (Heward 2000; Sawyer 1993); UK (Chatham 1997; Enright 2004); Netherlands (de Jong 2001); Switzerland (Bieli 2017); Canada (Asher 1983); Russia (Amelina 2006); Austria (Albinni 2004); and Turkey (Zeren 2019). While most were single‐centre studies (Albinni 2004; Amelina 2006; Bieli 2017; de Jong 2001; Enright 2004; Sawyer 1993; Zeren 2019), it was unclear if three studies were single or multicentre (Asher 1983; Chatham 1997; Heward 2000).
Participants
Participant characteristics were not consistently reported across studies. Two studies did not report the exact mean age or age range of participants, but indicated that they were adults (Amelina 2006; Chatham 1997). One further study explicitly stated that participants were adults and gave a mean age of 22.5 years (Heward 2000). Three studies reported age ranges that included children, adolescents and young adults; 6 to 18 years (Albinni 2004), 9 to 18 years (Bieli 2017), and 9 to 24 years (Asher 1983). The remaining four studies gave more detailed information on participant age, reporting mean ages and the standard deviation according to treatment groups (de Jong 2001; Enright 2004; Sawyer 1993; Zeren 2019). In each study, ages were similar between groups, but while the mean age in two studies suggested that participants were young adults (de Jong 2001; Enright 2004), the mean age in the remaining studies indicated children and adolescent participants (Sawyer 1993; Zeren 2019).
Six of the studies did not report on the gender split in participants (Albinni 2004; Amelina 2006; Asher 1983; Chatham 1997; Heward 2000; Sawyer 1993). Four studies reported on gender split by treatment group. One study had equal numbers of males and females (de Jong 2001), one study had slightly more females than males (Zeren 2019), and in the remaining studies there were slightly more males than females (Bieli 2017; Enright 2004).
Interventions
There was great variation as to the method and level of training employed by the included studies. In the intervention group, three studies used 80% of maximal effort (Chatham 1997; Enright 2004; Heward 2000); one study used 60% of maximal effort (Sawyer 1993); one study used 40% of maximal effort (de Jong 2001); two studies used 30% of maximal effort (Amelina 2006; Zeren 2019) and three studies did not specify the level of resistance (Albinni 2004; Asher 1983; Bieli 2017). The frequency of training also varied. In two studies the frequency and duration of training was unclear (Chatham 1997; Heward 2000). Five studies used similar training regimens (Amelina 2006; Asher 1983; Bieli 2017; Sawyer 1993; Zeren 2019). Of these, two studies used a duration for each session of 10 to 15 minutes twice daily (Amelina 2006; Bieli 2017); two studies used 15 minutes twice daily (Asher 1983; Zeren 2019) and one study used 30 minutes in total daily (Sawyer 1993). The remaining two studies used a regimen of training three times per week, but the duration of the sessions either varied (Enright 2004) or was not stated (Albinni 2004).
Outcomes
The outcome measures selected by the studies also varied greatly. All studies reported some measure of respiratory or inspiratory muscle strength. Most studies reported at least one measure of pulmonary function, principally FEV1 (Albinni 2004; Amelina 2006; Asher 1983; Bieli 2017; de Jong 2001; Enright 2004; Sawyer 1993; Zeren 2019) and FVC (Albinni 2004; Amelina 2006; Bieli 2017; de Jong 2001; Enright 2004; Zeren 2019). Seven studies reported on exercise capacity (Albinni 2004; Amelina 2006; Asher 1983; Bieli 2017; de Jong 2001; Sawyer 1993; Zeren 2019), specifically maximal oxygen uptake (VO2max) (Albinni 2004; Asher 1983; de Jong 2001) and exercise duration (Bieli 2017; Sawyer 1993;Zeren 2019 ). One study reported on exercise capacity but did not specify the outcome measure (Amelina 2006).
Three studies reported a measure of health‐related quality of life using either the Chronic Respiratory Disease Questionnaire (CRDQ) (Chatham 1997; Enright 2004) or a combination of the Cystic Fibrosis Questionnaire (CFQ) and the Cystic Fibrosis Clinical Score (CFCS) (Bieli 2017). Other studies also reported on related outcomes such as perceived breathlessness (Albinni 2004; de Jong 2001) and fatigue (de Jong 2001).
Excluded studies
A total of seven studies were excluded (seeCharacteristics of excluded studies). One study was excluded as the allocation was not randomised (Keens 1977), whereas two studies were excluded as they were not interventional trials (Patterson 2004; Sartori 2008). A further three studies were excluded as the intervention was not appropriate and could not be deemed a form of RMT (Howard 2000; Irons 2012; Vivodtzev 2013). Although one study used a form of RMT, it was combined with another form of exercise training, and was excluded as changes could not be attributed to RMT alone (Santana‐Sosa 2014).
Studies awaiting classification
There are five studies currently listed as 'awaiting classification', which require more detail about the study prior to classification (Emirza 2020; Giacomodonato 2015; NCT03190031; NCT03737630; Ozaydin 2010). Three of these studies are currently published as abstracts only (Emirza 2020; Giacomodonato 2015; Ozaydin 2010). Two of these studies were identified from clinicaltrials.gov and have no results published to date (NCT03190031; NCT03737630).
Study design
Five studies stated that participants were randomised to either the control or intervention group, but gave no further details regarding study design (Emirza 2020; Giacomodonato 2015; NCT03190031; NCT03737630; Ozaydin 2010).
Participants
One study included 10 participants with CF aged between 21 and 40 years; there were six males and four females (Giacomodonato 2015). Another study included 28 participants with CF with a mean (SD) age 13.18 (3.65) years and a mean (SD) baseline value for FEV1 % predicted of 89.51% (19.47) (Ozaydin 2010). A third study included 28 participants with CF aged 8 to 18 years but gave no further details (Emirza 2020). Two studies included 10 people with CF (NCT03737630) and 38 people with CF (NCT03190031), but gave no further details of participants.
Interventions
The Giacomodonato study allocated participants to either RME training with normocapnic hyperpnoea or standard chest physiotherapy (Giacomodonato 2015). Participants in the intervention group were asked to maintain 70% of 12s MVV until this could not be sustained, for 15 minutes daily over eight weeks.
Ozaydin allocated 14 participants to inspiratory muscle training (IMT) using a threshold loading device at 30% to 80% maximal inspiratory pressure (MIP) and 14 participants to sham training at 10% MIP, for 20 minutes on five days per week (Ozaydin 2010).
The Emirza study allocated participants to either expiratory muscle training at 30% of maximal expiratory pressure (MEP) or sham training using the same device set at the lowest pressure setting of 5 cm H2O (Emirza 2020). Training was completed for at least five days a week during a six‐week period.
In NCT03190031 participants performed endurance respiratory muscle training at 70% to 80% of MVV or IMT at 70% to 80% of MIP for 20 minutes, five times a week for eight weeks (NCT03190031). No further details were available on either study
Investigators in NCT03737630 compared moderate‐load IMT to low‐load IMT, but again no further details were available (NCT03737630). .
Outcomes
The Giacomodonato study stated that it had measured RME, six‐minute walk test (6MWT) distance, health‐related quality of life (HRQoL) using the CFQ and lung function (FVC, FEV1, MIP, MEP) pre‐ and post‐intervention. However, the abstract only reported 6MWT distance between the groups following the intervention and we await the full publication for further results (Giacomodonato 2015).
The Ozaydin study also measured the 6MWT distance and pulmonary function; in addition the investigators measured peripheral muscle strength (hand grip, shoulder abductors, elbow flexors) (Ozaydin 2010).
The Emirza study measured peak cough flow, MIP, MEP, spirometry and 6MWT. They reported significant improvements in peak cough flow and MEP, and non‐significant differences for other measures (although values were not reported). We await the full publication for further details of the results (Emirza 2020).
Of the two studies listed on the registry, one measured change from baseline in posture, QoL, respiratory muscle strength, pulmonary function and functional capacity (NCT03737630). The second study assessed RME measured by an incremental hyperpnea test, respiratory muscle strength, cycling perfomance and HRQoL (NCT03190031).
Risk of bias in included studies
Risk of bias judgements were made for each of the following domains using the Cochrane risk of bias tool.
Allocation
Generation of allocation sequence
Although all 10 of the included studies state that they had randomised their participants to the treatment groups, only two studies indicated the method of allocation by stating that they employed the minimisation method (de Jong 2001) or pre‐filled envelopes specifying group assignments generated by a computer‐based programme (Zeren 2019). We graded these two studies as having a low risk of bias, whereas we graded the remaining eight studies as having an unclear risk of bias.
Concealment of allocation sequence
Of the included studies, only one study was deemed to have a low risk of bias in regards to concealment of allocation (Zeren 2019). The use of pre‐filled envelopes specifying group allocation enabled blinding of both participants and physiotherapists prior to the commencement of training programmes. All other studies made no specific references as to how, or even whether, investigators concealed allocation. Therefore, these remaining studies were deemed to have an unclear risk of bias in relation to this criteria.
Blinding
Performance bias
We graded all the included studies as having a high risk of performance bias since in all studies there was a clear difference between the experimental and control training. This ranged from no details being provided for the control group (Asher 1983) and 'no training' (Albinni 2004; Enright 2004; Heward 2000; Zeren 2019), through to minimal training and "sham" training (Amelina 2006; Chatham 1997; de Jong 2001; Sawyer 1993) and standard chest physiotherapy (Bieli 2017). Although the methodological difficulties of blinding the participants to this type of intervention are acknowledged, this can be addressed in some cases (e.g. RMT versus sham) but not all (e.g. training versus no training).
Detection bias
One study blinded the outcome assessors for all assessments, although the paper did not state if the same assessor was used (Zeren 2019). Two studies blinded the outcome assessors at the final data collection session, but did not state whether this was the case at the initial assessment or if the same assessors were used (Enright 2004; Sawyer 1993). A third study reports that the observers were blinded, although it does not expand on the level of this (Asher 1983). The remaining six studies make no overt reference to any blinding of outcome assessors and are deemed a high risk of bias (Albinni 2004; Amelina 2006; Bieli 2017; Chatham 1997; de Jong 2001; Heward 2000).
Incomplete outcome data
Only one study referred to the intention‐to‐treat principle (Bieli 2017). The trial reported that six out of 22 participants withdrew from the study, of these four participants discontinued the study in the control period, suggesting that withdrawal was not directly linked to the intervention in these cases. However, participants who withdrew did have a tendency to be older with characteristics of more advanced lung disease (Bieli 2017). We judged this study to have a low risk of bias. We judged a further study to have a low risk of bias as investigators stated that there were no withdrawals, although some participants did not complete all training sessions and it was unclear whether investigators used the intention‐to‐treat principle (Zeren 2019).
Three studies were judged to have a high risk of bias (Asher 1983; de Jong 2001; Sawyer 1993). In the Asher study, two participants did not perform one of the post‐treatment outcome measures, due to expiration up to residual volume resulting in coughing and there are no details on the regimen of the control group (Asher 1983). In the de Jong study, one participant in the intervention group withdrew after experiencing earache at a training intensity equating to 40% PImax (de Jong 2001). In the Sawyer study, two participants did not complete their pulmonary function tests: one was due to an oversight on the part of the researchers; and the other did not complete the test. There is no indication as to which group these participants are from (Sawyer 1993).
The remaining five studies were judged to have an unclear risk of bias (Albinni 2004; Amelina 2006; Chatham 1997; Enright 2004; Heward 2000). Two studies gave limited information on withdrawals; in the Amelina study, one participant in the intervention group did not complete the trial (Amelina 2006) and in the Chatham study, three participants in the control group did not complete the trial (Chatham 1997). Neither of these two studies offered any explanation for these withdrawals; however, as they are both abstracts published in conference proceedings and that there are likely to be editorial constraints responsible for this. Furthermore, both trials failed to provide statistical data on their control groups, merely stating that there was no change in their outcomes; therefore they have been graded as having an unclear risk of bias. The remaining three trials do not provide any information with regards to participant withdrawals (Albinni 2004; Enright 2004; Heward 2000).
Selective reporting
One study reported on all outcome measures selected, although some health‐related quality of life domains were unreported; nevertheless the study was deemed to have a low risk of selective reporting bias (Bieli 2017). One study reported that the investigators carried out post‐training measures of pulmonary function but do not report the results (Heward 2000). It is acknowledged that this study is only published as an abstract; however, there is a potential risk of bias due to the limited reporting of their outcomes. Likewise for the study by Amelina, two outcomes (respiratory muscle strength and dyspnoea) are reported to have been analysed, but no data are provided for them (Amelina 2006). There was insufficient information provided by the other publications to make a judgement on the risk of bias due to selective reporting from seven trials and have been judged to have an unclear risk of bias (Albinni 2004; Asher 1983; Chatham 1997; de Jong 2001; Enright 2004; Sawyer 1993; Zeren 2019 ).
Other potential sources of bias
All the included studies have been graded an unclear risk of bias as none provided sufficient information to arrive at a definitive conclusion.
Effects of interventions
Due to the lack of studies using comparable intensities of RMT or outcome measures, or both, we are unable to conduct meta‐analyses at this time; but all available data are presented in the Data and analyses section. All outcome measures were recorded at the end of the study period in each study.
In the summary of findings table, the quality of the evidence has been graded for pre‐defined outcomes (see above) and definitions of these gradings provided. The quality of evidence for the key parameters was graded as very low (summary of findings Table 1).
Primary outcomes
1. Pulmonary function
Eight of the 10 included studies reported some measure of pulmonary function; two included studies did not report on this outcome (Chatham 1997; Heward 2000). The quality of the evidence was assessed for FEV1 % predicted and FVC % predicted and judged to be very low (summary of findings Table 1).
a. FEV1
Eight studies reported FEV1 in either litres (L) (de Jong 2001; Enright 2004; Sawyer 1993), % predicted (Amelina 2006; Asher 1983; de Jong 2001; Zeren 2019) or using the z score (Bieli 2017); one study did not define the unit of measurement in the two published abstracts (Albinni 2004). We judged the quality of the evidence to be very low (summary of findings Table 1).
One study reported FEV1 (L) at six weeks (de Jong 2001) and two studies reported at eight weeks (Enright 2004; Sawyer 1993). There was no difference (P > 0.05) between groups in terms of FEV1 measured in L in any study irrespective of working at 80% (Enright 2004), 60% (Sawyer 1993), 40% (de Jong 2001) or 20% (Enright 2004) of maximal effort (Analysis 1.1; Analysis 2.1; Analysis 3.1; Analysis 5.1).
One study reported data for analysis for FEV1 % predicted at 40% of maximal capacity at six weeks (de Jong 2001) and one study reported post treatment data and change from baseline data for FEV1 % predicted at 30% of maximal capacity at eight weeks (Zeren 2019). Again no differences were found between treatment groups for any comparison (Analysis 3.2; Analysis 4.1; Analysis 4.2). A further study comparing 30% of maximal capacity to control reported on FEV1 % predicted, but only presented within‐group changes (Amelina 2006). One study did not specify the level of resistance, but stated there was no difference in FEV1 % predicted after eight weeks of training (Asher 1983).
One cross‐over study (unspecified level of resistance) reported the FEV1 z score and found no difference between the treatment groups (P = 0.436) (Bieli 2017).
One study did not specify the level of resistance or units of measurement and did not report any data, but stated that there was no change in FEV1 in either the RMT or the control group at 12 weeks (Albinni 2004).
b. FVC
Seven studies reported FVC in either L (de Jong 2001; Enright 2004), % predicted (Amelina 2006; de Jong 2001; Zeren 2019) or using the z score (Bieli 2017); one study did not define the unit of measurement in the two published abstracts (Albinni 2004). We judged the quality of the evidence to be very low (summary of findings Table 1).
Between‐group comparisons did not reveal a difference in FVC (L) irrespective of working at 80% at eight weeks (Enright 2004), 40% at six weeks (de Jong 2001) or 20% at eight weeks (Enright 2004) of maximal effort (P > 0.05) (Analysis 1.2; Analysis 3.2; Analysis 5.2).
This was also true for FVC % predicted as reported by two studies: one study reported data for analysis for FVC % predicted at 40% of maximal capacity at six weeks (de Jong 2001) and the second at 30% of maximal capacity at eight weeks (Zeren 2019). Again, no differences were found between treatment groups (Analysis 3.4; Analysis 4.3 ). Zeren also found no difference between treatments in the change from baseline in FVC % predicted at the same time point (Analysis 4.4). A further study comparing 30% of maximal capacity to control only reported within‐group improvement in FVC % predicted (Amelina 2006).
There was no difference in FVC z score between groups as reported by Bieli (P = 0.472) (Bieli 2017).
One study did not specify the level of resistance or units of measurement and did not report any data, but stated that there was no change in FVCin either the RMT or the control group at 12 weeks (Albinni 2004).
c. PEF
One study reported absolute post‐treatment values and change from baseline scores in PEF % predicted at eight weeks (Zeren 2019); there were no differences found between groups (Analysis 4.5; Analysis 4.6).
2. Exercise capacity
Seven studies reported some measure of exercise capacity (Albinni 2004; Amelina 2006; Asher 1983; Bieli 2017; de Jong 2001; Sawyer 1993; Zeren 2019). Details are given below for most studies, however, one study did not provide any units of measurement nor was there any explanation as to the method of assessment; but investigators did state that there was no improvement observed (Amelina 2006). The quality of the evidence was judged to be very low (summary of findings Table 1).
a. VO2max
Three studies reported VO2max as mL/kg/min‐1, but not in a form that we could analyse (Albinni 2004; Asher 1983; de Jong 2001). One study reported no difference at six weeks between groups when working at 40% of maximal effort (P = 0.99) (de Jong 2001). A further study reported no difference in the mean (SD) VO2max (mL/kg/min‐1) at 31.6 (5.0) mL/kg/min‐1 and 29.9 (6.4) mL/kg/min‐1 pre and post‐intervention at eight weeks (Asher 1983). A third study only reported within‐group improvements, with no data to allow inclusion in our analysis (Albinni 2004).
b. Exercise duration
Two studies reported this outcome (Bieli 2017; Sawyer 1993). The cross‐over study (unspecified level of resistance) did not provide data we could analyse, but reported no difference between groups in exercise duration measured using a constant workload cycling test, (P = 0.169) (Bieli 2017). In the second study, between‐group comparisons found a 10% improvement when working at 60% of maximal effort (P < 0.03) (Sawyer 1993).
C. Six‐minute walk test
One study reported this outcome at eight weeks (Zeren 2019). While the distance achieved improved from baseline in both groups during the study, there was no difference in between‐group comparisons of absolute distance walked or the change from baseline (Analysis 4.7; Analysis 4.8).
3. Health‐related quality of life
Three studies reported a measure of health‐related quality of life; two studies used the CRDQ (Chatham 1997; Enright 2004) and one study used the CFQ and the CFCS (Bieli 2017). The quality of the evidence was judged to be very low (summary of findings Table 1).
The CRDQ evaluates four domains considered important to individuals with chronic airflow obstruction; dyspnoea, mastery, fatigue and emotion (Chauvin 2008). Enright found no difference between groups in the two parameters of mastery and emotion when working at 80% of maximal effort (Analysis 1.3; Analysis 1.4); however, Chatham did find an improvement between groups in these parameters at the same level of effort (P < 0.01) (Chatham 1997). Using the CFQ, Bieli found no difference in health‐related quality of life between treatment groups (no specified level of resistance) (Bieli 2017).
Bieli also measured symptom severity using the CF clinical score (CFCS) which indicates overall symptom severity, but no difference was reported between groups at baseline or post‐intervention (Bieli 2017).
Secondary outcomes
1. Respiratory muscle function
Four studies reported PImax (Amelina 2006; Asher 1983; Sawyer 1993; Zeren 2019), but only two studies provided data for analysis (Sawyer 1993; Zeren 2019). The quality of the evidence was judged to be very low (summary of findings Table 1).
a. PImax
After data analysis, Sawyer reported a greater increase in favour of the treatment group (60% of maximal effort) at 10 weeks, MD 26.00 (95% CI 8.63 to 43.47) (Analysis 2.2). The second study compared 30% resistance to control at eight weeks (Zeren 2019); data again showed greater absolute values, MD 14.63 (95% CI 5.63 to 23.63) and a greater increase from baseline in favour of the treatment group, MD 24.26 (95% CI 19.31 to 30.07) (Analysis 4.9; Analysis 4.10). A third study compared 30% resistance to control, but only reported within‐group changes in PImax (Amelina 2006).
Asher (unspecified level of resistance) utilised two inspiratory measures (prevailing intramural pressure‐functional residual capacity (Pim‐FRC) and PImax) suggesting that one measurement technique was used but at two different lung volumes (Asher 1983). The study reported changes in both measures in the RMT group (P < 0.025 and P < 0.05 respectively). The investigators also reported that, for the Pim‐FRC measure, only three participants registered an increase that was more than two SDs from the control group; and for the PImax measure, two participants had an increase greater than two SDs from the control values.
b. IC
No studies reported this outcome.
c. PEmax
One study reported this outcome (Zeren 2019); there was no difference in absolute or change values at eight weeks (Analysis 4.11; Analysis 4.12).
2. Respiratory muscle strength and RME
Five studies reported RME (Albinni 2004; Amelina 2006; Bieli 2017; Chatham 1997; de Jong 2001), but only three studies reported between‐group comparisons (Albinni 2004; Bieli 2017; de Jong 2001).
One study presented values for mean (SD) and a P value which we were able to include in our analysis (de Jong 2001); results showed a difference in favour of the RMT group after six weeks, MD 12.00 (95% CI 0.55 to 23.45) (Analysis 3.5). The remaining two studies which did not specify the level of resistance, did not provide data we could analyse. Albinni reported an improvement in RME in the training group (P = 0.002) (Albinni 2004). Bieli also reported that RME was longer in the training group (P < 0.01) (Bieli 2017).
One study reported a within‐group improvement in the training group when working at 80% of maximal effort, but no data from the control group were reported (Chatham 1997). Likewise the final study reported a within‐group improvement in the training group when working at 30% of maximal effort, but no data from the control group were reported (Amelina 2006).
3. Frequency and duration of respiratory infections, hospitalisations
No studies reported this outcome.
4. Adherence to the IMT regimen
Zeren reported on adherence to the training programme based upon once weekly attendance at a supervised session and self‐reported diaries (Zeren 2019); adherence was high after eight weeks, but there was no difference between groups (Analysis 4.13).
5. Death or survival
No studies reported this outcome.
6. Adverse effects
One study reported that one participant out of 16 experienced earache whilst performing IMT at 40% of maximal effort (de Jong 2001).
7. Costs
No studies reported this outcome.
8. Oxygen saturation
One study reported resting oxygen saturations and change in oxygen saturations during test (Zeren 2019). Investigators found no differences between the groups observed in absolute post‐treatment values or in the change from baseline after eight weeks (Analysis 4.14; Analysis 4.15; Analysis 4.16; Analysis 4.17).
9. Postural stability
One study reported measurements of postural stability at eight weeks using the 'Postural Stability Test' for static postural stability and the 'Limits of Stability Test' for dynamic postural stability (Zeren 2019). No differences were reported between groups in the overall score or individual section scores for either absolute post‐treatment values or in the change from baseline for these assessments (Analysis 4.18; Analysis 4.19; Analysis 4.20; Analysis 4.21).
Discussion
Summary of main results
The main finding of this Cochrane Review is that there is insufficient evidence to conclude if RMT has a positive effect on health outcomes in people with CF. This finding is based upon the small number of included studies (n = 10) and the small sample sizes used across the studies (n = 11 to 39). Of the 10 included studies, only six (comprising 134 participants) were fully published studies, highlighting the need for further research (Asher 1983; Bieli 2017; de Jong 2001; Enright 2004; Sawyer 1993; Zeren 2019). Abstracts from conference proceedings limit the amount of detailed data that are presented and thus the data that can be extracted.
Pulmonary function is routinely measured in clinical practice to monitor chest disease severity, specifically FEV1 and FVC. No differences were reported between groups in pulmonary function, including both FEV1 and FVC (measures either as L or % predicted) at any time point and in any study. Only three of the studies included in the review reported that they assessed health‐related quality of life (Bieli 2017; Chatham 1997; Enright 2004). Although no statistically significant difference was reported in two of the studies (Bieli 2017; Enright 2004), one study reported a significantly greater improvement in the two parameters of mastery and emotion in the treatment group (P < 0.01) (Chatham 1997). Six of the 10 studies reported some measure of exercise capacity (Albinni 2004; Asher 1983; Bieli 2017; de Jong 2001; Sawyer 1993; Zeren 2019). Of these, only one study reported a significant improvement with a 10% increase in exercise duration (P < 0.03) when working at 60% of maximal effort (Sawyer 1993).
Descriptive analysis of considered studies suggests that PImax and RME time are the measures that can best detect the effects of a RMT intervention. Although it is acknowledged that this is not supported by a meta‐analysis of studies, they are the measures the included studies report as showing significant improvement within the RMT groups. Adverse events were consistently not reported by the studies, with only one making specific reference to this (de Jong 2001).
Overall completeness and applicability of evidence
Due to the life‐limiting nature of CF, the age of the participants recruited to studies in this population is of particular importance. Only half of the included studies stated the ages of participants (ranging from 6 to 25 years); five studies did not disclose details of participants' age except to state that four studies were in adults and one in children. With the current average life expectancy standing at around 49 years and the number of CF adults increasing (CFF 2019; UK CF Trust 2019), the participants in these studies may not be representative of the diverse CF population. Studies specifically targetting paediatric or older adult participants would be beneficial.
Due to the progressive nature of CF, the pulmonary function of the participants could limit the effectiveness of RMT in comparison to a healthy population. Some of the included studies lack details in the clinical status and pulmonary function of participants, and some limited recruitment to those with higher lung functions (e.g. over 70% predicted FEV1) so this may limit the applicability of the evidence. With the recent introduction of CFTR modulator therapies the presentation of the CF population is changing, often with more stability in clinical outcomes (Bell 2020), which may also affect the applicability of these results in the future.
There is an apparent under‐use of assessing dyspnoea and exercise capacity following RMT which may limit the external validity of the research base. In healthy individuals, both an individual’s perception of breathlessness and their maximal exercise capacity has found to improve following RMT (El‐Manshawi 1986; Romer 2002).
Quality of the evidence
Overall, the methodological quality of the included studies was inconsistent and none addressed all aspects completely. A systematic review requires homogeneity between the included studies to allow firm conclusions to be drawn. Despite finding 10 studies which met the inclusion criteria of this review, the variation in their methodologies and outcomes was such that no combined analyses could be made. These differences occurred in all the major aspects of the studies including the outcomes employed, the units of measurement for certain outcomes and the method and extent to which the clinical status of the participants was established or reported.
Following the GRADE assessments, we deemed the outcomes pulmonary function, exercise capacity, health‐related quality of life and postural stability and respiratory muscle function to have very low‐quality evidence (summary of findings Table 1). We downgraded the quality of the evidence due to the variations in resistance levels used across the studies, serious risks of bias (see below) and imprecision (small numbers of participants and numerical results not being available for some of the studies).
The execution of the included studies (randomisation and blinding) ranged from being fully acknowledged, considered and reported to either being merely stated as "randomised to the two groups" or not being mentioned. The external validity (with particular regard to the participant demographics) was explicit in only five of the studies (Bieli 2017; de Jong 2001; Enright 2004; Sawyer 1993; Zeren 2019). This aspect is of particular significance given that people who have CF are the target population. The nature of the disease means that two people of similar age, height and weight may have been affected by the condition differently and therefore may not "match" with regards to clinical status.
Although all studies state that they randomised their participants to the treatment groups, only two studies indicated the method of allocation, one by stating that they employed the minimisation method (de Jong 2001), the other reporting utilisation of pre‐filled envelopes specifying group allocations generated by a computer‐based programme (Zeren 2019). These studies were graded as having a low risk of bias, whereas the remaining eight studies were graded as having an unclear risk of bias.
All the included studies were graded as having a high risk of performance bias, however studies are encouraged to specify more detail with regards to the training group. Although it may be difficult to blind the participants to which treatment arm they are randomised to, five studies made use of "sham" training for the control (Amelina 2006; Chatham 1997; de Jong 2001; Enright 2004; Sawyer 1993). One study reported a blinded outcome assessor for all measurements (Zeren 2019); two studies blinded the outcome assessors at the final data collection session (Enright 2004; Sawyer 1993), whereas the majority of studies make no overt reference to any blinding. Out of the ten studies, none reported on all outcome measures thus suggesting a potential risk of bias. Two studies report withdrawals, but offer no explanation for these (Amelina 2006; Chatham 1997). Overall, all of the included studies have been graded an unclear risk of bias as none provided sufficient information to arrive at a definitive conclusion.
Potential biases in the review process
We are not aware of any potential biases in the review process.
Agreements and disagreements with other studies or reviews
Overall, the current systematic review supports previous versions of this review and continues to highlight the need for more research in this area, specifically studies of high methodological quality.
Comparison 1: RMT (80% of maximal effort) versus control, Outcome 1: FEV1 (L)
Comparison 1: RMT (80% of maximal effort) versus control, Outcome 2: FVC (L)
Comparison 1: RMT (80% of maximal effort) versus control, Outcome 3: Chronic Respiratory Disease Questionnaire (mastery)
Comparison 1: RMT (80% of maximal effort) versus control, Outcome 4: Chronic Respiratory Disease Questionnaire (emotion)
Comparison 2: RMT (60% of maximal effort) versus control, Outcome 1: FEV1 (L)
Comparison 2: RMT (60% of maximal effort) versus control, Outcome 2: PImax (cm H₂O)
Comparison 3: RMT (40% of maximal effort) versus control, Outcome 1: FEV1 (L)
Comparison 3: RMT (40% of maximal effort) versus control, Outcome 2: FEV1 (% predicted)
Comparison 3: RMT (40% of maximal effort) versus control, Outcome 3: FVC (L)
Comparison 3: RMT (40% of maximal effort) versus control, Outcome 4: FVC (% predicted)
Comparison 3: RMT (40% of maximal effort) versus control, Outcome 5: Inspiratory muscle endurance (% PImax)
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 1: FEV1 (% predicted) absolute
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 2: FEV1 (% predicted) change from baseline
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 3: FVC (%) absolute
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 4: FVC (%) change from baseline
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 5: Peak expiratory flow (%) absolute
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 6: Peak expiratory flow (%) change from baseline
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 7: Six‐minute walk test absolute
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 8: Six‐minute walk test change from baseline
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 9: Maximal inspiratory pressure (PImax) absolute
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 10: Maximal inspiratory pressure (PImax) change from baseline
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 11: Maximal expiratory pressure (PEmax) absolute
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 12: Maximal expiratory pressure (PEmax) change from baseline
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 13: Adherence
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 14: Resting oxygen saturations absolute
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 15: Resting oxygen saturations change from baseline
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 16: Oxygen saturation change during test (absolute)
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 17: Oxygen saturation change during test (change from baseline)
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 18: Postural stability test absolute values after treatment (8 weeks)
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 19: Postural stability test change from baseline (8 weeks)
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 20: Limits of stability test absolute values after treatment (8 weeks)
Comparison 4: RMT (30% of maximal effort) versus control, Outcome 21: Limits of stability test change from baseline (8 weeks)
Comparison 5: RMT (20% of maximal effort) versus control, Outcome 1: FEV1 (L)
Comparison 5: RMT (20% of maximal effort) versus control, Outcome 2: FVC (L)
| Respiratory muscle training compared with control for cystic fibrosis | ||||||
| Patient or population: adults and children with cystic fibrosis Settings: outpatients Intervention: respiratory muscle traininga Comparison: controla | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Control | Respiratory muscle training | |||||
| FEV1 % predicted Follow‐up: 1 ‐ 3 months | No study reported any differences between the respiratory muscle training group and the control group. | NA | 83 (4) | ⊕⊝⊝⊝ | 1 study reported data for FEV1 % predicted at 40% of maximal capacity (de Jong 2001). 2 studies reported FEV1 % predicted at 30% of maximal capacity (Amelina 2006; Zeren 2019). 1 study reported FEV1 % predicted, but did not specify the resistance used (Asher 1983). 3 studies reported FEV1 measured in L and 1 measured z score; 1 study did not report the units of measurement. Results were similar to those for FEV1 % predicted. | |
| FVC: % predicted Follow‐up: 1 ‐ 3 months | No study reported any differences between the respiratory muscle training group and the control group. | NA | 72 (3) | ⊕⊝⊝⊝ | 1 study reported data for analysis for FVC (% predicted) at 40% of maximal capacity (de Jong 2001) and two studies at 30% of maximal capacity (Amelina 2006; Zeren 2019). 2 studies reported FVC in L and 1 measured z score; 1 study did not report the units of measurement. Results were similar to those for FVC % predicted. | |
| Exercise capacity: VO2max (mL/kg/min) Follow‐up: 1 ‐ 3 months | No study reported any differences between the respiratory muscle training group and the control group. | NA | 54 (3 studies including 1 cross‐over study) | ⊕⊝⊝⊝ | One study with an unspecified level of resistance reported an improvement within the respiratory muscle training group. | |
| HRQoL: total score Follow‐up: 1 ‐ 3 months | 2 studies reported no differences between the respiratory muscle training group and the control group. 1 study reported improvements in the parameters of mastery and emotion in the respiratory muscle training group compared to the control group. | NA | 69 (3 studies including 1 cross‐over study) | ⊕⊝⊝⊝ | 2 studies used the Chronic Respiratory Disease Questionnaire (CRDQ) and 1 study used the cystic fibrosis questionnaire (CFQ). | |
| Respiratory muscle function: maximal inspiratory pressure (PImax) Follow‐up: 1 ‐ 3 months | There was a greater improvement in the respiratory muscle training groups in 2 of the 4 studies measuring this outcome: MD 26.00 (95% CI 8.63 to 43.47) (Sawyer 1993); and MD 14.63 (95% CI 5.63 to 23.63) (Zeren 2019). The remaining 2 studies reported no differences between the respiratory muscle training group and the control group (Amelina 2006; Asher 1983). | NA | 87 (4 studies including 1 cross‐over study) | ⊕⊝⊝⊝ | Of the studies reporting a difference, the Sawyer study measured at 60% of maximal effort (Sawyer 1993) and the Zeren study measured at 30% resistance (Zeren 2019). 1 of the remaining studies reported at 30% of maximal effort (Amelina 2006) and 1 did not specify the level of resistance (Asher 1983). | |
| Respiratory muscle function: inspiratory capacity Follow‐up: 1 ‐ 3 months | No studies reported this outcome. | NA | ||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a. The resistance level of the respiratory muscle training intervention was variable; three studies used 80% of maximal effort, one study used 60% of maximal effort, one study used 40% of maximal effort, one study used 30% of maximal effort and three studies did not specify the level of resistance. Control groups were also variable; cycle ergometer, H20, treatment as usual, standard chest physiotherapy, low resistance threshold loading device, no training or sham training. b. Downgraded twice due to serious risk of bias: the included studies lacked methodological detail relating to methods of randomisation, allocation concealment and blinding. Most of the studies were at high risk of bias due to lack of blinding, incomplete outcome data or selective reporting, or both. c. Downgraded due to imprecision: studies included a small number of participants and numerical results were not available for some of the studies. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 FEV1 (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.2 FVC (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.2.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.3 Chronic Respiratory Disease Questionnaire (mastery) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.3.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.4 Chronic Respiratory Disease Questionnaire (emotion) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.4.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 FEV1 (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.2 PImax (cm H₂O) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.2.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 FEV1 (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.2 FEV1 (% predicted) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.2.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.3 FVC (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.3.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.4 FVC (% predicted) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.4.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.5 Inspiratory muscle endurance (% PImax) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.5.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 FEV1 (% predicted) absolute Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.2 FEV1 (% predicted) change from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.2.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.3 FVC (%) absolute Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.3.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.4 FVC (%) change from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.4.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.5 Peak expiratory flow (%) absolute Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.5.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.6 Peak expiratory flow (%) change from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.6.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.7 Six‐minute walk test absolute Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.7.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.8 Six‐minute walk test change from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.8.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.9 Maximal inspiratory pressure (PImax) absolute Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.9.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.10 Maximal inspiratory pressure (PImax) change from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.10.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.11 Maximal expiratory pressure (PEmax) absolute Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.11.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.12 Maximal expiratory pressure (PEmax) change from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.12.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.13 Adherence Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.13.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.14 Resting oxygen saturations absolute Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.14.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.15 Resting oxygen saturations change from baseline Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.15.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.16 Oxygen saturation change during test (absolute) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.16.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.17 Oxygen saturation change during test (change from baseline) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.17.1 Two to six months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.18 Postural stability test absolute values after treatment (8 weeks) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.18.1 Overall score | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.18.2 Anterior/posterior SI | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.18.3 Medial/lateral SI | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.19 Postural stability test change from baseline (8 weeks) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.19.1 Overall score | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.19.2 Anterior/posterior SI | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.19.3 Medial/lateral SI | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.20 Limits of stability test absolute values after treatment (8 weeks) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.20.1 Overall score | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.20.2 Forward DS | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.20.3 Backward DS | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.20.4 Left DS | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.20.5 Right DS | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.21 Limits of stability test change from baseline (8 weeks) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.21.1 Overall score | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.21.2 Forward DS | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.21.3 Backward DS | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.21.4 Left DS | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.21.5 Right DS | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 FEV1 (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.1.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.2 FVC (L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 5.2.1 One to three months | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
