Inspiratory muscle training in people with chronic obstructive pulmonary disease (COPD): a systematic review

ABSTRACT This systematic review aimed to demonstrate the effectiveness of inspiratory muscle training (IMT) in people with chronic obstructive pulmonary disease (COPD), analyzing the effects of IMT on inspiratory muscle strength and endurance, exercise tolerance and reduction of dyspnea. A systematic search was carried out in the PubMed, Cochrane and Lilacs databases, from August 2021 to February 2023, searching for studies published from 2016. The descriptors used for the search followed the description of the MeSH/DeCS terms, namely: “Pulmonary Disease, Chronic Obstructive,” “Breathing Exercises,” “Exercise Tolerance,” “Dyspnea,” and “Muscle strength,” with the languages: English and Portuguese, using the Boolean operators “AND” and “OR.” Ten studies met the inclusion criteria, including 733 patients. In all examined studies, there was a significant increase in inspiratory muscle strength and endurance compared to the control group; of the ten studies analyzed, four showed advances in reducing dyspnea and exercise tolerance. Notably, inspiratory muscle training is effective in improving dyspnea, exercise tolerance, and in increasing inspiratory muscle strength and endurance in people with moderate to severe COPD.


INTRODUCTION
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 , chronic obstructive pulmonary disease (COPD) is common, preventable, and treatable, and is characterized by persistent respiratory symptoms and airflow limitation due to alveolar and/or airway changes, usually caused by significant exposure to harmful particles or gases.Smoking is by far the main risk factor for this disease, accounting for 40% to 70% of cases 2 .Among the typical clinical symptoms are chronic and progressive dyspnea, as well as cough and sputum production, all of which are factors that impact the health and functionality of these individuals, who may develop limitations such as: reduced exercise performance, functional losses in the lower limbs, and decreased musculoskeletal strength 3 .
The prevalence of the disease has increased worldwide, and it is now considered the third leading cause of death 4 .In Brazil, according to data from the Department of Health Surveillance (Secretaria de Vigilância em Saúde -SVS), which follow the methodology of the Global Burden of Disease (GBD), COPD is the fifth leading cause of death among all ages 5 .In recent decades, it was the fifth largest cause for hospitalization in the Brazilian Unified Health System (SUS) among patients aged over 40 years, corresponding to about 200,000 hospitalizations, with an annual expenditure of approximately 72 million reais 6 .In the more advanced stages, COPD significantly impairs patients' quality of life, due to the most frequent and severe exacerbations, as well as functional disability associated with chronic respiratory failure, in addition to fatigue and exercise intolerance.Still, those affected in advanced stages may present weight loss, muscle mass reduction, and even cachexia, all attributed to the systemic inflammatory status.
Inspiratory muscle training (IMT), which has already been widely for treating COPD, is defined as persistent respiratory training that uses an inspiratory training device.According to the statement by the American Thoracic Society and the European Respiratory Society 7 , this therapeutic resource can intensify inspiratory muscle function (strength and endurance); alleviate the sensation of dyspnea, recovering well-being; improve exercise performance; and increase total lung capacity.
IMT promotes pulmonary air outflow, increasing maximal inspiratory pressure (MIP) and, consequently, increasing inspiratory muscle strength and endurance 7 .
However, despite its importance for the pulmonary rehabilitation of this public, in the last seven years, few studies were produced proving the effectiveness of the training in people with this pathology.Therefore, this aimed to evaluate clinical studies that indicated the effectiveness of IMT applied in the short, medium, and long term in people with COPD, analyzing the potential benefits of training for inspiratory muscle strength and endurance, reduction of dyspnea, and exercise tolerance.

Research strategy
This systematic review was developed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 8 .To increase the quality of the work with a rigorous design methodology, the search was carried out by consulting several online databases.
In the National Library of Medicine (PubMed), the filters used were "clinical trials"; "controlled and random testing"; "last seven years of publication"; and "adult population."In the Cochrane Library, the study models with intervention therapies and the filters "last seven years of publication" and "studies published in English and Portuguese languages" were prioritized.In the database Latin American and Caribbean Health Sciences Literature (LILACS), the selected filters were "main subject chronic obstructive pulmonary disease"; "controlled clinical trials"; "English and Portuguese languages"; and "last seven years of publication." The search comprised the period from August 2021 to February 2023, and the descriptors used followed the description of the Medical Subject Headings (MeSH)/ Health Sciences Descriptors (DeCS), which were: "pulmonary disease, chronic obstructive"; "breathing exercises"; "exercise tolerance"; "dyspnea"; and "muscle strength," with the Boolean operators "AND/E" and "OR/OU."

Inclusion and exclusion criteria
This review included randomized clinical trials that had as their object of observation individuals aged over 18 years, diagnosed with moderated to severe COPD, and in which IMT was employed as one of their interventions.
Similarly, studies focused on individuals with other chronic respiratory diseases and who were in another type of rehabilitation program were excluded.Studies with titles and abstracts that did not contemplate the subject of this study were also disregarded, as well as incomplete studies.

Data extraction
In the formulation of the guiding question, the strategy used was the Population, Intervention, Comparison, and Outcome (PICO); in the delimitation of the population, people with COPD were considered; IMR was selected as the applied intervention; the included studies had a control group and an intervention group; and the main outcomes analyzed were inspiratory muscle strength and endurance, exercise tolerance, and reduction of dyspnea.The data collection procedures occurred in four stages, namely: identification, selection, eligibility, and inclusion.
The entire review process of the articles identified with the search strategy was carried out independently by two researchers, by first reading titles and abstracts to evaluate the status of the articles.When there was a divergence of opinion among the researchers, the opinion of a third researcher was requested.

RESULTS
In the identification stage of this research, 558 studies were found in PubMed, 107 in Cochrane, and 12 in LILACS, totaling 677 articles.After applying the inclusion and exclusion criteria, 52 articles were encompassed by the analysis, with the subsequent exclusion of 21 duplicate articles.Then, during the full reading of the remaining 31 articles, 10 were selected, composing this study universe of analysis.The flowchart (Figure 1) shows the screening process.5 diverged from the theme of the review; 5 were not randomized; 6 did not use IMT as one of the study interventions; 5 had a population that had other chronic respiratory diseases.

Figure 1. Article selection flowchart
Thus, 10 studies, from the total of 733 patients, met the inclusion criteria and were selected for review.After analyzing the articles and choosing them according to the proposed methodology, we applied the data extraction form to collect the main information of each study-authorship, year of publication, type of study, sample of the population surveyed, study groups, intervention, and results.All this information was gathered and is organized in Chart 1.All articles included older people, with the lowest age observed being 59 years and the highest 70 years.Only two studies did not adjust the analysis by sex 15,16 , and one study analyzed only males 13 .The main variables that this review chose to observe in the studies were increased inspiratory muscle strength and endurance, as well as decreased dyspnea and/or improved exercise tolerance.
Some of the studies used the 6-minute walk test (6MWT), as well as the cycling test on cycle ergometer.From this, the information on the variables were gathered, as summarized in Chart 1.

Methodological qualification
The quality of the chosen articles was measured by the Cochrane risk-of-bias tool for randomized trials (RoB 2) 19 , which contains five domains for assessing methodological quality and the risk of bias due to: randomization processes; deviations from the intended interventions; lack of information; data measurement; and selection of reported results.The five items in RoB 2 are classified into "low risk of bias," "uncertain risk of bias," and "high risk of bias."This tool was applied by two independent evaluators and, in case of divergence of opinions, they sought a consensus; when the difficulty persisted, a third evaluator interfered, deciding the classification of the risk of bias (Chart 2).
In addition to the methodological evaluation for the analysis of the risk of bias, we also used the PEDro 20 scale (Chart 3), whose objective is to help researchers quickly identify whether the selected articles followed the appropriate methodological rigor for a clinical trial.
Eligibility criteria have been specified The subjects were randomly distributed into groups (in a crossover study, the subjects were randomly placed in groups according to the treatment received) Initially, the groups were similar concerning the most important prognostic indicators All subjects were blinded in the study 0 1 All the therapists who administered the therapy did so blindly 0 0 0 1 1 1 0 0 0 0 All evaluators who measured at least one key outcome did so blindly Measurements of at least one key outcome were obtained in more than 85% of the subjects initially distributed in the groups All subjects from whom outcome measurements were presented received the treatment or control condition according to allocation or, when this was not the case, data analysis of at least one of the key outcomes was performed by "intention to treat" The results of the intergroup statistical comparisons have been described for at least one key result The study presents both precision measures and measures of variability for at least one key outcome Total score for PEDro scale 9 8 10 11 10 10 7 6 8 8 0 indicates that the study did not contemplate the criterion, and 1 indicates that the study contemplated it.
The common intolerance to physical exercise presented by the population affected by COPD is caused by a ventilatory disorder, a dysfunction of the peripheral muscles; consequently, these people experience physical exercise restriction, reduced activities of daily living (ADLs), airflow limitation, pulmonary hyperinflation, and inspiratory muscle weakness 21 .
In patients with COPD, the metaboreflex of the inspiratory muscles is increased, and one of the IMT responses is to assist its reduction.According to Richardson et al. 22 , patients with COPD present a decrease in type I fibers, which are rich in mitochondria; thus, there is a loss of oxidative capacity of the musculoskeletal system of these individuals.
During IMT exercises, there is a decrease in metaboreflex in patients with COPD.Among the mechanisms that may contribute to this alteration in muscle metabolic activity, one can include the decrease in the supply of oxygen to the musculature or the lower efficiency of the muscular oxidative metabolism.
Gosselink et al. 23 conducted a meta-analysis of 32 randomized clinical trials on the effects of IMT in patients with COPD, demonstrating that increasing patients' MIP to 13cmH 2 O after training was associated with clinical improvement.Similarly, in the study by Chuang et al. 10 , a randomized clinical trial with 55 participants, aged 66 years or older, of both men and women, showed that after eight weeks of IMT there was an improvement of approximately 18cmH 2 O in the MIP of the individuals.The MIP is an index of inspiratory muscle strength, being the highest pressure that can be generated during an inspiration with airway occlusion, measured with a respiratory pressure meter.
Similarly, the randomized clinical trial by Arnedillo et al. 16 with 16 participants, aged 65 years or older, without defining the gender of the participants, showed an increase in inspiratory muscle strength after eight weeks of training.However, the group that did not receive the intervention did not present any alteration in this variable, which allows us to infer that the IMT actually increases the strength of the inspiratory muscles, with consequent clinical improvement.
Several studies have shown that the population studied has impaired respiratory muscle strength [24][25][26][27] .Therefore, the improvement in exercise tolerance may be a result of increased inspiratory muscle strength, which was evidenced by Ramirez-Sarmiento et al. 28 in a randomized clinical trial that performed IMT for 30 minutes per day, five times per week, over five weeks of intervention, attesting that IMT induces functional improvement and adaptive changes in inspiratory muscle structures.Dekhuijzen et al. 29 , also in a randomized clinical trial, showed that a rehabilitation program that uses IMT increases the strength of the inspiratory muscles in patients with COPD, in agreement with what Charususin et al. 12 concluded in a randomized clinical trial with 219 patients, both men and women, aged 65 years or older.
From a mechanistic perspective, according to Mehani 13 , IMT improves the capacity of the inspiratory muscles, significantly increasing the size of type II muscle fibers.Furthermore, IMT can increase the shortening speed of these muscles, allowing more time for expiration and reducing pulmonary hyperinflation.
This review showed that 6 of the 10 included studies [10][11][12][13]15,16 , reported that IMT improves exercise tolerance, and the same proportion [10][11][12]14,15,17 attested that the treatment reduced dyspnea in patients with COPD. Th result is similar to the previous study by Bavarsad et al. 30 , in which they proved that short-term IMT has beneficial effects on exercise tolerance and on the reduction of dyspnea, especially in patients with COPD.However, these findings defy the studies by Cutrim et al. 9 , Beaumont et al. 14 and Xu et al. 17 since they found no evidence that IMT brings improvements in exercise tolerance.
Dyspnea is due to alveolar dysfunctions that cause increased subjective feelings of tiredness, shortness of breath, and difficulty breathing in patients with COPD when performing any physical activity [31][32][33] .In this scenario, IMT proved to be a mitigating intervention in six of the included studies [10][11][12]14,15,17 . On the cntrary, the study by Cutrim et al. 9 did not observe progress resulting from IMT in dyspnea, but these findings were possibly affected by the sample size, since the studies that demonstrated the benefit of IMT included robust samples 10,14,15,17 .
Despite the important findings of this review regarding the advantages of IMT for inspiratory muscle strength, reduction of dyspnea, and exercise tolerance in patients with COPD, it is necessary to highlight some limitations, such as the heterogeneity of the IMT program applied, their duration ranged from 4 to 36 weeks and from 5 to 60 minutes per session, and their intensity from 15% to 60% of MIP.Another limitation is the size of the study samples, with some with a very small number of participants.Still, the data from this review cannot be extrapolated to all degrees of COPD since the studies focused on patients with moderate to severe classification.Finally, the temporal choice of articles published in the last seven years can also be considered a limitation.

CONCLUSION
This systematic review suggests that inspiratory muscle training is effective in improving dyspnea, exercise tolerance, and inspiratory muscle strength and endurance in patients with COPD in moderate to severe stages.One of the limitations presented in the clinical trials included in the review was the heterogeneity of IMT interventions; the studies did not follow a standard protocol, and many of them did not clearly specify the modalities of IMT programs applied to patients.
We observed that even the studies that adopted IMT of low frequency and intensity obtained positive results, even in a short period of time.Further clinical studies on IMT and its relationship with COPD are needed.
selected and read in full to assess their eligibility (n=31) Articles considered eligible for systematic review (n=10) Articles excluded after full reading (n=21): Chart 2. Cochrane risk-of-bias tool for randomized trials quality scale