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Efficacy of respiratory support therapies during pulmonary rehabilitation exercise training in chronic obstructive pulmonary disease patients: a systematic review and network meta-analysis

BMC Medicine volume 22, Article number: 389 (2024) Cite this article

Abstract

Background

Exercise training is fundamental in pulmonary rehabilitation (PR), but patients with chronic obstructive pulmonary disease (COPD) often struggle with exercise intolerance. Respiratory support during exercise in COPD patients may be a beneficial adjunct therapy. In this study, the effect of different respiratory support therapy during pulmonary rehabilitation exercise training in COPD patients was assessed through a network meta-analysis.

Methods

Five databases were searched to obtain randomized controlled trials involving different respiratory support therapies during PR exercise training in COPD patients. The Cochrane Handbook tool was employed to assess the risk bias of included studies. Network meta-analysis was performed using the STATA software. The study protocol was registered at PROSPERO (CRD42023491139).

Results

A total of 35 studies involving 1321 patients and 6 different interventions were included. Network meta-analysis showed that noninvasive positive pressure ventilation (NPPV) is superior in improving exercise capacity (6-Minute Walk Test distance, peak work rate, endurance time), dyspnea, and physiological change (peak VO2, tidal volume, minute ventilation and lactate level) in stable COPD patients who were at GOLD stage III or IV during PR exercise training. The final surface under the cumulative ranking curve value indicated that NPPV therapy achieved the best assistive rehabilitation effect.

Conclusions

The obtained results indicate that NPPV is most powerful in assisting exercise in severe COPD patients under stable condition. Researchers should focus more on the safety, feasibility, and personalization of interventions. Furthermore, there is a need for additional high-quality trials to assess the consistency of evidence across various respiratory support approaches.

Trial registration

The study was registered at PROSPERO (CRD42023491139).

Peer Review reports

Background

Chronic obstructive pulmonary disease (COPD) ranks as the fourth leading cause of death globally, posing significant challenges in terms of health, economy, and healthcare [1]. The World Health Organization has projected that COPD will rise to become the third leading cause of death by 2030 [1]. Despite optimal medication in stable conditions, individuals with severe COPD often struggle with dyspnea and fatigue, particularly during physical exertion [2]. Pulmonary rehabilitation (PR) is a comprehensive program involving multidisciplinary care, individualized treatment plans, exercise training, education, and behavior modification, aimed at enhancing the physical and mental well-being of patients with chronic respiratory conditions and fostering long-term healthy habits [3]. Guidelines advocate for PR as a crucial self-management tool for COPD patients, leading to improvements in exercise capacity, quality of life, symptom management, and reduced hospital admissions following exacerbations [4].

Exercise training is a crucial component of pulmonary rehabilitation and is strongly supported by high-level evidence as an effective intervention for COPD management [3, 4]. There is no consensus on the optimal exercise prescription in clinical practice, but the guidelines recommend developing personalized exercise prescriptions based on comprehensive patient evaluation, including exercise types, frequency, intensity, duration, exercise goals, and precautions [4]. The types of exercise are recommended for COPD patients include endurance training, resistance training, flexibility training, respiratory muscle training, and a combination of multiple methods. The exercise intensity could range from low intensity (30% to 40% maximum power) to high intensity (60% to 80% maximum power), with a frequency of 3–5 times per week of exercise training, each lasting 20–60 min and at least 8–12 weeks [4, 5]. However, some individuals may struggle to exercise at the required intensity and duration, leading to limited benefits, especially if they have significant ventilation restrictions and relatively preserved muscle strength [6]. Dynamic pulmonary hyperinflation is a commonly seen pathological change in COPD patients during exercise. Dynamic pulmonary hyperinflation and expiratory airflow obstruction limits the normal increase in tidal volume, leading to worsened breathlessness and reduced exercise capacity [7,8,9]. Moreover, dynamic pulmonary hyperinflation and the concomitant high mean intrathoracic pressure swings would adversely affect central hemodynamic regulation. Consequently, the oxygen supply through blood to peripheral limbs is further reduced, making the limbs discomfort and decreased exercise tolerance [10]. Respiratory support strategies are recommended to alleviate the exercise-induced breathless and limns discomfort and also to enhance the effectiveness of pulmonary rehabilitation. These respiratory support strategies included conventional oxygen therapy (COT, oxygen administered through nasal cannulas or a face mask) during exercise training, high-flow nasal cannula (HFNC), noninvasive positive pressure ventilation (NPPV), nocturnal-noninvasive positive pressure ventilation (N-NPPV, which means conducting exercise training during the daytime and NPPV at night), and heliox (a mixture of helium and oxygen gas) [11,12,13,14]. Each type of respiratory support therapy has varying effects on pulmonary rehabilitation.

While previous systematic reviews and meta-analyses have [15,16,17,18] focused on the effects of respiratory support therapies on enhancing exercise capacity, quality of life, and symptoms, traditional pairwise meta-analyses are limited in comparing only two treatments at a time. Therefore, this study utilized network meta-analysis (NMA) to provide a comprehensive analysis of the relative efficacy of different respiratory support methods for COPD during pulmonary rehabilitation exercise training. By evaluating multiple interventions, this approach offers high-quality evidence for ranking optimal intervention strategies, assisting healthcare professionals in making informed treatment decisions [19, 20]. The study systematically reviewed the efficacy and safety of various respiratory support methods in COPD patients undergoing pulmonary rehabilitation exercise training through randomized controlled trials. The findings aim to identify the most effective respiratory support methods, offering detailed evidence-based information to guide future clinical practice and improve the nursing care of COPD patients, while also serving as a reference for future research.

Methods

Search strategy

The network meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension statement for reporting of systematic reviews incorporating network meta-analyses [21]. The PRISMA checklist is seen in Additional file 1: PRISMA 2020 checklist. The protocol was registered with the International Prospective Register of Systematic Reviews in December 2023 (registration number CRD42023491139). Databases including PubMed, Cochrane Library, EMBASE, CINAHL, and Web of Science were used to search articles from the database’s inception through December 2023. References in the identified articles and relevant published reports were manually surveyed to identify studies eligible for inclusion in our review. The main search strategies were as follows: (COPD OR ‘chronic obstructive pulmonary disease’ OR ‘Chronic Obstructive Airway Disease’ OR ‘Chronic Airflow Obstruction’ AND (‘Respiratory Support’ OR ‘Oxygen Therapy’ OR NPPV OR ‘Non Positive Pressure Ventilation’ OR HFNC OR ‘high-flow nasal cannula’ OR ‘nasal cannula’ OR ‘venturi mask’) AND (PR OR ‘pulmonary rehabilitation’ OR ‘exercise training’) AND (random* OR randomized controlled trial OR RCT). See Additional file 2: Table S1 for a more detailed presentation of the search strategy.

Inclusion and exclusion criteria

The inclusion criteria for studies were as follows: (1) randomized controlled trials assessing the effectiveness of various respiratory support therapies during pulmonary rehabilitation exercise training; (2) participants diagnosed with COPD according to the Global Initiative for Chronic Obstructive Lung Disease guidelines (GOLD); (3) the intervention group received respiratory support therapy (including nasal cannula, face mask, non-invasive ventilation, nasal high-flow therapy, etc.) during supervised pulmonary rehabilitation exercise sessions, while the control group breathed air without respiratory support therapy; pairwise comparisons between interventions were also conducted; (4) outcomes comprised exercise capacity (defined as peak exercise capacity, constant work rate (endurance) exercise capacity or functional exercise capacity (6-Minute Walk Distance) measured pre and post exercise training, without respiratory support therapy), health-related quality of life (HRQL, measured using disease-specific or generic HRQL instruments, e.g., COPD Assessment Test score (CAT score), Chronic Respiratory Disease Questionnaire (CRQ), and St. George’s Respiratory Questionnaire (SGRQ), etc.), physiological changes related to exercise training (e.g., peak oxygen uptake (peak VO2), blood lactate levels, minute ventilation), and dyspnea (e.g., Borg score, visual analogue scale score). The analysis of this study is based on the changes relative to the baseline values.

The exclusion criteria for studies were as follows: (1) participants with non-COPD respiratory disease or participants with concomitant neuromuscular disease, a restrictive thoracic disorder, significant cardiac failure, or cardiac disease, if data from participants with COPD could not be analyzed separately. (2) Only abstracts were available without full texts, and efficacy was not reported. (3) Studies with incomplete data, such as protocols, were also excluded.

Literature selection and data extraction

The search was carried out by the first author and recorded in a Microsoft Excel file. Duplicate entries were subsequently removed. Each title and abstract were manually reviewed by two independent reviewers (X. Chen and L. Xu). If necessary, a third reviewer (Y. Wu) was consulted for resolution. All full texts that met the inclusion criteria were included in the analysis.

A pre-set standardized form was used by two reviewers (X. Chen and L. Xu) who independently extracted the main information. Disagreements were resolved by discussion with a third reviewer. The main data were as follows: (1) basic information, including first author, country, and year of publication; (2) characteristics of participants, including sample size, age, gender, and pulmonary rehabilitation exercise training program; (3) intervention details, including the name of treatment, treatment parameters, treatment duration, process, and follow-up period; (4) information on outcome indicators, including exercise capacity, health-related quality of life, physiological changes related to exercise training, dyspnea, and dropout rate.

Risk of bias

The two researchers independently assessed the methodological quality of included studies using the Cochrane Collaboration Risk of Bias Tool, which covers six domains: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other bias. According to the Cochrane Handbook version 6.1.0, we graded methodological quality as low risk, high risk, or unclear risk of bias [22]. We used Review Manager 5.3 to present the result of methodological quality. Additionally, Grading of Recommendations Assessment Development and Evaluation (GRADE) framework was used to assess the certainty of evidence contributing to network estimates of the main outcomes [23]. Five downgrade factors (i.e., the risk of bias, inconsistency, imprecision, indirectness, and publication bias) were considered to rate the level of evidence. Each factor was judged as “not serious” (not degraded), “serious” (degraded by one level), or “very serious” (degraded by two levels); finally, a high, moderate, low, or very low level of evidence quality was identified [24]. For the outcomes with less than ten included studies, the test for funnel plot asymmetry was skipped according to the recommendations [25].

Data analysis

The network meta-analysis was conducted using the Stata 17.0 software, specifically utilizing the network package and network graphs package [26]. A network diagram was created with nodes and lines to visually represent different interventions, with node size indicating the number of populations and line thickness representing the number of studies. For dichotomous variables, the effect size was estimated using odds ratios (OR) with 95% confidence intervals (CI), while for continuous variables, standardized mean differences (SMD) with 95% CI were used. The analysis of this study is based on the changes relative to the baseline values. The results of the analysis included all possible pairwise comparisons, incorporating mixed comparisons that combined direct and indirect comparisons. Local inconsistency between direct and indirect comparisons was assessed using the node-splitting test, with inconsistency indicated by a P-value < 0.05 [27]. In cases of observed inconsistency, non-transitivity and potential modifiers affecting treatment effects were investigated. The efficacy of different respiratory support therapies was estimated based on the surface under the cumulative ranking curve (SUCRA). The SUCRA value ranges from 0 to 100%, where a SUCRA value of 100% indicates that the treatment was the most effective, and the smaller the value, the poorer the treatment effect.

Results

Literature screening process and results

As illustrated in Fig. 1, the initial electronic search yielded 2331 potentially relevant publications. After eliminating 885 duplicates, 1466 records underwent screening based on title and abstract, resulting in the exclusion of 1407 records. Out of the remaining 59 studies eligible for full-text review, 24 studies were excluded based on predetermined inclusion and exclusion criteria. Ultimately, 35 randomized controlled trials were included in the analysis [11,12,13,14, 28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58].

Fig. 1
figure 1

PRISMA flow diagram

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Description of included studies

As shown in Additional file 2:Table S2, these studies were published in English between 1997 and 2023, and include 1321 COPD patients from 19 countries. Among them, 32 randomized controlled trials used a parallel design [11,12,13,14, 28,29,30,31, 34,35,36,37,38,39,40,41,42,43,44,45,46, 48,49,50,51,52,53,54,55,56,57,58], and 3 adopted a crossover design [32, 33, 47]. Six types of interventions were reported among all the trials; the treatments were conventional oxygen therapy (COT, namely nasal cannula/face mask), high flow nasal cannula (HFNC), noninvasive positive pressure ventilation (NPPV), nocturnal-noninvasive positive pressure ventilation (N-NPPV), heliox (a mixture of helium and oxygen gas), and air (room air/compressed air). The average age of participants ranged from 59 to 76 years old, with the majority being males. They were all stable severe COPD patients with GOLD stage III or IV (forced expiratory volume in 1 s (FEV1) < 50% predicted). Exercise training programs were primarily conducted in outpatient settings and supervised throughout. Most studies require keeping arterial oxygen saturation (SaO2) ≥ 88 ~ 92% during exercise training. These programs typically lasted 6 to 12 weeks, with two to three sessions per week lasting 30 to 45 min each at a moderately high intensity in exercise training. Assessments were done at baseline (pre) and post-treatment phase. The most commonly measured outcomes included 6-Minute Walk Test distance (6MWD), peak work rate, endurance time, dyspnea (Borg score), minute ventilation, peakVO2, and quality of life.

Risk of bias

Additional file 3: Fig. S1 depict the methodological quality assessment of the included studies. Out of the twenty-two studies [11,12,13, 29, 32,33,34,35,36,37,38, 40, 41, 44, 45, 48, 49, 52, 53, 56,57,58], specific randomized methods were observed in all, indicating a low risk. Allocation concealment was found to be at low risk in eighteen studies [11, 13, 28, 29, 31, 33, 34, 37, 41, 42, 44, 45, 48, 49, 51, 52, 54, 56]. Eleven trials implemented blinding for patients and personnel [13, 14, 32, 33, 40, 41, 44, 47, 53, 56, 58], while nineteen trials had blinded outcome assessors [11,12,13,14, 32, 33, 37, 40,41,42, 44, 47, 48, 50, 52,53,54, 56, 57]. The majority of studies exhibited a low risk of missing data, selective reporting, and other biases. The overall network structure of the treatment arms can be viewed in Additional file 4: Fig. S2.

Primary outcome

  1. (1)

    Exercise capacity: 6-Minute Walk Distance (6MWD)

Fifteen studies enrolling 625 participants reported 6MWD, and the main result of this NMA revealed that only NPPV was associated with statistically significant improvement in 6MWD when compared to air (SMD = 0.36, 95% CI = 0.02–0.70) or oxygen (SMD = 0.44, 95% CI = 0.03–0.85) (Fig. 2A and Table 1). According to the SUCRA, NPPV (78.9%) showed the greatest increase in patient’s 6MWD when compared with the others, followed by N-NPPV (70.4%) and HFNC (60.1%) (Additional file 2: Table S3A, Additional file 5: Fig. S3A).

Fig. 2
figure 2

Network structure of the primary outcomes. A Exercise capacity: 6 Minute Walk Test—distance. B Exercise capacity: peak work rate. C Exercise capacity: endurance time. D Physiological change: peak VO2

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Table 1 League table for primary outcomes: (A) Exercise capacity: 6 Minute Walk Test - distance, (B) Exercise capacity: peak work rate, (C) Exercise capacity: endurance time, and (D) Physiological change: peak VO2
Full size table
  1. (2)

    Exercise capacity: peak work rate

Twelve studies enrolling 385 participants reported peak work rate, and the main result of this NMA revealed that only NPPV was associated with statistically meaningful improvement in peak work rate when compared to air (SMD = 0.69, 95% CI = 0.21–1.17) or oxygen (SMD = 0.56, 95% CI = 0.02–1.09) (Fig. 2B and Table 1B). According to the SUCRA, NPPV (94%) showed best in improving patient’s peak work rate and Heliox (56.2%) followed. (Additional file 2: Table S3B, Additional file 5: Fig. S3B).

  1. (3)

    Exercise capacity: endurance time

Fourteen studies enrolling 525 participants reported endurance time, and the main result of this NMA revealed that NPPV (SMD = 0.38, 95% CI = 0.07–0.70) and oxygen (SMD = 0.31, 95% CI = 0.06–0.56) were associated with statistically significant improvement in endurance time when compared to air (Fig. 2C and Table 1C). According to the SUCRA, HFNC (83.4%) was associated with the greatest improvement among six interventions, followed by NPPV (64.5%) and heliox (61.7%) (Additional file 2: Table S3C, Additional file 5: Fig. S3C).

  1. (4)

    Physiological change: peak VO2

Thirteen studies enrolling 424 participants reported peak VO2, and the main result of this NMA revealed that only NPPV was associated with statistically significant improvement in peak VO2 when compared to oxygen (SMD = 0.65, 95% CI = 0.25–1.05), heliox (SMD = 0.67, 95% CI = 0.06–1.29), or air (SMD = 0.75, 95% CI = 0.37–1.13) (Fig. 2D and Table 1D). According to the SUCRA, NPPV (93.3%) was associated with the greatest improvement among five interventions, followed by N-NPPV (68.7%) (Additional file 2: Table S3D, Additional file 5: Fig. S3D).

Secondary outcome

  1. (1)

    Dyspnea (Borg score)

Seventeen studies enrolling 696 participants reported dyspnea, and this NMA revealed that NPPV (SMD =  − 0.47, 95% CI =  − 0.75 ~  − 0.19), HFNC (SMD =  − 0.46, 95% CI =  − 0.87 ~  − 0.05), and oxygen (SMD =  − 0.36, 95% CI =  − 0.62 ~  − 0.10) were associated with a significantly higher decrease in dyspnea when compared to air (Fig. 3A and Table 2A). According to the SUCRA, NPPV (67.5%) was associated with the greatest improvement among five interventions (Additional file 2: Table S4A, Additional file 6: Fig. S4A).

Fig. 3
figure 3

Network structure of the secondary outcomes. A Dyspnea (Borg score). B Physiological change: tidal volume. C Physiological change: minute ventilation. D Physiological change: lactate level. E Quality of life

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Table 2 League table for secondary outcomes: (A) Dyspnea (Borg score), (B) Physiological change: tidal volume, (C) Physiological change: minute ventilation, (D) Physiological change: lactate level, and (E) Quality of life
Full size table
  1. (2)

    Physiological change: tidal volume

Six studies enrolling 224 participants reported tidal volume, and only NPPV was associated with significant improvement in tidal volume when compared to air (SMD = 0.47, 95% CI = 0.02–0.91) or oxygen (SMD = 0.66, 95% CI = 0.19–1.12) (Fig. 3B and Table 2B). According to the SUCRA, NPPV (98%) was associated with the greatest improvement among four interventions (Additional file 2: Table S4B, Additional file 6: Fig. S4B).

  1. (3)

    Physiological change: minute ventilation

Fourteen studies enrolling 436 participants reported minute ventilation, and only NPPV was associated with significant improvement in minute ventilation when compared to air (SMD = 0.28, 95% CI = 0.00–0.56) or oxygen (SMD = 0.38, 95% CI = 0.03–0.73) (Fig. 3C and Table 2C). According to the SUCRA, NPPV (93.9%) was associated with the greatest improvement among four interventions (Additional file 2: Table S4C, Additional file 6: Fig. S4C).

  1. (4)

    Physiological change: lactate level

Ten studies enrolling 342 participants reported lactate level, and only NPPV was associated with a significantly higher decrease in lactate level when compared to air (SMD =  − 0.53, 95% CI =  − 0.91 ~  − 0.15) or oxygen (SMD =  − 0.60, 95% CI =  − 1.01 ~  − 0.20) (Fig. 3D and Table 2D). According to the SUCRA, NPPV (95.6%) was associated with the greatest change among four interventions (Additional file 2: Table S4D, Additional file 6: Fig. S4D).

  1. (5)

    Quality of life

Nineteen studies enrolling 846 participants reported quality of life, and six interventions were compared pairwise, and none of the respiratory support therapies were associated with significantly different changes in quality of life (Fig. 3E and Table 2E). According to the SUCRA, NPPV (71.1%) was associated with the greatest improvement among four interventions (Additional file 2: Table S4E, Additional file 6: Fig. S4E).

Inconsistency test and publication bias

A node-splitting test was conducted for inconsistency analysis, the results showed no statistical inconsistency in each pair of comparisons, and the overall consistency analysis effect was stable (all P > 0.05). Funnel plots of publication bias across the included studies (Additional file 7: Fig. S5) revealed general symmetry and no significance among the reviewed studies in this NMA.

Certainty of evidence

Based on the GRADE approach, the overall quality of the evidence ranged from critically low to moderate. This downgrade was primarily due to within-study bias, imprecision, and incoherence. Within-study bias mainly stemmed from the significant influence of high-risk-of-bias studies on network estimates in all comparisons. Imprecision was evident as the 95% CI of most comparisons extended beyond the area of equivalence, suggesting insufficient data to confirm definitive effects. Additional information on the quality of evidence can be found in Additional file 2: Table S5.

Discussions

Many COPD patients failed to exercise at the required intensity and duration, leading to limited benefits of PR. This is partially because that COPD patients have higher than expected demand for pulmonary ventilation due to increased respiratory work, dead space, and gas exchange disorders. Expiratory airflow obstruction and dynamic pulmonary hyperinflation cause delayed lung emptying and limited maximum ventilation function. These consequently result in worsen dyspnea, hypoxia, and increased lactate level, leading to limbs fatigue and decreased exercise tolerance [59]. Respiratory support in short-term and long-term exercise training can enhance the exercise performance of individuals by improving oxygen intake, decreasing the sensation of dyspnea, reducing hypoxic drive ventilation, and delaying the onset of lactate acidosis [59]. To the best of our knowledge, this is the first network meta-analysis on the basis of 35 RCTs involving 1321 patients, to assess the impact of different respiratory support therapy methods during pulmonary rehabilitation exercise training in COPD patients and rank them based on their efficacy.

The exercise performance influenced by NPPV

The results indicate that noninvasive positive pressure ventilation (NPPV) provides the most significant benefits in enhancing exercise capacity (6MWD, peak work rate, endurance time), reducing dyspnea, and improving physiological parameters (peak VO2, tidal volume, minute ventilation, and lactate level) in stable COPD patients (who were at GOLD stage III or IV; FEV1 < 50% predicted) undergoing pulmonary rehabilitation exercise training. These findings align with previous research demonstrating the positive impact of NPPV on exercise capacity, physiological measures, and dyspnea in COPD populations [15,16,17].

The reasons for that NPPV in exercise training has improved exercise ability in certain aspects partially may be explained as below. First, evidence has shown that NPPV may improve gas exchange and/or reduce the work of breathing by counteracting with intrinsic positive end-expiratory pressure [60]. Second, NPPV reduces pulmonary intrinsic pressure and consequently could have decreasing or delaying the occurrence of dynamic hyperinflation [61]. Furthermore, at high levels of inspiratory pressure, NPPV may consistently increase dynamic lung compliance and tidal volume, leading to improved arterial blood gasses and facilitating muscle oxygen availability [60]. The study observed a notable increase in peak VO2, tidal volume and minute ventilation after NPPV-assisted training. The enhanced physiological regulation suggests a potential link to enhanced oxidative metabolism and improved oxygen intake kinetics [62]. Additionally, the reduction in lactate levels in the NPPV group implies that the muscles involved in exercise exhibit improved antioxidant capacity [63], leading to alleviate the strain on respiratory muscles and reduce leg fatigue. Although the results of this study are promising, there are still studies mentioning the use of NPPV during exercise training as a difficult, expensive, and time-consuming intervention. However, there are currently no research reports systematically analyzing its economic effectiveness [64]. Further investigation is needed to determine whether NPPV could be a cost-effective addition to exercise training for individuals with severe, stable COPD, considering the implications on staff time and resources.

The exercise performance influenced by the other respiratory support methods

Nocturnal-noninvasive positive pressure ventilation (N-NPPV) during exercise training means conducting exercise training during the day and NPPV at night. This approach may increase the likelihood of COPD patients participating in daytime exercise training, prolong exercise time, and avoid the drawbacks of NPPV and exercise training simultaneously. Although this study did not find a statistically significant difference in the benefits of N-NPPV, it ranked second only to NPPV in terms of various indicators. Further research is necessary to confirm its effectiveness.

Although high flow nasal cannula (HFNC) is easier to implement and more tolerable than NPPV, this study did not find any significant differences between HFNC and other measures, except that it may alleviate dyspnea compared to non-adjuvant respiratory support therapy. This result deviated from the report from Prieur et al. [15] which showed that HFNC treatment in a single training session increased functional exercise ability. The possible physiological mechanism might be that the sustained airflow promoted CO2 flushing in the upper respiratory tract and provided continuous positive airway pressure, contributing to a decrease in respiratory frequency and work of breath [65]. Nevertheless, no benefits in exercise capacity have been observed after multiple PR sessions in this study. Further extensive clinical trials are required to validate this finding.

The impact of supplementing heliox, a mixture of helium and oxygen gas, is comparable to that of bronchodilators, as it can decrease airflow resistance during respiration and enhance lung mechanics in patients [66]. Nevertheless, this study did not observe any positive effects of heliox, highlighting the need for further research to establish its efficacy. Additionally, challenges related to transportation, storage, monitoring, and cost were identified [66]. Oxygen administered through nasal cannulas or a face mask may be effective in improving exercise endurance time and dyspnea, which is similar to the results of Nonoyama et al. [18].

Quality of life influenced by respiratory support therapy

Improvement in quality of life was shown in before-after exercise training in each individual respiratory support therapy, but there was no statistically significant difference observed among these therapies. This lack of significance may be attributed to pulmonary rehabilitation (PR) being a comprehensive intervention that encompasses evidence-based practices and multidisciplinary collaboration, including disease self-management, exercise training, nutritional support, and psychological support. Respiratory support therapy is just one component of the comprehensive PR program and its impact on enhancing quality of life within the PR program is limited, hence making it challenging to discern differences solely based on this measure. Nonetheless, the importance of respiratory support therapy should not be overlooked. Exercise training, the cornerstone of pulmonary rehabilitation, in combination with other PR interventions, can lead to improved treatment outcomes and enhanced quality of life for patients.

Implications for clinical practice and future research

The proposal to incorporate respiratory support therapy during exercise aims to lessen the breathing effort during intense physical activity, enabling patients to engage in more strenuous exercise, reduce breathing difficulties, alleviate oxygen desaturation, and enhance the ability of individuals with severe COPD to tolerate exertion. The findings of this study indicate that noninvasive positive pressure ventilation (NPPV) provides the most significant benefits in enhancing exercise capacity, physiological responses, and breathlessness in stable COPD patients undergoing pulmonary rehabilitation exercise training. However, it should be notice that all the included COPD patients in this study turned out to be at GOLD stage III or IV (FEV1 < 50% predicted). For moderate to severe COPD [67, 68], NPPV is a suitable and routine therapy, because of their impaired lung function, ventilatory restrictio,n and hypoxemia. During exercise training, respiratory problems are more pronounced. Under this circumstances within such patients, the necessary and potential benefits to the use of NPPV during exercise training becomes prominent. While NPPV during exercise training may offer benefits to certain COPD patients, obstacles to implementing this technology include lack of confidence in the ventilator model, settings, portability, battery life, equipment weight, and the time needed to initiate therapy. Besides, the optimal adjunctive modality for patients with COPD of other severities (mild to moderate) remains unclear. These necessitates further practice and research. In the future, personalized respiratory support therapy models tailored to individual patients based on comprehensive considerations should be explored to assess the clinical value and cost-effectiveness of different respiratory support therapy in exercise training. Researchers can develop innovative devices, design high-quality studies, conduct multi-centered practical validations, and establish more precise exercise training programs to meet patient needs.

Limitations

Certain limitations are inherent in this study. First, there is heterogeneity among studies, including variations in participants, study characteristics (e.g., types of interventions, study designs, evaluation methods), and relatively small sample sizes. They all may significantly limit the internal validity of our findings. However, the analysis in this study focused on changes relative to baseline values rather than post-intervention values. This approach helped to minimize significant baseline differences between individuals or groups, enhancing the statistical power to detect performance indicators. Second, the lack of direct comparisons between interventions could potentially weaken the strength and comprehensiveness of the conclusions derived from the indirect analysis. Third, insufficient research exists to compare various exercise training plans for post hoc subgroup analysis. Therefore, the optimal settings for devices during exercise, frequency, and duration of exercise training programs for individuals with COPD are still unclear. As a result, the application of the evidence to specific individual’s need may be impacted. Therefore, further large-scale trials are necessary to validate and elucidate these issues. Fourth, there was an uneven distribution in the number of comparisons and sample sizes across interventions, which might have influenced the results. Additionally, in this network meta-analysis, many randomized controlled trials exhibited biases that could impact the study's quality. These discrepancies among factors may potentially influence the assessment of evidence.

Conclusions

Effective respiratory support intervention during pulmonary rehabilitation exercise training for COPD patients is crucial for improving health quality. Analysis results show that specific respiratory support interventions can enhance exercise capacity and tolerance compared to unassisted training. These interventions include NPPV, HFNC, and oxygen administered through nasal cannulas or face masks during exercise. NPPV appears to be the most promising intervention based on probability ranking in stable severe COPD patients (GOLD stage III or IV, FEV1 < 50% predicted). Future research in this field should be expanded to provide more conclusive evidence for practical applications. The limited number of studies included in most pairwise comparisons resulted in low-quality evidence. Therefore, it is advised that additional clinical trials be included in future network meta-analyses to validate the current findings.

Availability of data and materials

All data analyzed in this study are available in this published article and supplementary materials.

Abbreviations

COPD:

Chronic obstructive pulmonary disease

NPPV:

Noninvasive positive pressure ventilation

peak VO2 :

Peak oxygen uptake

PR:

Pulmonary rehabilitation

COT:

Conventional oxygen therapy

HFNC:

High-flow nasal cannula

NMA:

Network meta-analysis

HRQL:

Health-related quality of life

CAT:

COPD Assessment Test score

CRQ:

Chronic Respiratory Disease Questionnaire

SGRQ:

St. George’s Respiratory Questionnaire

OR:

Odds ratios

CI:

Confidence intervals

SMD:

Standardized mean differences

SUCRA:

Surface under the cumulative ranking curve

N-NPPV:

Nocturnal-noninvasive positive pressure ventilation

FEV1 :

Forced expiratory volume in 1 s

SaO2 :

Arterial oxygen saturation

6MWD:

6-Minute Walk Test distance

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Acknowledgements

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Funding

This research was supported by Sichuan Science and Technology Program (Grant NO. 2023YFS0237).

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Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan Province, 610041, China

    Xinrong Chen, Ling Xu, Cui Yang, Mei Feng, Ying Wu & Jing Zhu

  2. Breast Center, Department of General Surgery, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan Province, 610041, China

    Shuqin Li

  3. Department of Nursing, Sanya People’s Hospital/West China (Sanya) Hospital, Sichuan University, Sanya, Hainan Province, 572029, China

    Xiaoling Wu

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Contributions

CXR, XL, WXL, WY, and FM conceptualized and designed the study. CXR, XL, LSQ, and WY acquired, analyzed, and interpreted the data. CXR and XL drafted the manuscript. CXR and WY revised the manuscript and edited images. XL and YC performed statistical analysis. ZJ obtained funding. WXL, WY, FM, and ZJ supervised the study. All authors read and approved the final manuscript.

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Correspondence to Mei Feng or Ying Wu.

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Not applicable. This study is a network meta-analysis of previously collected data, thus additional ethical approval was not required.

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Supplementary Information

Additional file 1: PRISMA 2020 checklist.

12916_2024_3605_MOESM2_ESM.doc

Additional file 2. Table S1-S5: Additional information on search strategy, included studies’ quality assessment and outcomes comparison. Table S1-Search strategy; Tale S2-The general information of the included studies; Table S3- The probability ranking for primary outcomes; Table S4-The probability ranking for secondary outcomes; Table S5-The evidence findings for all comparisons.

Additional file 3: Fig. S1: Risk of bias graph and summary.

12916_2024_3605_MOESM4_ESM.tif

Additional file 4: Fig. S2: The overall network structure of the treatment arms. The lines between nodes represent direct comparisons in various trials, and the size of each circle is proportional to the size of the population involved in each specific treatment. That is, the more subjects with that specific treatment, the larger size of that specific circle is. The thickness of the lines is proportional to the number of trials connected to the network. That is, the more trials involving that specific direct-comparison, the thicker of the lines between that specific direct-comparison is. Finally, there is no specific meaning regarding distance of the circles from one another. Oxygen supply: nasal cannula/face mask; HFNC: high flow nasal cannula; NPPV: noninvasive positive pressure ventilation; N-NPPV: nocturnal-noninvasive positive pressure ventilation; Heliox: a mixture of helium and oxygen gas; Air: room air/compressed air.

12916_2024_3605_MOESM5_ESM.jpeg

Additional file 5: Fig. S3: The probability ranking for primary outcome: A. Exercise capacity: 6 Minute Walk Test – distance; B. Exercise capacity: peak work rate; C. Exercise capacity: endurance time; D. Physiological change: peak VO2.

12916_2024_3605_MOESM6_ESM.jpeg

Additional file 6: Fig. S4: The probability ranking for secondary outcomes: A. Dyspnea (Borg score); B. Physiological change: tidal volume; C. Physiological change: minute ventilation; D. Physiological change: lactate level; E. Quality of life.

12916_2024_3605_MOESM7_ESM.jpeg

Additional file 7: Fig. S5: Funnel plots of the outcomes: (A) Exercise capacity: 6 Minute Walk Test – distance; (B) Exercise capacity: peak work rate; (C) Exercise capacity: endurance time; (D) Physiological change: peak VO2; (E) Dyspnea (Borg score); (F) Physiological change: tidal volume; (G) Physiological change: minute ventilation; (H) Physiological change: lactate level; (I) Quality of life.

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Chen, X., Xu, L., Li, S. et al. Efficacy of respiratory support therapies during pulmonary rehabilitation exercise training in chronic obstructive pulmonary disease patients: a systematic review and network meta-analysis. BMC Med 22, 389 (2024). https://doi.org/10.1186/s12916-024-03605-7

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BMC Medicine

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