Abstract
Objective
Inspiratory muscle training (IMT) is used to improve inspiratory muscle strength in patients with COPD. However, the effect of IMT on diaphragmatic function has not yet been thoroughly evaluated. This study aimed to evaluate the effect of IMT on maximum diaphragmatic excursion (DEmax) using ultrasonography in patients with COPD.
Methods
This was a single-centre, randomised, prospective, parallel-group, unblinded controlled trial involving 38 participants with stable COPD. Participants underwent a standardised 12-week pulmonary rehabilitation (PR) programme followed by a 12-week IMT programme, consisting of home-based IMT and low-frequency outpatient PR sessions supervised by physiotherapists (once every 2 weeks), versus low-frequency outpatient PR alone as a control. The DEmax and exercise tolerance were measured.
Results
Out of the 38 patients initially enrolled in the PR programme, 33 successfully completed it and were subsequently randomised to the IMT programme. Finally, 15 (94%) and 14 (88%) patients from the IMT and control groups, respectively, completed the study. Following the IMT programme, DEmax increased in the IMT group (mean±sd 50.1±7.6 mm to 60.6±8.0 mm, p<0.001), but not in the control group (47.4±7.9 mm to 46.9±8.3 mm, p=0.10). Changes in DEmax and exercise tolerance (peak oxygen uptake) were greater in the IMT group than in the control group (both p<0.01).
Conclusions
IMT following the PR programme improved DEmax and exercise tolerance. Therefore, DEmax may be an important outcome of IMT.
Shareable abstract
This study aimed to evaluate the effect of IMT on maximum diaphragmatic excursion using ultrasonography in patients with COPD. IMT following the PR programme improved maximum diaphragmatic excursion (DEmax) and exercise tolerance. https://bit.ly/3yMfj9v
Introduction
COPD is a progressive disease characterised by minimally reversible airflow limitation. The chief limitation imposed by COPD is the inability of patients to manage their daily activities due to breathlessness. Although the pathophysiological mechanisms involved in the development of dyspnoea and poor exercise tolerance in patients with COPD are complex, dynamic lung hyperinflation (DLH) plays a central role [1]. Despite compensatory mechanisms, the major consequences of DLH are increased ventilatory workload and decreased pressure-generating capacity of the inspiratory muscles [2]. The diaphragm is the main muscle involved in respiration, and diaphragm dysfunction exists in all stages of COPD [3]. Therefore, we evaluated the diaphragm using ultrasound and reported that maximum diaphragmatic excursion (DEmax) was closely associated with exercise tolerance and DLH in patients with COPD [4].
Exercise training is a central component of pulmonary rehabilitation (PR) programmes and inspiratory muscle training (IMT) is used to improve inspiratory muscle function, including that of the diaphragm. While available evidence indicates inconsistent effectiveness of IMT without a clear training dose–response relationship in patients with COPD [5], both the American Thoracic Society and the European Respiratory Society [6] advocate for IMT as a supplemental intervention in PR programmes for treating patients with chronic lung diseases, particularly when inspiratory muscle weakness is evident. The proposed beneficial effects of IMT include improvements in inspiratory muscle strength and endurance, functional exercise capacity, dyspnoea, and quality of life [7–9]. IMT may be associated with an improvement in diaphragmatic mobility; however, the underlying mechanisms are poorly understood. In a previous study, IMT enhanced diaphragm muscle strength and reduced the required electrical activity of the diaphragm in relation to its peak activity, potentially alleviating dyspnoea during exercise in COPD patients [10]. However, it is unclear whether IMT improves DEmax. In addition, although IMT alone significantly improves inspiratory muscle strength, exercise capacity and quality of life, the additive effect of IMT was reported to be questionable in a programme conducting PR and IMT simultaneously [11, 12].
This study was conducted to examine the hypothesis that in patients with COPD strengthening inspiratory muscles would improve DEmax, which might reduce DLH and improve exercise tolerance when IMT training was performed in a sequential design, i.e. after a standardised PR programme. While the primary objective of this study was to evaluate whether IMT performed after a standardised PR programme was associated with an improvement in DEmax in patients with COPD, the secondary objective was to evaluate the effect of IMT on exercise tolerance, DLH and perception of dyspnoea.
Materials and methods
Study design, participants and standardised PR
This was a single-centre, randomised, prospective, parallel-group, unblinded controlled trial. Clinically stable COPD patients who visited the Department of Respiratory Medicine and Allergology at Kindai University Hospital between April 2019 and January 2023 and were referred to the PR unit were included. The main inclusion criteria were as follows: 1) age between 65 and 85 years at the time of consent; 2) stable disease without infection or acute exacerbation within 3 months prior to enrolment; and 3) dyspnoea on exertion (modified Medical Research Council (mMRC) grade scale 1–3). Eligible patients were registered and received standardised PR before randomisation (figure 1). Details of standardised PR and randomisation are shown in the supplemental methods. This study was approved by the Committee for Ethics of the Kindai University School of Medicine (No 31-086) and registered in the UMIN-CTR (number: 000043099). All the participants provided written informed consent. This research was conducted according to the principles of the World Medical Association Declaration of Helsinki.
FIGURE 1.
The study protocols. After registration, a standardised pulmonary rehabilitation (PR) programme was implemented for all patients. Standardised initial PR included twice-weekly sessions of monitored exercise training and self-training at home for 12 weeks, followed by randomisation to the IMT or control group. After randomisation, all patients were instructed to continue self-training at home and attend outpatient maintenance PR supervised by physiotherapists (once every 2 weeks). The inspiratory muscle training (IMT) group underwent IMT at home for 12 weeks.
12-week IMT programme
During the 12-week IMT programme, all patients were instructed to perform self-training at home (home exercise programme, shown in the supplemental methods) and attend outpatient maintenance PR supervised by physiotherapists (once every 2weeks) (figure 1). IMT was performed according to the method laid out by Langer et al. [10] with the intervention group receiving IMT training (self-training, 30 breaths per set, 2 sets per day) using the POWERbreathe K3 device (POWERbreathe International, Stratford-upon-Avon, UK) for 12 weeks at home. All patients started IMT at 30% of maximum inspiratory pressure (PImax) at baseline. Details of training quality and adherence are shown in the supplemental methods.
Measurements
Details of measurements including DEmax, lung function test, PImax and calculation of predicted values of PImax and 6-min walk distance (6MWD) are presented in the supplemental methods. Maximum DEmax was measured using ultrasonography (Xario 200; Canon Medical Systems, Tokyo, Japan). Excursions of the right hemidiaphragm were measured using a 3.5-MHz convex probe (figure S1) [4].
A symptom-limited cardiopulmonary exercise test was performed on a bicycle ergometer according to the Ramp 10 Watts (W) protocol (load increase of 10 W per 1 min − 1 W per 6 s) incremental loading testing. Continuous inspiratory capacity (IC) measurements were taken every minute throughout the exercise regimen and again at its conclusion. We measured the change in IC (ΔIC=IC lowest − IC at rest) during exercise as a surrogate marker for DLH [13, 14]. During the incremental loading testing and constant-loading testing, we analysed the following indices: endurance time, peak oxygen uptake (peak V˙O2), minute ventilation (V˙E), ventilatory equivalents for carbon dioxide (V˙E/V˙CO2), V˙E/V˙CO2 slope, peak tidal volume-to-inspiratory capacity ratio (peak VT/IC), inspiratory time-to-total respiratory cycle time (ti/ttot), inspiratory tidal volume (VTI), and expiratory tidal volume (VTE).
To assess the respiratory muscle strength, we measured the PImax generated against an occluded airway at a residual volume (IOP-01; Kobata Instrument Manufacturing Ltd., Osaka, Japan) [15].
The 6MWD protocol according to American Thoracic Society guidelines was used as an index of exercise tolerance; the 10-point Borg scale was used to assess the intensity of dyspnoea, and leg fatigue was evaluated post-6MWD [16]. Additionally, the COPD assessment test (CAT) was conducted to assess the patient's condition.
The primary outcome was the change in DEmax from baseline to the end of the IMT programme, and the secondary outcomes were changes in ΔIC during the constant-loading testing and other outcomes during the incremental loading testing. ΔIC was measured to estimate DLH, peak V˙O2, and 6MWD for exercise tolerance; and V˙E and V˙E/V˙CO2 for ventilation volume. These parameters, along with other physiological indices, were measured at registration, baseline (after standardised PR), and post-intervention. Values at the end of the IMT programme minus values at baseline are expressed as Δ except for IC. ΔʹIC indicates ΔIC at the end of the IMT programme minus ΔIC at baseline. Data are presented as mean±sd or median (interquartile range).
Statistical analysis
Details of sample size estimation are shown in the supplemental methods. Outcomes before and after the intervention were analysed using a two-way repeated measures analysis of variance. The relationships between ΔDEmax and changes in the exercise measurements (Δpeak V˙O2, ΔV˙E, ΔV˙E/V˙O2, ΔV˙E/V˙CO2 slope, Δpeak VT/IC, Δti/ttot and ΔʹIC=Δ(ΔIC)) were evaluated by calculating Pearson correlation coefficients. Statistical data were analysed using the JMP software, version 17 (JMP, SAS Institute Inc., Cary, NC, USA). For all analyses, statistical significance was set at p<0.05.
Results
38 patients were registered for this study (table S1), but five patients were excluded as they were registered during the coronavirus disease 2019 pandemic and could not continue rehabilitation. Therefore, 33 patients received a standardised PR programme before randomisation (from −12 weeks to baseline), which improved exercise tolerance (peak V˙O2 11.9±3.0 mL·min−1·kg−1 to 13.0±3.1 mL·min−1·kg−1, p<0.001; 6MWD 412±88 m to 445±92.5 m, p<0.001); however, it did not improve DEmax (48.6±7.9 mm to 48.8±8.0 mm, p=0.91). CAT was also improved after the standardised PR programme (13±4 to 9±4, p<0.001).
Effects of 12-week IMT
Following the completion of the standardised PR programme, 33 patients were allocated to the IMT (n=17) and control (n=16) groups (figure 2). Throughout the 12-week IMT programme, four participants withdrew: one due to self-interruption and another due to experiencing worsening dyspnoea from excessive use of the IMT device in the IMT group, while the control group experienced two acute exacerbations. Finally, 15 (94%) and 14 (88%) patients in the IMT and control groups completed the 12-week IMT programme, respectively (figure 2). There were no differences in the baseline parameters (table 1), or changes in the parameters during the initial standardised PR programme (table S2), between the IMT and control groups. The numbers of patients with good adherence to home-based maintenance PR in the IMT and control groups were 14 and 13, respectively. Data on the adherence and training quality of the IMT programme are shown in table S4.
FIGURE 2.
Flow chart of patient selection. IMT: inspiratory muscle training.
TABLE 1.
Characteristics of study participants at baseline: inspiratory muscle training (IMT) versus control
| All subjects (n=29) | IMT group (n=15) | Control group (n=14) | p-value | |
|---|---|---|---|---|
| Male/female, n/n (%/%) | 28/1 (97/3) | 14/1 (93/7) | 14/0 (100/0) | 0.80 |
| Age, years | 75±4 | 76±3 | 76±4 | 0.74 |
| Body mass index, kg·m−2 | 22.7±2.3 | 22.7±2.51 | 23.7±1.98 | 0.28 |
| GOLD (1/2/3/4), n | 2/13/12/2 | 1/7/6/1 | 1/6/6/1 | 0.50 |
| DEmax, mm | 48.8±8.0 | 49.5±7.9 | 47.4±7.9 | 0.65 |
| PImax, cmH2O | 65.1±21.4 | 65.7±16.8 | 64.3±26.1 | 0.86 |
| %PImax, % | 62.9±18.7 | 66.0±18.7 | 59.5±24.4 | 0.59 |
| 6MWD, m | 437±91 | 456±81 | 434±108 | 0.53 |
| 6MWD, % pred | 80.7±18.3 | 82.5±15.3 | 79.0 ±21.2 | 0.17 |
| mBorg scale dyspnoea | 4 (2 to 5) | 4 (2 to 4) | 5 (2 to 7) | 0.23 |
| mBorg scale leg fatigue | 2 (1 to 4) | 2 (1 to 4) | 4 (1 to 5) | 0.39 |
| CAT | 10 (5 to 11) | 8 (5 to 10) | 10 (5 to 12) | 0.28 |
| Spirometry | ||||
| IC, L | 2.30±0.48 | 2.30±0.46 | 2.28±0.48 | 0.62 |
| FEV1, L | 1.49±0.50 | 1.49±0.49 | 1.56±0.50 | 0.73 |
| FEV1, % pred | 59.1±18.3 | 59.1±16.3 | 59.0±20.3 | 0.84 |
| FVC, L | 3.10±0.67 | 3.01±0.46 | 3.24±0.80 | 0.40 |
| FVC, % pred | 96.4±17.5 | 93.0±18.0 | 100±16.3 | 0.28 |
| Incremental loading testing | ||||
| Peak Load, W | 75.2±25.1 | 78.9±22.4 | 71.2±27.2 | 0.27 |
| Peak V˙O2, mL·min−1·kg−1 | 13.1±3.1 | 13.0±2.5 | 13.1±3.8 | 0.97 |
| V˙E, L·min−1 | 43.3±12.0 | 44.8±12.1 | 41.7±11.7 | 0.49 |
| V˙E/V˙CO2, mL/mL | 48.0±8.8 | 49.4±7.9 | 46.6±9.8 | 0.41 |
| V˙E/V˙CO2 slope | 48.6±11.3 | 50.1±8.8 | 47.0±13.7 | 0.47 |
| Peak VT/IC | 56.1±12.3 | 57.6±9.9 | 54.4±14.6 | 0.74 |
| VTI, mL | 1273±333 | 1330±339 | 1212±327 | 0.34 |
| VTE, mL | 1243±322 | 1295±321 | 1187±325 | 0.37 |
| ti/ttot, % | 53±13 | 54±10 | 54±15 | 0.95 |
| Constant-loading testing | ||||
| Endurance time, s | 568±143 | 592±156 | 554±129 | 0.37 |
| Peak V˙O2, mL·min−1·kg−1 | 12.6±3.7 | 13.2±2.3 | 11.8±4.8 | 0.30 |
| V˙E, L·min−1 | 41.4±11.4 | 44.1±12.3 | 38.4±10.0 | 0.18 |
| V˙E/V˙CO2, mL/mL−1 | 51±10.0 | 51.6±8.6 | 50.6±11.6 | 0.71 |
| Peak VT/IC | 0.54±0.22 | 0.56±0.25 | 0.51±0.18 | 0.33 |
| VTI, mL | 1192±312 | 1264±284 | 1114±332 | 0.20 |
| VTE, mL | 1165±301 | 1234±263 | 1092±331 | 0.21 |
| ti/ttot, % | 45±13 | 49±0.14 | 41±13 | 0.14 |
| IC at rest, L | 2.15±0.49 | 2.30±0.49 | 1.96±0.46 | 0.07 |
| ΔIC from rest, L | −0.46±0.20 | −0.43±0.18 | −0.49±0.21 | 0.50 |
Data are presented as mean±sd or median (interquartile range), unless otherwise stated. 6MWD: 6-min walk distance; CAT: COPD assessment test; DEmax: maximum diaphragmatic excursion; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; IC: inspiratory capacity; PImax: maximum inspiratory pressure; ti/ttot: inspiratory duty cycle; V˙E: minute ventilation; V˙E/V˙CO2:minute ventilation/carbon dioxide production; V˙O2: oxygen uptake; VT/IC: tidal volume/inspiratory capacity; VTI: inspiratory tidal volume; VTE: expiratory tidal volume.
In the IMT group, DEmax, peak VO2 and PImax increased from baseline to 12 weeks, but did not increase in the control group (table S3). As a result, ΔDEmax (figure 3), peak VO2 (figure 4), and ΔPImax were significantly higher in the IMT group than in the control group (table 2). IMT also significantly improved most of the other parameters (CAT score, dyspnoea score, V˙E/V˙CO2, peak VT/IC, VTI, VTE, and VTI − VTE), but not in the control group (table S3), and the changes were significantly greater in the IMT group (table 2). Meanwhile, against our hypothesis, ΔIC did not change after the intervention (baseline to 12 weeks) in both groups (data not shown) and ΔʹIC were comparable between the two groups (table 2). IMT did not improve the 6MWD, and the Δ6MWD was comparable between the two groups. IMT increased the endurance time on the constant work rate exercise test by +139±124 s from baseline (p<0.01) (table 2). In the two-way repeated measures analysis of variance, a significant interaction between time and treatment group was observed for ΔDEmax (figure 3) and Δpeak V˙O2 (figure 4). Significant improvement in DEmax was only observed in the IMT group after the intervention (figure 3).
FIGURE 3.
Change of maximum diaphragmatic excursion (DEmax) as measured by an ultrasonography at baseline and week 12. Error bars indicate the standard deviation. **: p<0.01.
FIGURE 4.
Change of peak oxygen uptake (V˙O2) as measured by a cycle ergometer at baseline and week 12. Error bars indicate the standard deviation. *: p<0.05.
TABLE 2.
Effect of inspiratory muscle training (IMT): changes from the baseline
| Changes from baseline | |||
|---|---|---|---|
| IMT group (n=15) | Control group (n=14) | p-value | |
| ΔDEmax, mm | 10.0±5.1 | −0.5±1.1 | <0.001 |
| ΔPImax, cmH2O | 22.7±9.2 | 3.4±11.1 | <0.001 |
| Δ6MWD, m | 12±12 | −7±38 | 0.09 |
| Δ6MWD, % pred | 5.6 ±0.4 | −7.7 ±1.1 | 0.45 |
| ΔmBorg scale dyspnoea | −1 (−2 to 0) | 0 (−2 to 1) | <0.01 |
| ΔmBorg scale leg fatigue | −1 (−2 to 0) | 0 (1 to 0.25) | 0.46 |
| ΔCAT | −2 (−2 to 0) | 0 (0 to 1) | <0.05 |
| Incremental loading testing | |||
| Δpeak V˙O2, mL·min−1·kg−1 | 1.22±1.0 | −0.8±1.4 | <0.001 |
| ΔV˙E, L·min−1 | 3.8±4.1 | −0.02±5.6 | <0.05 |
| ΔV˙E/V˙CO2, mL/mL | −2.8±2.8 | 0.9±3.6 | <0.01 |
| ΔV˙E/V˙CO2 slope | −7.2±9.4 | −0.6±9.2 | <0.05 |
| Δpeak VT/IC, % | 6.9±5.9 | −1.5±5.9 | <0.01 |
| ΔVTI, mL | 229±206 | 3±300 | <0.01 |
| ΔVTE, mL | 231±297 | 73±138 | <0.01 |
| Δti/ttot, % | 6±6 | 0±6 | 0.053 |
| Constant-loading testing | |||
| Δendurance time, s | 131±124 | 28±81 | <0.01 |
| Δpeak V˙O2, mL·min−1·kg−1 | 0.70±2.9 | 0.11±4.3 | 0.53 |
| ΔV˙E, L·min−1 | 5.6±13.8 | −0.45±10.4 | 0.31 |
| ΔV˙E/V˙CO2, mL/mL | −1.58±7.4 | −0.4±9.7 | 0.21 |
| Δpeak VT/IC, % | 16±24 | −1.0±1.6 | <0.01 |
| ΔVTI, mL | 349±250 | 3.0±330 | <0.01 |
| ΔVTE, mL | 321±254 | 25±330 | <0.01 |
| Δti/ttot, % | 3±13 | 5±12 | 0.67 |
| ΔIC at rest, L | 0.23±0.07 | −0.04±0.06 | <0.01 |
| ΔʹIC, L | 0.02±0.11 | 0.00±0.15 | 0.53 |
Data are presented as mean±sd or median (interquartile range), unless otherwise stated. 6MWD: 6-min walk distance; CAT: COPD assessment test; DEmax: maximum diaphragmatic excursion; IC: inspiratory capacity; PImax: maximum inspiratory pressure; ti/ttot: inspiratory duty cycle, V˙E: minute ventilation; V˙E/V˙CO2: minute ventilation/carbon dioxide production; V˙O2: oxygen uptake; VT/IC: tidal volume/inspiratory capacity; VTI: inspiratory tidal volume; VTE: expiratory tidal volume. Δ: value at the end of IMT programme minus value at baseline except for IC, Δ′IC=Δ(ΔIC at the end of IMT programme minus ΔIC at baseline).
Within the IMT group, ΔDEmax exhibited moderate to strong correlations with ΔPImax, Δpeak V˙O2, ΔV˙E, ΔV˙E/V˙CO2, ΔV˙E/V˙CO2 Slope, Δpeak VT/IC, Δti/ttot, ΔVTI, ΔVTI − VTE, Δpeak dyspnoea perception (Borg scale), and ΔCAT score, while ΔDEmax demonstrated modest correlations with Δ6MWD and ΔʹIC (table 3). Furthermore, in the IMT group, ΔDEmax was strongly correlated with Δendurance time (table 3).
TABLE 3.
Correlations between ΔDEmax and ventilatory parameters/dyspnoea in the inspiratory muscle training (IMT) group (n=15)
| Pearson correlation coefficient (r) | p-value | |
|---|---|---|
| ΔPImax, cmH2O | 0.69 | p<0.001 |
| Δ6MWD, m | 0.34 | 0.07 |
| Δ6MWD, % pred | 0.35 | 0.20 |
| ΔmBorg scale dyspnoea | −0.57 | p<0.001 |
| ΔmBorg scale leg fatigue | −0.01 | 0.98 |
| ΔCAT | −0.52 | p<0.01 |
| Incremental loading testing | ||
| Δpeak V˙O2, mL·min−1·kg−1 | 0.76 | p<0.001 |
| ΔV˙E, L·min−1 | 0.56 | p<0.01 |
| ΔV˙E/V˙CO2, mL/mL | −0.63 | p<0.01 |
| ΔV˙E/V˙CO2 slope | −0.63 | p<0.01 |
| Δpeak VT/IC, % | 0.73 | p<0.001 |
| ΔVTI, mL | 0.52 | p<0.05 |
| ΔVTE, mL | 0.40 | p<0.05 |
| Δti/ttot, % | 0.54 | p<0.01 |
| Constant-loading testing | ||
| Δendurance time, s | 0.83 | p<0.001 |
| Δpeak V˙O2, mL·min−1·kg−1 | 0.78 | p<0.001 |
| ΔV˙E, L·min−1 | 0.39 | 0.15 |
| ΔV˙E/V˙CO2, mL/mL | −0.63 | 0.45 |
| Δpeak VT/IC, % | 0.53 | p<0.05 |
| ΔVTI, mL | 0.51 | p<0.05 |
| ΔVTE, mL | 0.49 | p<0.05 |
| Δti/ttot, % | 0.11 | 0.68 |
| ΔIC, L | 0.54 | p<0.05 |
| ΔʹIC, L | 0.37 | p<0.05 |
6MWD: 6-min walk distance; CAT: COPD assessment test; DEmax: maximum diaphragmatic excursion; IC: inspiratory capacity; PImax: maximum inspiratory pressure; ti/ttot: inspiratory duty cycle; V˙E: minute ventilation; V˙E/V˙CO2: minute ventilation/carbon dioxide production; V̇O2: oxygen uptake; VT/IC: tidal volume/inspiratory capacity; VTI: inspiratory tidal volume; VTE: expiratory tidal volume. Δ: value at the end of IMT programme minus value at baseline except for IC, Δ′IC=Δ(ΔIC at the end of IMT programme minus ΔIC at baseline).
Discussion
The main finding of this study was that DEmax and exercise tolerance, expressed as peak V˙O2, increased after 12 weeks of home-based IMT compared with the control arm. To the best of our knowledge, this is the first study to demonstrate that IMT increases DEmax in patients with COPD.
As the diaphragm is the most important inspiratory muscle, sufficient diaphragmatic mobilisation is the key to securing the training effect of IMT. However, the DEmax has not been examined as an IMT outcome in previous studies. Herein, we demonstrated that the DEmax increased with IMT training and may be an important outcome of IMT training. Wu et al. [17] measured diaphragmatic mobilisation, expressed as transdiaphragmatic pressure (Pdi) and the corrected root mean square (RMS) of the diaphragmatic electromyogram (EMGdi) (RMSdi%), during IMT in patients with COPD. They reported that Pdi and RMSdi% were higher during IMT, demonstrating an effective training effect on the diaphragm muscle. Langer et al. [10] also measured EMGdi and demonstrated that the ratio of EMGdi to its maximum (EMGdi/EMGdimax) decreased post-IMT. They concluded that a reduction in EMGdi/EMGdimax helped explain the decrease in the perceived respiratory discomfort. EMGdi and Pdi may be more accurate for diaphragm muscle activation and function; however, these methods are relatively invasive and not easily implemented in clinical practice. However, the ultrasound measurement of DEmax would be a more practical and reliable measure for incorporation into PR assessment.
We measured DEmax, but not diaphragm muscle thickness, because of the inconsistent results for diaphragm thickness. Baria et al. [18] reported no significant difference in diaphragm thickness between COPD patients and controls, whereas Okura et al. [19] found a significant association between diaphragm thickness in COPD patients and controls. Measurement of diaphragmatic thickening fraction is a reproducible assessment [20]. However, the correlation between diaphragmatic thickening and effort is not strong, and only one-third (or less) of the variation in inspiratory effort can be explained by ultrasound measurements of diaphragm thickening [21]. Furthermore, the evaluation of diaphragm thickness and thickening fraction is difficult to perform in patients with severe COPD because the length of the zone of apposition is shorter in those with COPD than in controls [22]. In contrast, studies including measurements of diaphragm excursion during inspiration and expiration have reported more consistent results. Therefore, we decided to measure diaphragm excursion rather than thickness. Nonetheless, diaphragm thickness, thickness fraction, and other important indices should also be evaluated in future studies.
Scheibe et al. [23] showed a strong correlation between diaphragm mobility and forced expiratory volume in 1 s. Compared with healthy controls, COPD patients had reduced diaphragm mobility, which plays an important role in decreased exercise tolerance, DLH and increased dyspnoea in patients with COPD [4, 24]. Furthermore, DEmax was strongly associated with DLH [4]. Lung hyperinflation and the associated decrease in IC are closely related to the degree of breathlessness (dyspnoea) experienced by patients with COPD during physical activity. Moreover, therapeutic restoration of lung hyperinflation through improved IC has been shown to be associated with improved dyspnoea intensity and exercise endurance [25]. IMT was not beneficial for DLH as measured by ΔIC, against our hypothesis. However, IMT improved static IC, which may result in enhanced exercise endurance. Therefore, measurement of DEmax was prioritised in this study, on the hypothesis that improvement of diaphragm mobility could improve ventilatory capacity and DLH. Nonetheless, diaphragm thickness, another important index, should also be evaluated in a future study.
In this study, in addition to DEmax, IMT improved dyspnoea and exercise tolerance, as assessed by peak V˙O2 and ventilation volume. The mechanism by which IMT improves dyspnoea is unknown; however, Gosselink et al. [7] highlighted that the effects of IMT include a delay in respiratory muscle fatigue, redistribution of blood flow to the respiratory and locomotor muscles, and reduction in the perception of discomfort of the respiratory muscles. However, the additive effects of IMT on PR are questionable in parallel-designed programmes. Recent randomised controlled trials evaluating IMT did not identify a significant advantage of IMT in reducing dyspnoea in a programme conducting PR and IMT simultaneously compared with PR alone, despite a significantly higher improvement in PImax in the IMT group [11, 12]. A meta-analysis of randomised controlled trial studies [5] focused on IMT indicated that while IMT did not have an additive effect on PR, it did independently enhance dyspnoea outcomes as measured using the Borg scale at submaximal exercise capacity, transition dyspnoea index and mMRC scale. The discrepancy between the findings of previous studies and those of the current study is probably due to scheduling differences and overlapping effects on exercise tolerance between standard PR [26, 27] and IMT alone [17]. We conducted IMT after the initial standardised PR programme, and IMT was performed alone during the low-frequency and low-intensity maintenance PR programme (once every 2 weeks). This design schedule may be better for maximising the effects of IMT than parallel design programmes that conduct IMT and standardised PR simultaneously.
The effect of IMT on exercise tolerance is controversial and may vary depending on the assessment index used. Meta-analysis [5] showed that IMT alone without PR improved exercise tolerance, measured using 6MWD; however, it did not have an additive effect on PR in parallel design studies. In the current sequential design study, IMT did not improve 6MWD; however, it improved the exercise tolerance, measured as peak V̇O2. In this study, the ventilation volume during exercise (V̇E/V̇CO2 and peak VT/IC) increased in the IMT group, possibly due to an increase in VTI. IMT improved diaphragm function and inspiratory muscles and increased at least ΔʹIC at rest and VTI after exercise, with comparable increase in VTE. As a result, exercise tolerance may have improved, although DLH did not improve. Therefore, increased ventilation volume during exercise may have contributed to the improvement in exercise tolerance. This increased ventilation volume may be due to the improvement in DEmax leading to increased respiratory strength, as shown in studies on mechanically ventilated patients [28]. Such improvements likely contributed to reduced dyspnoea during exercise following the 12-week IMT programme and enhanced exercise tolerance.
Contrary to our hypothesis, IMT in patients with COPD had no benefit for DLH, as measured by ΔIC. We hypothesised that IMT might improve dyspnoea and exercise tolerance by addressing DLH, given its pivotal role in the pathophysiology of COPD [1], elevating ventilatory workload while diminishing the pressure-generating capacity of the inspiratory muscles. Furthermore, DEmax was strongly associated with DLH [4] with adequate prediction of the improvement in exercise tolerance after PR in patients with COPD [29]. As a potential mechanism underlying the improved dyspnoea and exercise tolerance after IMT without changing the DLH, improvement in breathing patterns, as discussed above, may play a role. Indeed, the strength of association with ΔDEmax was numerically greater for Δpeak VT/IC (r=0.73) than for ΔʹIC (r=0.37) in this study. Although further studies are required, the improved breathing patterns may prolong the time required to reach the DLH threshold.
One patient in this study experienced worsening dyspnoea due to overuse of the IMT device. Frequent instruction from a physiotherapist is necessary to maintain the IMT at home. However, the IMT can be performed without severe adverse events if the titration protocol is reliable.
A limitation of this study is that the sample size was relatively small and the study was conducted at a single institution, where patients' baseline conditions were relatively well preserved. However, this study is worth reporting as it demonstrates the importance of home-based IMT after a standardised PR programme for patients with COPD. Nonetheless, diaphragm thickness, another important index, should also be evaluated in a future study.
In conclusion, IMT after standardised PR improved DEmax associated with improvements in inspiratory muscle strength, exertional dyspnoea, CAT score and exercise tolerance. An improvement in DEmax may be an important outcome of IMT. In the future, a large-scale multicentre randomised controlled trial is warranted.
Supplementary material
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Supplementary material 00035-2024.supplement (621.3KB, pdf)
Footnotes
Provenance: Submitted article, peer reviewed.
This study is registered at https://www.umin.ac.jp/ctr/ with identifier number 000043099.
Ethics statement: This study was approved by the Ethics Committee of Kindai University School of Medicine (R04-192).
Conflict of interest: The authors have nothing to disclose.
Support statement: This work was supported by Grants-in-Aid for Scientific Research (22K17664). Funding information for this article has been deposited with the Crossref Funder Registry.
Data availability
The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy and/or ethical restrictions.
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Supplementary Materials
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Supplementary material 00035-2024.supplement (621.3KB, pdf)
Data Availability Statement
The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy and/or ethical restrictions.