Staging criteria for COPD (chronic obstructive pulmonary disease) include symptoms and lung function parameters, but the role of reduced inspiratory muscle strength related to disease severity remains unclear. Therefore the present study tested whether inspiratory muscle strength is reduced in COPD and is related to disease severity according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria and assessed its clinical impact. PImax (maximal inspiratory mouth occlusion pressure), SnPna (sniff nasal pressure) and TwPmo (twitch mouth pressure) following bilateral anterior magnetic phrenic nerve stimulation were assessed in 33 COPD patients (8 GOLD0, 6 GOLDI, 6 GOLDII, 7 GOLDIII and 6 GOLDIV) and in 28 matched controls. Furthermore, all participants performed a standardized 6 min walking test. In comparison with controls, PImax (11.6±2.5 compared with 7.3±3.0 kPa; P<0.001), SnPna (9.7±2.5 compared with 6.9±3.3 kPa; P<0.001) and TwPmo (1.6±0.6 compared with 0.8±0.4 kPa; P<0.001) were markedly lower in COPD patients. TwPmo decreased with increasing COPD stage. TwPmo was correlated with walking distance (r=0.75; P<0.001), dyspnoea (r=−0.61; P<0.001) and blood gas values following exercise (r>0.57; P<0.001). Inspiratory muscle strength, as reliably assessed by TwPmo, decreased with increasing severity of COPD and should be considered as an important factor in rating disease severity and to reflect burden in COPD.

INTRODUCTION

COPD (chronic obstructive pulmonary disease) is predicted to become the third most frequent cause of death in the world by 2020 [1]. Treatment guidance adapted to disease severity is rated following staging criteria according to several important guidelines, namely the American Thoracic Society, the European Respiratory Society and the British Thoracic Society as well as GOLD (the Global Initiative for Chronic Obstructive Lung Disease) [2]. Within these guidelines, disease severity is rated according to symptoms and FEV1 (forced expiratory volume in 1 s) only. However, it has been clearly pointed out that FEV1, although essential for diagnosis and disease progression, does not adequately reflect all symptomatic manifestations of COPD [3]. Furthermore, other factors such as BMI (body mass index), dyspnoea and exercise capacity have been indicated to be predictive for death, and this has been summarized in the BODE (BMI, Airflow Obstruction, Dyspnea, and Exercise Capacity) index [3].

In addition to these clinical parameters, inspiratory muscle strength, as assessed by the PImax (maximal inspiratory mouth occlusion pressure), has been shown to be an independent determinant of survival in COPD patients [4]. Moreover, hypercapnic respiratory failure following inspiratory muscle weakness [5] is suggested to be the leading cause of death in COPD patients [6], thus underlining the importance of reduced inspiratory muscle strength in the course of COPD. However, studies on respiratory muscle function have produced contradicting results [712], and impairments in inspiratory muscle strength have not been related to disease severity in any study. Therefore the present prospective study was aimed at testing whether inspiratory muscle strength is reduced in COPD and if it is related to disease severity according to GOLD criteria [13,14]. Finally, the clinical impact of reduced inspiratory muscle strength in COPD has been addressed.

MATERIALS AND METHODS

The protocol was approved by the Institutional Review Board for Human Studies of the Albert–Ludwigs University, Freiburg, Germany, and was performed in accordance with the ethical standards stated in the Declaration of Helsinki. Informed written consent was obtained from all participants.

Participants

Thirty-three male outpatients suffering from COPD according to GOLD guidelines [13,14] were studied. All patients included in the study were clinically stable with no episode of exacerbation in the 2 months preceding the study. Medication was provided according to GOLD guidelines [13,14]. None of the patients included in the study received oral steroids or suffered from malnutrition, but further selection was not performed to provide data on a representative collective of COPD patients. In addition, 28 healthy non-smoking men matched for age and BMI served as controls. All participants were naive to magnetic stimulation.

Lung function, blood gas analysis and exercise testing

Lung function parameters were measured immediately prior to tests on inspiratory muscle strength using body plethysmography (Masterlab-Compact®; Jaeger) according to the European Respiratory Society statement [15]. ITGV (intrathoracic gas volume) assessed during body plethysmography was used as the best available measure of FRC (functional residual capacity) in COPD patients [8]. A standardized 6 min walking test was performed with measurement of the 6MWD (6 min walking distance), dyspnoea was assessed by the BDS (Borg dyspnoea scale), and blood gas was analysed [16].

Pressure and airflow recordings

All airflow and pressure recordings were measured using the pneumotachograph ZAN 100 Flowhandy II® and the pressure transducer ZAN400®. PImax1.0 (PImax sustained for 1 s) was assessed at RV (residual volume) as described previously [17]. SnPna (sniff nasal pressure) was obtained at FRC based on previous recommendations [18]. TwPmo (twitch mouth pressure) was recorded during BAMPS (bilateral anterior magnetic phrenic nerve stimulation) (Magstim® 2002) [19,20]. Supramaximality of BAMPS has been reliably demonstrated in several previous studies and was therefore not re-tested in the current protocol [19,21,22]. A fully automated and controlled inspiratory pressure trigger was used at 0.5 kPa, as has been described previously [23,24]. Furthermore, TwPmo was corrected for lung volume (termed TwPmo-c), as TwPdi (twitch transdiaphragmatic pressure) decreases by 0.34 kPa/l above normal ITGV [8]. The ratio between TwPes (twitch oesophageal pressure) and TwPdi, and hence between TwPmo and TwPdi, is approx. 0.4 in COPD patients [8], given that TwPmo is virtually analogous to TwPes. However, since lung volume correction has been established for twitch pressures only, neither PImax nor SnPna pressures could be corrected for lung volume. To confirm adequacy of pressure transduction as demonstrated previously [24], in three COPD patients TwPes, TwPga (twitch gastric pressure) and TwPdi were measured using a thin conventional double-balloon catheter (ZAN) according to previous recommendations [25,26]. fb (breathing frequency), FRC and the ttrig-max (time between trigger impulse and pressure maximum of TwPmo) were automatically calculated. Ptrig (pressure during trigger impulse) and Ftrig (inspiratory flow during trigger impulse) were measured to control adherence to trigger criteria [23].

Statistical analysis

Statistical analysis was performed using Sigma-Stat® (Version 3.1; Systat Software). All normally distributed data are presented as means±S.D. An unpaired Student's t test was used when comparing two groups. When comparing more than two groups, one-way ANOVA was performed using the F-test. Pearson Product Moment Correlation was used for metric data. Linear regression analysis was performed when appropriate [27]. Bland and Altman analysis was used for agreement in method comparison [28]. A P value <0.05 was considered statistically significant.

RESULTS

To provide detailed information on disease severity, data on all single stages of COPD according to GOLD criteria are presented in Tables 1 and 2. However, these findings were purely descriptive. Further statistical analysis was performed summarizing early and advanced stages of COPD to ensure a reasonable number of cases. Therefore a group comparison was performed between control subjects, COPD0-II and COPDIII-IV only.

Table 1
Anthropometric data and lung function parameters in patients with COPD0-IV and controls

Values are expressed as means (S.D.). NS, not significant; %pred, percentage predicted; TLC, total lung capacity.

nAge (years)BMI (kg/m2)Smoking (pack years)FEV1 (%pred)FVC (%pred)FEV1/FVC (%)TLC (%pred)RV (%pred)ITGV (%pred)
Controls 28 52 (11) 26 (3) 0 (0) 105 (15) 105 (16) 81 (5) 97 (13) 106 (26) 86 (15) 
COPD0-IV 33 57 (13) 26 (4) 37 (26) 63 (31) 83 (29) 59 (14) 112 (16) 198 (94) 133 (47) 
P-value  NS NS <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 
COPD0-II 20 53 (13) 26 (4) 28 (20) 83 (19) 100 (18) 68 (9) 107 (13) 150 (44) 110 (29) 
COPDIII-IV 13 64 (10) 24 (5) 53 (29) 32 (13) 56 (21) 46 (7) 120 (16) 272 (104) 169 (47) 
P-value  0.02 NS 0.006 <0.001 <0.001 <0.001 0.02 <0.001 <0.001 
COPD0 46 (13) 27 (4) 19 (11) 100 (14) 108 (16) 77 (3) 106 (9) 123 (21) 97 (16) 
COPDI 60 (17) 27 (3) 20 (13) 83 (4) 108 (14) 63 (4) 112 (12) 158 (44) 118 (33) 
COPDII 55 (6) 26 (4) 46 (23) 60 (6) 82 (9) 62 (9) 103 (19) 179 (49) 121 (36) 
COPDIII 68 (8) 27 (3) 40 (20) 42 (6) 72 (12) 48 (7) 113 (7) 208 (31) 138 (12) 
COPDIV 60 (10) 21 (4) 67 (33) 20 (7) 38 (11) 43 (5) 129 (19) 346 (111) 205 (48) 
nAge (years)BMI (kg/m2)Smoking (pack years)FEV1 (%pred)FVC (%pred)FEV1/FVC (%)TLC (%pred)RV (%pred)ITGV (%pred)
Controls 28 52 (11) 26 (3) 0 (0) 105 (15) 105 (16) 81 (5) 97 (13) 106 (26) 86 (15) 
COPD0-IV 33 57 (13) 26 (4) 37 (26) 63 (31) 83 (29) 59 (14) 112 (16) 198 (94) 133 (47) 
P-value  NS NS <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 
COPD0-II 20 53 (13) 26 (4) 28 (20) 83 (19) 100 (18) 68 (9) 107 (13) 150 (44) 110 (29) 
COPDIII-IV 13 64 (10) 24 (5) 53 (29) 32 (13) 56 (21) 46 (7) 120 (16) 272 (104) 169 (47) 
P-value  0.02 NS 0.006 <0.001 <0.001 <0.001 0.02 <0.001 <0.001 
COPD0 46 (13) 27 (4) 19 (11) 100 (14) 108 (16) 77 (3) 106 (9) 123 (21) 97 (16) 
COPDI 60 (17) 27 (3) 20 (13) 83 (4) 108 (14) 63 (4) 112 (12) 158 (44) 118 (33) 
COPDII 55 (6) 26 (4) 46 (23) 60 (6) 82 (9) 62 (9) 103 (19) 179 (49) 121 (36) 
COPDIII 68 (8) 27 (3) 40 (20) 42 (6) 72 (12) 48 (7) 113 (7) 208 (31) 138 (12) 
COPDIV 60 (10) 21 (4) 67 (33) 20 (7) 38 (11) 43 (5) 129 (19) 346 (111) 205 (48) 
Table 2
Blood gas analysis and data from 6 min walking test in patients with COPD0-IV and controls

Values are expressed as means (S.D.). NS, not significant.

PaO2 (mmHg)PaCO2 (mmHg)pHSaO2 (%)
n6MWD (m)BDSRestExerciseRestExerciseRestExerciseRestExercise
Controls 28 624 (67) 0 (1) 81 (8) 85 (7) 37 (3) 37 (3) 7.42 (0.02) 7.40 (0.06) 95 (7) 96 (2) 
COPD0-IV 33 459 (136) 4 (3) 71 (12) 70 (14) 41 (8) 42 (11) 7.41 (0.02) 7.40 (0.03) 93 (6) 90 (7) 
P-value  <0.001 <0.001 <0.001 <0.001 NS NS NS NS <0.001 <0.001 
COPD0-II 20 541 (82) 2 (2) 75 (11) 78 (11) 37 (3) 37 (3) 7.42 (0.02) 7.41 (0.03) 93 (8) 94 (4) 
COPDIII-IV 13 338 (105) 7 (2) 66 (12) 58 (9) 46 (10) 51 (12) 7.40 (0.02) 7.38 (0.03) 93 (3) 84 (6) 
P-value  <0.001 <0.001 0.03 <0.001 <0.001 <0.001 0.03 0.004 NS <0.001 
COPD0 596 (73) 1 (2) 79 (7) 84 (8) 39 (2) 38 (3) 7.43 (0.01) 7.43 (0.02) 94 (4) 96 (2) 
COPDI 503 (87) 1 (1) 80 (10) 80 (9) 35 (3) 36 (3) 7.42 (0.03) 7.40 (0.03) 91 (13) 96 (1) 
COPDII 500 (38) 4 (2) 63 (7) 65 (9) 35 (2) 35 (3) 7.42 (0.03) 7.40 (0.03) 93 (3) 90 (6) 
COPDIII 388 (105) 7 (2) 70 (11) 61 (9) 40 (2) 45 (8) 7.40 (0.02) 7.37 (0.04) 93 (2) 85 (4) 
COPDIV 279 (75) 7 (3) 61 (12) 54 (9) 54 (11) 58 (12) 7.40 (0.02) 7.39 (0.03) 94 (4) 83 (7) 
PaO2 (mmHg)PaCO2 (mmHg)pHSaO2 (%)
n6MWD (m)BDSRestExerciseRestExerciseRestExerciseRestExercise
Controls 28 624 (67) 0 (1) 81 (8) 85 (7) 37 (3) 37 (3) 7.42 (0.02) 7.40 (0.06) 95 (7) 96 (2) 
COPD0-IV 33 459 (136) 4 (3) 71 (12) 70 (14) 41 (8) 42 (11) 7.41 (0.02) 7.40 (0.03) 93 (6) 90 (7) 
P-value  <0.001 <0.001 <0.001 <0.001 NS NS NS NS <0.001 <0.001 
COPD0-II 20 541 (82) 2 (2) 75 (11) 78 (11) 37 (3) 37 (3) 7.42 (0.02) 7.41 (0.03) 93 (8) 94 (4) 
COPDIII-IV 13 338 (105) 7 (2) 66 (12) 58 (9) 46 (10) 51 (12) 7.40 (0.02) 7.38 (0.03) 93 (3) 84 (6) 
P-value  <0.001 <0.001 0.03 <0.001 <0.001 <0.001 0.03 0.004 NS <0.001 
COPD0 596 (73) 1 (2) 79 (7) 84 (8) 39 (2) 38 (3) 7.43 (0.01) 7.43 (0.02) 94 (4) 96 (2) 
COPDI 503 (87) 1 (1) 80 (10) 80 (9) 35 (3) 36 (3) 7.42 (0.03) 7.40 (0.03) 91 (13) 96 (1) 
COPDII 500 (38) 4 (2) 63 (7) 65 (9) 35 (2) 35 (3) 7.42 (0.03) 7.40 (0.03) 93 (3) 90 (6) 
COPDIII 388 (105) 7 (2) 70 (11) 61 (9) 40 (2) 45 (8) 7.40 (0.02) 7.37 (0.04) 93 (2) 85 (4) 
COPDIV 279 (75) 7 (3) 61 (12) 54 (9) 54 (11) 58 (12) 7.40 (0.02) 7.39 (0.03) 94 (4) 83 (7) 

Anthropometric data and lung function parameters are presented in Table 1. Results of the 6 min walking test and blood gas values are given in Table 2. All COPD patients clearly stated that their exercise capacity was limited by dyspnoea and not by skeletal muscle exhaustion or weakness of the legs. Volitional (PImax1.0 and SnPna) and non-volitional (TwPmo) tests on inspiratory muscle strength and corresponding data are shown in Table 3. TwPmo was assessed sufficiently in all patients and in 21 controls. Six controls declined magnetic stimulation and two controls declined sniff manoeuvres. In one control subject the generated pressure–time curves did not meet the requirements of previously published criteria [23,24]. Values for TwPmo in COPD patients and controls are shown in Figure 1. TwPmo-c values are shown in Figure 2. Correlation analysis between tests on inspiratory muscle strength, lung function parameters and the 6 min walking test with correlation coefficients exceeding 0.55 are shown in Table 4. TwPmo-c did not correlate with any of these parameters. In addition, multiple linear regression analysis revealed that FEV1 (P=0.15), FEV1/FVC (forced vital capacity) (P=0.25) nor TwPmo (P=0.07) were significant predictors for 6MWD, although TwPmo almost reached statistical significance.

Table 3
Tests on inspiratory muscle strength and corresponding data in patients with COPD0-IV and controls

Values are expressed as means (S.D.). NS, not significant. *n=26; †n=21.

nPImax1.0 (kPa)SnPna (kPa)TwPmo (kPa)TwPmo-c (kPa)ttrig-max (ms)Ftrig (ml/s)Ptrig (kPa)
Controls 28 11.6 (2.5) 9.7 (2.5)* 1.6 (0.6)† 1.6 (0.6)† 183 (30)† 34 (20)† 0.5 (0.0)† 
COPD0-IV 33 7.3 (3.0) 6.9 (3.3) 0.8 (0.4) 1.0 (0.3) 183 (53) 43 (20) 0.5 (0.1) 
P-value  <0.001 <0.001 <0.001 <0.001 NS 0.03 NS 
COPD0-II 20 8.1 (3.0) 8.2 (3.3) 1.0 (0.3) 1.1 (0.3) 195 (55) 45 (23) 0.5 (0.1) 
COPDIII-IV 13 6.2 (2.7) 4.9 (1.9) 0.5 (0.4) 0.9 (0.3) 165 (48) 41 (16) 0.5 (0.0) 
P-value  NS 0.003 <0.001 NS NS NS NS 
COPD0 10.0 (2.8) 10.5 (3.8) 1.2 (0.2) 1.2 (0.2) 178 (34) 48 (22) 0.5 (0.1) 
COPDI 7.0 (2.0) 6.6 (2.1) 1.1 (0.2) 1.2 (0.3) 190 (72) 38 (16) 0.5 (0.0) 
COPDII 6.6 (2.9) 6.6 (1.2) 0.7 (0.3) 0.8 (0.4) 224 (55) 48 (31) 0.5 (0.0) 
COPDIII 7.6 (2.6) 6.2 (1.5) 0.7 (0.4) 0.9 (0.4) 185 (44) 43 (17) 0.5 (0.0) 
COPDIV 4.6 (1.8) 3.3 (1.1) 0.3 (0.1) 0.8 (0.2) 141 (44) 39 (15) 0.5 (0.0) 
nPImax1.0 (kPa)SnPna (kPa)TwPmo (kPa)TwPmo-c (kPa)ttrig-max (ms)Ftrig (ml/s)Ptrig (kPa)
Controls 28 11.6 (2.5) 9.7 (2.5)* 1.6 (0.6)† 1.6 (0.6)† 183 (30)† 34 (20)† 0.5 (0.0)† 
COPD0-IV 33 7.3 (3.0) 6.9 (3.3) 0.8 (0.4) 1.0 (0.3) 183 (53) 43 (20) 0.5 (0.1) 
P-value  <0.001 <0.001 <0.001 <0.001 NS 0.03 NS 
COPD0-II 20 8.1 (3.0) 8.2 (3.3) 1.0 (0.3) 1.1 (0.3) 195 (55) 45 (23) 0.5 (0.1) 
COPDIII-IV 13 6.2 (2.7) 4.9 (1.9) 0.5 (0.4) 0.9 (0.3) 165 (48) 41 (16) 0.5 (0.0) 
P-value  NS 0.003 <0.001 NS NS NS NS 
COPD0 10.0 (2.8) 10.5 (3.8) 1.2 (0.2) 1.2 (0.2) 178 (34) 48 (22) 0.5 (0.1) 
COPDI 7.0 (2.0) 6.6 (2.1) 1.1 (0.2) 1.2 (0.3) 190 (72) 38 (16) 0.5 (0.0) 
COPDII 6.6 (2.9) 6.6 (1.2) 0.7 (0.3) 0.8 (0.4) 224 (55) 48 (31) 0.5 (0.0) 
COPDIII 7.6 (2.6) 6.2 (1.5) 0.7 (0.4) 0.9 (0.4) 185 (44) 43 (17) 0.5 (0.0) 
COPDIV 4.6 (1.8) 3.3 (1.1) 0.3 (0.1) 0.8 (0.2) 141 (44) 39 (15) 0.5 (0.0) 

Box plots for TwPmo in patients with COPD0-II, COPDIII-IV and controls

Figure 1
Box plots for TwPmo in patients with COPD0-II, COPDIII-IV and controls
Figure 1
Box plots for TwPmo in patients with COPD0-II, COPDIII-IV and controls

Box plots for TwPmo-c in patients with COPD0-II, COPDIII-IV and controls

Figure 2
Box plots for TwPmo-c in patients with COPD0-II, COPDIII-IV and controls

TwPmo in controls was not corrected because lung volumes did not exceed normal intrathoracic gas volume.

Figure 2
Box plots for TwPmo-c in patients with COPD0-II, COPDIII-IV and controls

TwPmo in controls was not corrected because lung volumes did not exceed normal intrathoracic gas volume.

Table 4
Correlations between tests on inspiratory muscle strength and relevant parameters in patients with COPD0-IV

Values are expressed as correlation coefficients and P-values. TwPmo-c revealed no correlation with any of the parameters in the Table. - represents correlation coefficients not exceeding 0.55 (which are considered not to be meaningful) or non-significant correlations with P≥0.05.

PImax1.0 correlationP-valueSnPna correlationP-valueTwPmo correlationP-value
Pack years −0.66 <0.001 
FEV1 0.59 <0.001 0.78 <0.001 0.76 <0.001 
FEV1/FVC 0.70 <0.001 0.68 <0.001 
RV −0.63 0.01 −0.67 <0.001 
ITGV −0.59 <0.001 −0.61 <0.001 
6MWD 0.64 <0.001 0.72 <0.001 0.75 <0.001 
BDS −0.63 <0.001 −0.61 <0.001 
PaO2 exercise 0.64 <0.001 0.66 <0.001 
PaCO2 exercise −0.57 <0.001 
SaO2 exercise 0.58 <0.001 
PImax1.0   0.77 <0.001 0.56 0.007 
SnPna 0.77 <0.001   0.68 <0.001 
TwPmo 0.56 0.007 0.68 <0.001   
TwPmo-c 
PImax1.0 correlationP-valueSnPna correlationP-valueTwPmo correlationP-value
Pack years −0.66 <0.001 
FEV1 0.59 <0.001 0.78 <0.001 0.76 <0.001 
FEV1/FVC 0.70 <0.001 0.68 <0.001 
RV −0.63 0.01 −0.67 <0.001 
ITGV −0.59 <0.001 −0.61 <0.001 
6MWD 0.64 <0.001 0.72 <0.001 0.75 <0.001 
BDS −0.63 <0.001 −0.61 <0.001 
PaO2 exercise 0.64 <0.001 0.66 <0.001 
PaCO2 exercise −0.57 <0.001 
SaO2 exercise 0.58 <0.001 
PImax1.0   0.77 <0.001 0.56 0.007 
SnPna 0.77 <0.001   0.68 <0.001 
TwPmo 0.56 0.007 0.68 <0.001   
TwPmo-c 

Mean PImax1.0 (4.8±1.7 kPa), mean SnPna (3.6±1.2 kPa) and mean TwPmo (0.3±0.2 kPa) were significantly lower in COPD patients with a PaCO2 (arterial partial pressure of CO2) ≥43 mmHg (n=7), when compared with mean PImax1.0 (8.0±2.9 kPa), mean SnPna (7.8±3.1 kPa) and mean TwPmo (1.0±0.4 kPa) in those with a PaCO2 <43 mmHg (n=26; P<0.01 in all instances).

Considering all single-twitch replies (n=9), in three COPD patients (GOLD stage I, III and III), mean TwPes was 1.0±0.4 kPa, mean TwPga was −0.9±0.1 kPa and mean TwPdi was 1.7±0.7 kPa. Regression analysis and Bland and Altman analysis was performed to evaluate correct pressure transduction for TwPmo in COPD patients only. No further conclusions were drawn from these results, since the sample size was too small. Regression analysis revealed a very close relationship between TwPmo and TwPes (r=0.98; P<0.0001). The mean of the difference between TwPmo and TwPes (bias) was 0.03 kPa and the limits of agreement (bias ±2 S.D.) ranged from −0.19 to 0.24 kPa.

DISCUSSION

The present study is the first to investigate inspiratory muscle strength in a representative collective of male COPD patients depending on disease severity according to GOLD criteria [13,14]. The major finding is that inspiratory muscle strength decreases with increasing disease severity. Even in patients with mild-to-moderate COPD, inspiratory muscle strength was markedly reduced compared with healthy matched controls. Interestingly, laboratory studies have shown that reduced muscle fibre strength compromising diaphragmatic contractility and reduced passive tension generation are present even in patients with mild-to-moderate COPD [1012]. Therefore the present clinical study confirms these laboratory investigations.

However, this finding is in contrast with previous clinical studies where reduced inspiratory muscle strength in COPD was solely attributed to reduced diaphragmatic force generation induced by hyperinflation, rather than compromised diaphragmatic contractility. This was based on the observation that the measured inspiratory muscle strength was suggested not to be reduced when retrospectively corrected for lung volume [8,2932]. However, only COPD patients with severe to very severe disease were included in these studies, and the stages of disease were not addressed. Furthermore, the present study indicates that inspiratory muscle strength is still reduced even after correction for lung volume. This is supported by the observation that hyperinflation is insufficient in predicting inspiratory muscle strength [8]. Moreover, inspiratory muscle strength was substantially lost, even early in the course of the disease when hyperinflation was not significantly detectable. Therefore mechanisms other than hyperinflation must be responsible for reduced inspiratory muscle strength in mild-to-moderate COPD. In the present study, further reduction in inspiratory muscle strength in severe to very severe stages was observed if TwPmo was not corrected for lung volume. In contrast, when TwPmo was corrected for lung volume there was still a marked reduction in TwPmo in all COPD patients compared with controls, but no significant difference could be detected between early and advanced COPD stages. Therefore two mechanisms are proposed to be responsible for reduced inspiratory muscle strength in COPD. First, reduced diaphragmatic contractility beginning in early stages of the disease that is independent of hyperinflation; and secondly, reduced diaphragmatic force generation due to hyperinflation in severe to very severe disease stages only.

There is one major reason suggested to be responsible for the discrepancies discussed above: inspiratory muscle strength was assessed using TwPmo in the present study, but TwPdi was used in previous studies [8,30,33]. However, TwPdi is likely to overestimate intrathoracic pressure generation due to an increasing gastric pressure component in patients with increasing hyperinflation [8,33]. Since intrathoracic (and not gastric) pressure generation is the clinically relevant part of diaphragm contractility [8], methods that exclusively assess intrathoracic pressure are suggested to be more suitable in rating inspiratory muscle strength when hyperinflation is present.

A point of criticism might be that group comparison is hindered by the fact that there is a statistical difference in age regarding controls and patients with COPDIII-IV. Diaphragm strength is known to be slightly reduced in the elderly [34]. However, this reduction occurred when comparing a difference in mean age of 44 years and was considered not to be of functional importance [34]. In addition, a marked reduction in inspiratory muscle strength was observed in patients with COPD0-II as outlined above. As this group had no difference in age compared with controls, findings on reduced inspiratory muscle strength are suggested not to be confused by poorly matched groups. It might be argued that TwPmo, as used in the present study, does not reliably assess intrathoracic pressure generation due to an elevated airway time constant in COPD [35,36]. This could lead to a dampened and delayed TwPmo compared with TwPes when measured at relaxed FRC [7]. Nonetheless, it has been clearly shown that gentle inspiratory efforts can markedly reduce the time constant in healthy subjects [37] and in COPD patients, thus enabling the adequate measurement of TwPmo in COPD [7]. Moreover, a fully automated and controlled inspiratory pressure trigger was used in the present study. Therefore a time-delayed pressure transduction could be avoided, as indicated by a ttrig-max that was non-delayed in COPD patients compared with controls. Additionally, the relationship between TwPmo and TwPes was very close to acceptable limits of agreement in the three COPD patients measured with enteral balloon catheters. At this point it has to be clearly stated that these findings can only be used as an indicator since the sample size was too small to generalize these results. Future studies on a representative collection of COPD patients are needed to confirm these findings. Nevertheless, we would suggest that intrathoracic pressure generation was reliably assessed by the measurement of TwPmo.

This suggestion is strongly supported by the fact that important clinical parameters such as 6MWD, dyspnoea and blood gas values were significantly correlated with inspiratory muscle strength. Therefore decreased inspiratory muscle strength is suggested to provide a substantial burden for COPD patients. This has only been demonstrated when using TwPmo, thus underlining the importance of non-volitional tests for the assessment of inspiratory muscle strength [32]. However, 6MWD could not be predicted when considering both lung function parameters and TwPmo. This indicates that there is a complex interaction between these important variables with regard to exercise limitation in COPD. Moreover, the relationship between inspiratory muscle strength and endurance in COPD patients was not assessed in the present study, and this should be investigated in future studies. In addition, it has been shown that hypercapnic respiratory failure due to inspiratory muscle weakness is the leading cause of death in patients suffering from COPD [5,6]. In accordance with previous observations [8], TwPmo was significantly lower in patients with a PaCO2 ≥43 mmHg compared with those with PaCO2 <43 mmHg. This again underlines the important role of a reduction in respiratory muscle strength.

In conclusion, inspiratory muscle strength decreases in COPD patients with increasing disease severity, as rated by GOLD criteria. Two mechanisms are proposed to be responsible for this: compromised diaphragmatic contractility beginning in early disease stages, and further reduction in inspiratory muscle strength following hyperinflation in advanced COPD. Reduced inspiratory muscle strength is related to several important clinical parameters such as exercise capacity, dyspnoea and gas exchange. However, the importance of reduced respiratory muscle strength compared with impaired lung function with regard to exercise limitation needs further investigation. Nevertheless, impaired inspiratory muscle function is suggested to provide a substantial burden for COPD patients. Therefore inspiratory muscle strength as assessed by PImax, SnPna and TwPmo should be considered as an important factor to rate disease severity and to reflect disability in COPD.

Abbreviations

     
  • BAMPS

    bilateral anterior magnetic phrenic nerve stimulation

  •  
  • BDS

    Borg Dyspnoea Scale

  •  
  • BMI

    body mass index

  •  
  • COPD

    chronic obstructive pulmonary disease

  •  
  • FEV1

    forced expiratory volume in 1 s

  •  
  • FRC

    functional residual capacity

  •  
  • Ftrig

    inspiratory flow at triggering

  •  
  • FVC

    forced vital capacity

  •  
  • GOLD

    Global Initiative for Chronic Obstructive Lung Disease

  •  
  • ITGV

    intrathoracic gas volume

  •  
  • 6MWD

    6 min walking distance

  •  
  • PaCO2

    arterial partial pressure of CO2

  •  
  • PImax

    maximal inspiratory mouth occlusion pressure

  •  
  • PImax1.0

    PImax sustained for 1 s

  •  
  • Ptrig

    pressure at triggering

  •  
  • RV

    residual volume

  •  
  • SnPna

    sniff nasal pressure

  •  
  • TwPdi

    twitch transdiaphragmatic pressure

  •  
  • TwPes

    twitch oesophageal pressure

  •  
  • TwPga

    twitch gastric pressure

  •  
  • TwPmo

    twitch mouth pressure

  •  
  • TwPmo-c

    TwPmo corrected for lung volume

  •  
  • ttrig-max

    time between trigger impulse and pressure maximum of twitch mouth pressure

We thank Roland Merklein (ZAN) for software assistance and technical advice.

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Author notes

1

Both authors contributed equally to this work.