influence of diaphragmatic mobility on exercise tolerance and dyspnea in patients with copd
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Respiratory Medicine (2007) 101, 2113–2118
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Influence of diaphragmatic mobility on exercisetolerance and dyspnea in patients with COPD
E. Paulina,b, W.P.S. Yamagutib, M.C. Chammasc, S. Shibaoc, R. Stelmachd,A. Cukierd, C.R.F. Carvalhob,�
aDepartment of Physical Therapy, Paranaense University, Prac-a Mascarenhas de Moras s/n, 87502-210 Umuarama, PR, BrazilbDepartment of Physical Therapy, University of Sao Paulo School of Medicine, Av. Dr. Arnaldo 455,05408-040 Sao Paulo, SP, BrazilcRadiology Department, University of Sao Paulo School of Medicine, Av. Dr. Eneas de Carvalho Aguiar s/n,01246-903 Sao Paulo, SP, BrazildDepartment of Respiratory Medicine, University of Sao Paulo School of Medicine, Av. Dr. Eneas de Carvalho Aguiar s/n,05403-000 Sao Paulo, SP, Brazil
Received 9 November 2006; accepted 24 May 2007Available online 20 July 2007
KEYWORDSUltrasonography;COPD;Diaphragm;Dyspnea;Exercise;Lung function
nt matter & 20072007.05.024
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SummaryBackground: Patients with chronic obstructive pulmonary disease (COPD) presentincreased airway resistance, air trapping, pulmonary hyperinflation, and diaphragmmuscle alterations, all of which affect pulmonary mechanics.Purpose: To evaluate the influence diaphragmatic mobility has on exercise tolerance anddyspnea in patients with COPD.Materials and methods: Fifty-four COPD patients with lung hyperinflation were evaluatedto assess pulmonary function, diaphragm mobility, exercise tolerance, and dyspnea(score). Twenty healthy (age- and body mass index-matched) subjects were evaluated ascontrols.Results: The COPD patients presented lower diaphragmatic mobility than did the controls(36.27710.96mm vs. 46.3379.46mm). Diaphragmatic mobility presented a linearcorrelation with distance covered on the 6-min walk test (6MWT) (r ¼ 0.38; p ¼ 0.005)and a negative correlation with dyspnea (r ¼ �0.36; p ¼ 0.007). Patients were thendivided into two subgroups based on the degree of diaphragmatic mobility: G1(p33.99mm) and G2 (X34mm). Those in G1 presented poorer 6MWT performance andgreater dyspnea upon exertion than did those in G2 (distance covered on the 6MWT:454.767100.67m vs. 521.63770.82m; dyspnea score: 5.2273.06 vs. 3.4872.77). The G1patients also presented greater residual volume (in liters) and lower maximal voluntary
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ventilation (in % of predicted values) than did the G2 patients (266.20755.30 vs.209.74748.49 and 39.00714.94 vs. 58.11720.96).Conclusion: Diaphragmatic mobility influences dyspnea and exercise tolerance in patientswith COPD.& 2007 Elsevier Ltd. All rights reserved.
Introduction
Chronic obstructive pulmonary disease (COPD) is character-ized by progressive obstruction of the airways that ispartially irreversible.1 Patients with COPD commonly pre-sent increased airflow resistance as well as air trapping andpulmonary hyperinflation. The hyperinflation alters thechest wall, putting the respiratory muscles at a mechanicaldisadvantage2,3 and thereby increasing respiratory drive andthe sensation of dyspnea.4 In addition, to prevent dyspnea,COPD patients reduce their activities of daily living, whichleads to social isolation, depression, anxiety, and loss ofphysical conditioning,5 as well as having a negative effect ontheir quality of life.6
Forced expiratory volume in 1 s (FEV1) is the mostcommonly used parameter to establish the severity ofpulmonary impairment and disease progression.1,7,8 How-ever, some studies have suggested that FEV1 does notadequately reflect the clinical manifestations of thedisease9,10 and is only weakly associated with the severityof dyspnea,11,12 health-related quality of life,13 and theability to perform activities of daily living.9 In addition, FEV1does not serve to be a predictor of mortality in COPDpatients.12,14
Pulmonary hyperinflation has been correlated withadaptation of the diaphragm muscle,15–17 in which thecapacity of the muscle to generate power is maintained butits displacement is reduced.18 The importance of thediaphragm in the lung mechanics associated with hyperin-flation has been the subject of ever-increasing discussionowing to widespread use of lung volume reduction surgery,19
which increases the range of movement for the diaphragmmuscle.20,21 However, to date, the relationship betweendiaphragmatic mobility and functional capacity remainsunknown for COPD patients.
The objective of the present study was to evaluate theinfluence of diaphragmatic mobility on exercise toleranceand dyspnea in patients with COPD.
Participants and methods
Subjects
Sixty patients with moderate or severe COPD were evalu-ated. The COPD diagnosis was based on the criteriaestablished by the American Thoracic Society.7 All patientswere clinically stable (no respiratory crises or hospitaliza-tions within the 30 days preceding the study outset) andwere receiving optimized clinical medical treatment.Patients suffering from other cardiorespiratory diseases orbeing oxygen-dependent for any reason were excluded, aswere patients presenting a body mass index (BMI) 430kg/m2
(classified as obese) or o18.5 kg/m2 (classified as under-weight). Patients presenting other respiratory diseasesor pleural scars on chest X-rays were also excluded.Twenty healthy, gender-, age-, and BMI-matched indivi-duals, none of whom presented any musculoskeletaldiseases or had a history of respiratory disease, were usedas controls. Anthropometric characteristics and pulmonaryfunction values for COPD patients and healthy subjects areshown in Table 1. The study was approved by the EthicsCommittee and all participants gave written informedconsent.
Pulmonary function tests
Spirometry and whole-body plethysmography were per-formed using standard equipment (GS II Pulmonary FunctionTesting System; Collins, Braintree, MA), including constantvolume body plethysmography, according to AmericanThoracic Society standards.7 The parameters measuredwere total lung capacity (TLC), functional residual capacity(FRC), inspiratory capacity (IC), residual volume (RV), FEV1,forced vital capacity (FVC), and airway resistance. Staticlung volumes are expressed as percentages of the predictedvalues calculated.22 In order to measure FEV1, dynamic lungvolumes, and maximal expiratory flows, a volume displace-ment spirometer (GS II; Collins, Braintree, MA, USA) wasused. Reported spirometry results were based on the bestcurve from three maneuvers and are presented as percen-tage of predicted according to Knudson et al.23 Predictedvalues of airway resistance were according to Clausen andZarnins.24
Diaphragmatic mobility
The subjects were evaluated in order to assess craniocaudaldisplacement of the intrahepatic branches of the portal veinusing an ultrasound scanner (Logiq 500, Pro Series;GE Medical Systems Milwaukee, WI) in mode B.25 Thepatients were evaluated in the dorsal decubitus position,using a 3.5-MHz convex transducer positioned over theright subcostal region, at an angle of incidence perpendi-cular to the craniocaudal axis. Initially, the majorleft branch of the portal vein was identified in the fieldof vision. This branch was identified in all the subjects.The position of the left portal vein or one of its brancheswas marked with a cursor at the end of forced expirationsand inspirations. The craniocaudal displacement wascalculated by measuring the distance, in millimeters,between these two points. Three measurements wererecorded for each subject, and the greatest value was usedfor analysis.
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Table 1 Characteristics of the study COPD patients and healthy subjects.
COPD patients (n ¼ 54) Healthy subjects (n ¼ 20) p
Gender (M:F) 42:12 16:4Age (years) 62.1578.06 58.3876.52 0.09BMI (kg/m2) 25.7874.40 26.4672.23 0.25
FEV1 (liters) 1.2470.50 3.2870.53 o0.001�
(% of predicted) 49.48718.00 125.91716.68 o0.000�
FVC (liters) 2.7370.83 4.1670.74 o0.001�
(% of predicted) 82.61721.74 125.09719.32 o0.000�
TLC (liters) 7.4071.41 6.4070.92 o0.000�
(% of predicted) 140.26715.80 121.1879.84 o0.000�
IC (liters) 2.1770.62 3.2670.53 o0.000�
(% of predicted) 94.78721.60 140.64726.23 o0.000�
RV (liters) 4.5471.18 2.3770.32 o0.000�
(% of predicted) 235.54758.46 124.6479.55 o0.000�
Data are presented as mean7SD. BMI: body mass index; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; TLC: totallung capacity; IC: inspiratory capacity; RV: residual volume.�po0.05.
Diaphragmatic mobility in patients with COPD 2115
Six-minute walk test
A six-minute walk test (6MWT) was carried out in a 30m longcorridor. Subjects were instructed to walk from end to endof the corridor and to cover the greatest distance possible inthe six minutes allotted. Patients who stopped walkingduring the test and needed a rest due to dyspnea wereinstructed to continue walking as soon as they felt able, butthe timer was not stopped. The subjects received verbalencouragement once every minute. Heart rate, respiratoryrate, peripheral oxygen saturation, and subjective dyspneascore (modified Borg scale) were determined before andafter each test.26 Two tests were performed, 1 h apart, andthe greatest distance covered on the 6MWTwas recorded asthe baseline value.27
Dyspnea
As mentioned above, dyspnea was assessed before and aftereach 6MWT using the modified Borg scale.26 Scores denotethe intensity of the dyspnea, ranging from 0 (no dyspnea) to10 (extremely intense dyspnea).
Statistical analysis
Data are expressed as mean7standard deviation. Kolmogorov–
Smirnov and Levene tests were used to analyze the normal-ity and homogeneity of variance. Correlations betweendiaphragmatic mobility and other parameters were assessedusing Spearman’s correlation test. Patients were allocatedto one of two subgroups according to diaphragmaticmobility, based on the median value: G1 (lower diaphrag-matic mobility, p33.99mm); and G2 (higher diaphragmaticmobility, X34mm). The Student’s t-test for paired datawas used to compare the difference of values obtained in
each group and the Mann–Whitney test was used forunpaired data. The level of statistical significance was setat po0.05.
Results
Out of a total of 60 COPD patients, 6 were excluded forpresenting an unstable clinical status. The mean age of thepatients was 62.1578.06 years, they were predominantly(77.7%) male, and the mean BMI was 25.7874.4 kg/m2. Allof the patients presented airflow limitation (mean FEV1/FVC ¼ 59.48714.25%) and pulmonary hyperinflation(TLC ¼ 140.26715.8% of predicted). Control subjects pre-sented similar anthropometric characteristics which areshown, together with the pulmonary function values forboth groups, in Table 1.
The COPD patients presented less diaphragmatic mobilitythan did the controls (36.27710.96mm vs. 46.3379.46mm). The COPD patients also covered shorter distancesin the 6MWT (492.07791.54m vs. 592.38742.62m). Dia-phragmatic mobility was found to correlate with RV(r ¼ �0.60; po0.000), IC (r ¼ 0.41; p ¼ 0.002), the RV/TLC ratio (r ¼ �0.72; po0.000), and the IC/TLC ratio(r ¼ 0.55; po0.000, Figure 1). Diaphragmatic mobilityalso correlated significantly with performance on the6MWT (r ¼ 0.38; p ¼ 0.005) and dyspnea score (r ¼ �0.36;p ¼ 0.007).
As can be seen in Table 2, patients in the G1 and G2subgroups presented similar values of pulmonary hyperin-flation, which was determined by calculating the percentageof predicted TLC (143.64717.24% vs. 137.67714.40%).However, patients in G1 presented greater air trapping(expressed as percentage of predicted RV) and lowermaximal voluntary ventilation (percentage of predicted)than did those in G2 (266.20755.30% vs. 209.74748.49%;
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0.00
0.20
0.40
0.60
0.80
1.00
1.20
0 10 20 30 40 50 60 70 80
Diaphragmatic mobility (mm)
IC/T
LC
(%
of
pre
dic
ted
)
r=0.55
Figure 1 Relationship between IC/TLC and diaphragmatic mobility in COPD patients.
Table 2 Average values of pulmonary function, capacity of exercise and dyspnea in the groups of patients with COPD.
Group with lesser mobility (G1)(n ¼ 26)
Group with greater mobility (G2)(n ¼ 28)
MVV (% of predicted) 39.00714.94 58.11720.96�
RV (% of predicted) 266.20755.30 209.74748.49�
TLC (% of predicted) 143.64717.24 137.67714.40IC (% of predicted) 86.76721.73 101.07717.77�
6MWT 454.767100.67 521.63770.82�
Borg initial 1.3671.28 1.2671.39Borg final 5.2273.06 3.4872.77�
Data are presented as mean7SD. MVV: maximal voluntary ventilation; RV: residual volume; TLC: total lung capacity; IC: inspiratorycapacity; 6MWT: 6-min walk test; G1: group with lesser diaphragm mobility; G2: group with greater diaphragm mobility.�po0.05 in comparison with G1.
E. Paulin et al.2116
and 39.00714.94% vs. 58.11720.96%, respectively). Pa-tients in G1 performed more poorly on the 6MWT than didthose in G2 (454.767100.67m vs. 521.63770.82m). Table 2also shows that dyspnea score at rest was similar in bothgroups (1.3671.28 and 1.2671.39, respectively). However,dyspnea score upon exertion was higher in G1 than in G2(5.2273.06 vs. 3.4872.77).
Discussion
Our data show that reduced diaphragmatic mobility isassociated with a reduction in physical and ventilatorycapacities as well as with an increase in dyspnea uponexertion in COPD patients. In addition, our results lendcredence to previous findings showing that COPD patientspresent reduced diaphragmatic mobility.
The loss of diaphragmatic mobility observed in our studyis similar to that reported in previous studies.16,17,28 There isevidence that, in COPD patients presenting hyperinflation,the diaphragm is the muscle most affected, shortening by40%,29,30 in contrast with the intercostal muscles, whichshorten by only 7%.31 The reduced respiratory musclemobility observed in COPD patients might be attributableto excessive actin–myosin filament overlap,32 sarcomereremodeling,33 or both. The main cause of the reduction in
diaphragmatic mobility is shortening of the apposition zoneresulting from the absence of the piston-like movement ofthe diaphragm.34 The reduced diaphragmatic mobilityobserved in the present study cannot be attributed tofactors such as pulmonary fibrosis, pleural scarring or otherlung diseases, since patients presenting such conditionswere excluded.
Based on Laplace’s law,35 it is widely accepted thatpulmonary hyperinflation leads to diaphragmatic mechan-ical disadvantage. In the present study, COPD patientspresented a wide range of diaphragmatic mobility(20.3�71.8mm) suggesting that the extent of alterationsin the diaphragm muscle varies even among patientspresenting the same degree of hyperinflation. Whenpatients were divided into two subgroups according to therange of diaphragmatic movement (higher and lowermobility), it was observed that both groups presented thesame degree of pulmonary hyperinflation. Our resultssuggest that the reduction in diaphragmatic mobility inCOPD patients occurs mainly due to air trapping and is notinfluenced by pulmonary hyperinflation. Clinically, thereduction in diaphragmatic mobility is related to the volumeof air a patient can exhale, rather than to the volume thatthe patient can inhale.
In the present study, the COPD patients who presentedlower diaphragmatic mobility also presented greater air
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Diaphragmatic mobility in patients with COPD 2117
trapping, suggesting that diaphragmatic mobility is asso-ciated with air trapping but not with pulmonary hyperinfla-tion. The impact of diaphragmatic mobility on functionalcapacity of COPD patients is yet to be determined. Ourresults show, for the first time, a positive correlationbetween exercise tolerance and diaphragmatic mobility.Interestingly, the patients presenting lower diaphragmaticmobility also demonstrated lower exercise tolerance, mostlikely due to diaphragmatic mechanical disadvantage, whichhampers ventilation,36 as evidenced by their poor perfor-mance on the 6MWT. Impaired ventilation, possibly resultingfrom air trapping, rectifies the diaphragm in COPD patients,2
alters the length/tension ratio of the muscle, and conse-quently its function, thereby hindering the ventilatoryresponse, especially during physical exertion.37 Thesediaphragmatic alterations might explain the fact that weidentified, within our sample, a group of patients presentingreduced diaphragmatic mobility, greater air trapping, andincreased dyspnea after submaximal exercise.
Determining FEV1 is essential to diagnosing and quantify-ing COPD-related ventilatory impairment.1,7,8 However,FEV1 does not reflect the systemic manifestations of thedisease or functional impairment of the patient. Recentstudies9,10 have questioned the use of FEV1 alone as anoutcome measure for various interventions or as a measureof disease severity in patients with COPD. Since using FEV1to assess pulmonary function makes it appear to remainunchanged over the course of clinical treatment,10 newmethods that are able to measure changes in the functionalstatus of COPD patients are required. In COPD patients,pulmonary rehabilitation increases exercise tolerance, im-proves health-related quality of life, and decreases dyspneawithout altering pulmonary function.38 The results of thepresent study suggest that diaphragmatic mobility is aparameter that could provide information on respiratorymechanics and functional capacity in COPD patients. Inaddition, our data indicate that assessment of diaphrag-matic mobility would be useful in assessing functionalimpairment in a more comprehensive manner than doesairflow limitation.
In the present study, diaphragmatic mobility was assessedonly on the right side, which might represent a methodo-logical limitation. Nevertheless, there is evidence in theliterature that right and left hemidiaphragms presentsimilar mobility.28 In addition, diaphragmatic mobilityassessed using ultrasonography to determine portal veindisplacement presents a high degree of concordance withdiaphragmatic mobility assessed using fluoroscopy.25 Thesediaphragmatic mobility values obtained in the present studyare similar to those previously outlined in the literature forCOPD patients.16,17,28 The correlations determined in thepresent study were not particularly strong, possibly due tothe fact that COPD is a systemic disease. Commonextrapulmonary effects of COPD include skeletal muscledysfunction, osteoporosis, weight loss, reduced exercisetolerance, and psychological disorders.39
In conclusion, loss of diaphragmatic mobility appears tobe a determining factor for decreased exercise toleranceand increased dyspnea in COPD patients. Determiningdiaphragmatic mobility could further the understanding oflimitations in these patients as well as informing decisionsrelated to therapeutic strategies.
Conflict of interest
All the authors declare that no financial or other potentialconflicts of interest exist.
Acknowledgments
Financial support for this study was provided by CAPES andCNPq.
References
1. Fabbri L, Pauwels RA, Hurd SS. Global strategy for the diagnosis,management, and prevention of chronic obstructive pulmonarydisease: GOLD executive summary update 2003. Am J RespirCrit Care Med 2004;1:105–41.
2. De Troyer A. Effect of hyperinflation on the diaphragm. EurRespir J 1997;10:708–13.
3. Polle DC, Sexton WL, Farkas GA, Powers SK, Reid MB. Diaphragmstructure and function in health and disease. Med Sci SportsExerc 1997;29:738–54.
4. McConnell AK, Romer LM. Dyspnoea in health and obstructivepulmonary disease. The role of respiratory muscle function andtraining. Sports Med 2004;34:117–32.
5. Lacasse Y, Rousseau L, Maltais F. Prevalence of depressivesymptoms and depression in patients with severe oxygen-dependent chronic obstructive pulmonary disease. J Cardio-pulm Rehab 2001;20:80–6.
6. Yen ML, Chen HH, Liao YC, Liao WY. Testing the functional statusmodel in patients with chronic obstructive pulmonary disease.J Adv Nurs 2004;46:342–50.
7. American Thoracic Society. Standards for the diagnosis and careof patients with chronic obstructive pulmonary disease. Am RevRespir Crit Care Med 1995;152:S77–S121.
8. British Thoracic Society. Guidelines of COPD. Thorax 1997;52:S1–S28.
9. Celli B. The importance of spirometry in COPD and asthma:effect on approach to management. Chest 2000;117:S15–9.
10. Van Schayck CP. Is lung function really a good parameter inevaluating the long-term effects of inhaled corticosteroids inCOPD? Eur Respir J 2000;15:238–9.
11. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measure-ment of dyspnea. Contents, interobserver agreement, andphysiologic correlates of two new clinical indexes. Chest1984;6:751–8.
12. Hajiro T, Nishimura K, Tsukino M, Ikeda A, Oga T, Izumi T. Acomparison of the level of dyspnea vs. disease severity inindicating the health-related quality of life of patients withCOPD. Chest 1999;116:1632–7.
13. Ferrer M, Alonso J, Morera J, et al. Chronic obstructivepulmonary disease stage and health-related quality of life.Ann Intern Med 1997;127:1072–9.
14. Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a betterpredictor of 5-year survival than airway obstruction in patientswith COPD. Chest 2002;121:1434–40.
15. George RB, Weill H. Fluorodensimetry: a method for analyzingregional ventilation and diaphragm function. JAMA 1971;217:171–6.
16. Iwasawa T, Kagei S, Gotoh T, Yoshiike Y, Matsushita K, KuriharaH. Magnetic resonance analysis of abnormal diaphragmaticmotion in patients with emphysema. Eur Respir J 2002;19:225–31.
17. Unal O, Arslan H, Uzum K, et al. Evaluation of diaphragmaticmovement with MR fluoroscopy in chronic obstructive pulmon-ary disease. J Clin Imaging 2000;24:347–50.
ARTICLE IN PRESS
E. Paulin et al.2118
18. Farkas GA, Roussos C. Diaphragm in emphysematous hamsters:sarcomere adaptability. J Appl Physiol 1983;54:1635–40.
19. Lando Y, Boiselle PM, Shade D, et al. Effect of lung volumereduction surgery on diaphragm length in severe chronicobstructive pulmonary disease. Am J Respir Crit Care Med1999;159:796–805.
20. Tschernko EM, Wisser W, Wanke T, et al. Changes in ventilatorymechanics and diaphragmatic function after lung volume reduc-tion surgery in patients with COPD. Thorax 1997;52:545–50.
21. Criner GJ, Cordova FC, Leyenson V, et al. Effect of lung volumereduction surgery on diaphragm strength. Am J Respir Crit CareMed 1998;157:1578–85.
22. Goldman HI, Becklake MR. Am Rev Tuberc 1959;79:457–67.23. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in
the normal expiratory flow-volume curve with growth andaging. Am Rev Respir Dis 1983;127:725–34.
24. Clausen JL, Zarnins LP. Body plethysmography: calculations-measurement of angles. Pulmonary function testing guidelinesand controversies: equipment, methods and normal values.New York: Academic Press; 1982. p. 141–2.
25. Toledo NSG, Kodaira SK, Massarollo PCB, Pereira OI, Mies S.Right hemidiaphragmatic mobility: assessment with US mea-surement of craniocaudal displacement of left branches ofportal vein. Radiology 2003;228:389–94.
26. Borg GAV. Psychophysical basis of perceived exertion. Med SciSports Exerc 1982;14:377–81.
27. American Thoracic Society. ATS Statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–7.
28. Suga K, Tsukuda T, Awaya H, et al. Impaired respiratorymechanics in pulmonary emphysema: evaluation with dynamicbreathing MRI. J Magn Reson Imaging 1999;10:510–20.
29. Sharp JT, Danon WS, Druz NB, Goldberg H, Fishman W.Respiratory muscle function in patients with chronic obstructive
pulmonary disease: its relationship to disability and torespiratory therapy. Am Rev Respir Dis 1974;110:154–67.
30. Rochester DF, Brown NMT. Determinants of maximal inspiratorypressure in chronic obstructive pulmonary disease. Am RevRespir Dis 1985;132:42–7.
31. Decramer M, De Troyer A. Respiratory changes in parasternalintercostal length. J Appl Physiol 1984;57:1254–60.
32. Hoppin FG. Theoretical basis for improvement followingreduction pneumoplasty in emphysema. Am J Respir Crit CareMed 1997;155:520–5.
33. Orozco-Levi M, Gea J, Lloreta JL, Felez M, Minguella J, SerranoS, et al. Subcelullar adaptation of the human diaphragm inchronic obstructive pulmonary disease. Eur Respir J 1999;13:371–8.
34. Gauthier AP, Verbanck S, Estenne M, Segebarth C, Macklem PT,Paiva M. Three-dimensional reconstruction of the in vivo humandiaphragm shape at different lung volumes. J Appl Physiol1994;76:495–506.
35. Whitelaw WA, Hajdo LE, Wallace JA. Relationships amongpressure, tension, and shape of the diaphragm. J Appl Physiol1983;62:180–6.
36. O’Donnell DE. Ventilatory limitations in chronic obstructivepulmonary disease. Med Sci Sports Exerc 2001;33:S647–55.
37. Yan S, Kaminski D, Sliwinski P. Inspiratory muscle mechanics ofpatients with chronic obstructive pulmonary disease duringincremental exercise. Am J Respir Crit Care Med 1997;156:807–13.
38. Wedzicha JA, Bestall JC, Garrod R, et al. Randomized controlledtrial of pulmonary rehabilitation in severe chronic obstructivepulmonary disease patients, stratified with the MRC dyspneascale. Eur Respir J 1988;12:363–9.
39. Emil FM, Wouters MD, Creutzberg EC, Schols AMWJ. Systemiceffects in COPD. Chest 2002;121:S127–30.