Lung hyperinflation in chronic obstructive pulmonary disease: Mechanisms, clinical implications and treatment

Expert Review of Respiratory Medicine

Volumn 8, Issue 6, 2014, Pages 731-749

  Langer, Daniel ^a,b,c   Ciavaglia, Casey E ^a   Neder, J Alberto ^a   Webb, Katherine A ^a   O'Donnell, Denis E ^a  

^a QUEEN S UNIVERSITY   (Canada)

^b UNIVERSITY OF LEUVEN   (Belgium)

^c UNIVERSITY HOSPITALS LEUVEN   (Belgium)

Author keywords

COPD; dyspnea; lung hyperinflation; respiratory mechanics; respiratory muscles

Indexed keywords

BRONCHODILATING AGENT;

ADAPTATION; ASSISTED VENTILATION; ATELECTASIS; BREATHING EXERCISE; BREATHING MUSCLE; CHRONIC OBSTRUCTIVE LUNG DISEASE; DIAPHRAGM; DYNAMIC LUNG HYPERINFLATION; DYSPNEA; EXERCISE; HEART FUNCTION; HUMAN; INSPIRATORY CAPACITY; LUNG HYPERINFLATION (DISEASE); LUNG RESECTION; MUSCLE TRAINING; PATHOPHYSIOLOGY; PHYSICAL ACTIVITY; RANDOMIZED CONTROLLED TRIAL (TOPIC); RESTING LUNG HYPERINFLATION; REVIEW; BREATHING MECHANICS; EXERCISE TOLERANCE; LUNG VOLUME; PHYSIOLOGY; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

DYSPNEA; EXERCISE TOLERANCE; HUMANS; LUNG VOLUME MEASUREMENTS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; RESPIRATORY MECHANICS;

EID: 84910645573     PISSN: 17476348     EISSN: 17476356     Source Type: Journal    
DOI: 10.1586/17476348.2014.949676     Document Type: Review

References (199)

1. McDonough JE, Yuan R, Suzuki M, et al. Small-Airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 2011;365(17):1567-75
2. Rodriguez-Roisin R, Drakulovic M, Rodriguez DA, et al. Ventilation-perfusion imbalance and chronic obstructive pulmonary disease staging severity. J Appl Physiol 2009;106(6):1902-8
3. Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187(4):347-65
4. Casanova C, Cote C, de Torres JP, et al. Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171(6):591-7
5. Zaman M, Mahmood S, Altayeh A. Low inspiratory capacity to total lung capacity ratio is a risk factor for chronic obstructive pulmonary disease exacerbation. Am J Med Sci 2010;339(5):411-14
6. O'Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160(2):542-9
7. O'Donnell DE, Guenette JA, Maltais F, Webb KA. Decline of resting inspiratory capacity in COPD: the impact on breathing pattern, dyspnea, and ventilatory capacity during exercise. Chest 2012;141(3):753-62
8. Tzani P, Aiello M, Elia D, et al. Dynamic hyperinflation is associated with a poor cardiovascular response to exercise in COPD patients. Respir Res 2011;12:150
9. Watz H, Waschki B, Meyer T, et al. Decreasing cardiac chamber sizes and associated heart dysfunction in COPD: role of hyperinflation. Chest 2010;138(1):32-8
10. Loring SH, Garcia-Jacques M, Malhotra A. Pulmonary characteristics in COPD and mechanisms of increased work of breathing. J Appl Physiol 2009;107(1):309-14
11. Garcia-Rio F, Lores V, Mediano O, et al. Daily physical activity in patients with chronic obstructive pulmonary disease is mainly associated with dynamic hyperinflation. Am J Respir Crit Care Med 2009;180(6):506-12
12. Lahaije AJ, van Helvoort HA, Dekhuijzen PN, et al. Resting and ADL-induced dynamic hyperinflation explain physical inactivity in COPD better than FEV1. Respir Med 2013;107(6): 834-40
13. Jones PW. Activity limitation and quality of life in COPD. COPD 2007;4(3):273-8
14. Marin JM, Carrizo SJ, Gascon M, et al. Inspiratory capacity, dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute-walk test in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163(6):1395-9
15. Oga T, Nishimura K, Tsukino M, et al. Exercise capacity deterioration in patients with COPD: longitudinal evaluation over 5 years. Chest 2005;128(1):62-9
16. Pride NB, Macklem PT. Lung mechanics in disease. In: Fishman P, editor. Handbook of physiology, section 3: the respiratory system, mechanics of breathing, part 2 A. American Physiological Society; Bethesda, MD, USA: 1986. p. 659-92
17. Brochard L. Intrinsic (or auto-) positive end-expiratory pressure during spontaneous or assisted ventilation. Intensive Care Med 2002;28(11):1552-4
18. Albuquerque AL, Nery LE, Villaca DS, et al. Inspiratory fraction and exercise impairment in COPD patients GOLD stages II-III. Eur Respir J 2006;28(5): 939-44
19. Guenette JA, Chin RC, Cory JM, et al. Inspiratory capacity during exercise: measurement, analysis, and interpretation. Pulm Med 2013;2013:e956081
20. O'Donnell DE, Deesomchok A, Lam YM, et al. Effects of BMI on static lung volumes in patients with airway obstruction. Chest 2011;140(2):461-8
21. Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977; 1(6077):1645-8
22. Celli BR, Decramer M, Lystig T, et al. Longitudinal inspiratory capacity changes in chronic obstructive pulmonary disease. Respir Res 2012;13:66
23. Deesomchok A, Webb KA, Forkert L, et al. Lung hyperinflation and its reversibility in patients with airway obstruction of varying severity. COPD 2010;7(6):428-37
24. O'Donnell DE, Maltais F, Porszasz J, et al. The Continuum of Physiological Impairment during Treadmill Walking in Patients with Mild-to-Moderate COPD: patient Characterization Phase of a Randomized Clinical Trial. PLoS One 2014;9(5):e96574
25. Hogg JC, McDonough JE, Suzuki M. Small airway obstruction in COPD: new insights based on micro-CT imaging and MRI imaging. Chest 2013;143(5):1436-43
26. Mitzner W. Emphysema - a disease of small airways or lung parenchyma? N Engl J Med 2011;365(17):1637-9
27. Corbin RP, Loveland M, Martin RR, Macklem PT. A four-year follow-up study of lung mechanics in smokers. Am Rev Respir Dis 1979;120(2):293-304
28. Yuan R, Hogg JC, Pare PD, et al. Prediction of the rate of decline in FEV(1) in smokers using quantitative Computed Tomography. Thorax 2009;64(11):944-9
29. Rambod M, Porszasz J, Make BJ, et al. Six-minute walk distance predictors, including CT scan measures, in the COPDGene cohort. Chest 2012;141(4): 867-75
30. Washko GR, Dransfield MT, Estepar RS, et al. Airway wall attenuation: a biomarker of airway disease in subjects with COPD. J Appl Physiol 2009;107(1):185-91
31. Barbosa EM Jr, Song G, Tustison N, et al. Computational analysis of thoracic multidetector row HRCT for segmentation and quantification of small airway air trapping and emphysema in obstructive pulmonary disease. Acad Radiol 2011; 18(10):1258-69
32. Diaz AA, Morales A, Diaz JC, et al. CT and physiologic determinants of dyspnea and exercise capacity during the six-minute walk test in mild COPD. Respir Med 2013; 107(4):570-9
33. Macklem PT. Therapeutic implications of the pathophysiology of COPD. Eur Respir J 2010;35(3):676-80
34. Parker CM, Voduc N, Aaron SD, et al. Physiological changes during symptom recovery from moderate exacerbations of COPD. Eur Respir J 2005;26(3):420-8
35. Stevenson NJ, Walker PP, Costello RW, Calverley PM. Lung mechanics and dyspnea during exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172(12):1510-16
36. Decramer M. Hyperinflation and respiratory muscle interaction. Eur Respir J 1997;10(4): 934-41
37. Gorman RB, McKenzie DK, Pride NB, et al. Diaphragm length during tidal breathing in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;166(11):1461-9
38. McKenzie DK, Butler JE, Gandevia SC. Respiratory muscle function and activation in chronic obstructive pulmonary disease. J Appl Physiol 2009;107(2):621-9
39. Polkey MI, Kyroussis D, Hamnegard CH, et al. Diaphragm strength in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;154(5):1310-17
40. Similowski T, Yan S, Gauthier AP, et al. Contractile properties of the human diaphragm during chronic hyperinflation. N Engl J Med 1991;325(13):917-23
41. Rochester DF, Braun NM. Determinants of maximal inspiratory pressure in chronic obstructive pulmonary disease. Am Rev Respir Dis 1985;132(1):42-7
42. Clanton TL, Levine S. Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation? J Appl Physiol 2009;107(1):324-35
43. Bellemare F, Cordeau MP, Couture J, et al. Effects of emphysema and lung volume reduction surgery on transdiaphragmatic pressure and diaphragm length. Chest 2002; 121(6):1898-910
44. Rochester DF. The diaphragm in COPD. Better than expected, but not good enough. N Engl J Med 1991;325(13):961-2
45. Levine S, Kaiser L, Leferovich J, Tikunov B. Cellular adaptations in the diaphragm in chronic obstructive pulmonary disease. N Engl J Med 1997;337(25):1799-806
46. Levine S, Gregory C, Nguyen T, et al. Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD. J Appl Physiol 2002;92(3):1205-13
47. Orozco-Levi M, Gea J, Lloreta JL, et al. Subcellular adaptation of the human diaphragm in chronic obstructive pulmonary disease. Eur Respir J 1999;13(2):371-8
48. Barr RG, Bluemke DA, Ahmed FS, et al. Percent emphysema, airflow obstruction, and impaired left ventricular filling. N Engl J Med 2010;362(3):217-27
49. Smith BM, Prince MR, Hoffman EA, et al. Impaired left ventricular filling in COPD and emphysema: is it the heart or the lungs? The Multi-Ethnic Study of Atherosclerosis COPD Study. Chest 2013;144(4):1143-51
50. Jorgensen K, Muller MF, Nel J, et al. Reduced intrathoracic blood volume and left and right ventricular dimensions in patients with severe emphysema: an MRI study. Chest 2007;131(4):1050-7
51. O'Donnell DE. Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006;3(2):180-4
52. O'Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158(5 Pt 1):1557-65
53. O'Donnell DE, Travers J, Webb KA, et al. Reliability of ventilatory parameters during cycle ergometry in multicentre trials in COPD. Eur Respir J 2009;34(4):866-74
54. Stubbing DG, Pengelly LD, Morse JL, Jones NL. Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. J Appl Physiol Respir Environ Exerc Physiol 1980;49(3):511-15
55. Vogiatzis I, Georgiadou O, Golemati S, et al. Patterns of dynamic hyperinflation during exercise and recovery in patients with severe chronic obstructive pulmonary disease. Thorax 2005;60(9):723-9
56. Guenette JA, Webb KA, O'Donnell DE. Does dynamic hyperinflation contribute to dyspnoea during exercise in patients with COPD? Eur Respir J 2012;40(2):322-9
57. Laveneziana P, Webb KA, Ora J, et al. Evolution of dyspnea during exercise in chronic obstructive pulmonary disease: impact of critical volume constraints. Am J Respir Crit Care Med 2011;184(12): 1367-73
58. O'Donnell DE, Hamilton AL, Webb KA. Sensory-mechanical relationships during high-intensity, constant-work-rate exercise in COPD. J Appl Physiol 2006;101(4): 1025-35
59. O'Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164(5):770-7
60. Guenette JA, Jensen D, Webb KA, et al. Sex differences in exertional dyspnea in patients with mild COPD: physiological mechanisms. Respir Physiol Neurobiol 2011;177(3):218-27
61. Ofir D, Laveneziana P, Webb KA, et al. Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177(6):622-9
62. Gelb AF, Gutierrez CA, Weisman IM, et al. Simplified detection of dynamic hyperinflation. Chest 2004;126(6):1855-60
63. Lahaije AJ, Willems LM, van Hees HW, et al. Diagnostic accuracy of metronome-paced tachypnea to detect dynamic hyperinflation. Clin Physiol Funct Imaging 2013;33(1):62-9
64. O'Donnell DE, Bertley JC, Chau LK, Webb KA. Qualitative aspects of exertional breathlessness in chronic airflow limitation: pathophysiologic mechanisms. Am J Respir Crit Care Med 1997;155(1):109-15
65. Roussos C, Campbell EJM. Respiratory muscle energetics. In: Fishman P, editor. Handbook of physiology, section 3: The respiratory system, mechanics of breathing, part 2 A. American Physiological Society; Bethesda, MD, USA: 1986. p. 481-509
66. Whipp BJ and Pardy RL. Breathing during exercise. In: Fishman P, editor. Handbook of physiology, section 3: the respiratory system, mechanics of breathing, part 2 A. American Physiological Society; Bethesda, MD, USA: 1986. p. 605-29
67. De Troyer A, Wilson TA. Effect of acute inflation on the mechanics of the inspiratory muscles. J Appl Physiol 2009;107(1):315-23
68. Decramer M. Effects of hyperinflation on the respiratory muscles. Eur Respir J 1989; 2(4):299-302
69. LeBlanc P, Bowie DM, Summers E, et al. Breathlessness and exercise in patients with cardiorespiratory disease. Am Rev Respir Dis 1986;133(1):21-5
70. Amann M, Regan MS, Kobitary M, et al. Impact of pulmonary system limitations on locomotor muscle fatigue in patients with COPD. Am J Physiol Regul Integr Comp Physiol 2010;299(1):R314-24
71. Borghi-Silva A, Oliveira CC, Carrascosa C, et al. Respiratory muscle unloading improves leg muscle oxygenation during exercise in patients with COPD. Thorax 2008;63(10):910-15
72. Chiappa GR, Queiroga F Jr, Meda E, et al. Heliox improves oxygen delivery and utilization during dynamic exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009; 179(11):1004-10
73. Chiappa GR, Vieira PJ, Umpierre D, et al. Inspiratory resistance decreases limb blood flow in COPD patients with heart failure. Eur Respir J 2014;43(5):1507-10
74. O'Donnell DE, D'Arsigny C, Fitzpatrick M, Webb KA. Exercise hypercapnia in advanced chronic obstructive pulmonary disease: the role of lung hyperinflation. Am J Respir Crit Care Med 2002;166(5):663-8
75. Chiappa GR, Borghi-Silva A, Ferreira LF, et al. Kinetics of muscle deoxygenation are accelerated at the onset of heavy-intensity exercise in patients with COPD: relationship to central cardiovascular dynamics. J Appl Physiol 2008;104(5): 1341-50
76. Montes de OM, Rassulo J, Celli BR. Respiratory muscle and cardiopulmonary function during exercise in very severe COPD. Am J Respir Crit Care Med 1996; 154(5):1284-9
77. Vassaux C, Torre-Bouscoulet L, Zeineldine S, et al. Effects of hyperinflation on the oxygen pulse as a marker of cardiac performance in COPD. Eur Respir J 2008; 32(5):1275-82
78. Sliwinski P, Kaminski D, Zielinski J, Yan S. Partitioning of the elastic work of inspiration in patients with COPD during exercise. Eur Respir J 1998;11(2):416-21
79. Chin RC, Guenette JA, Cheng S, et al. Does the respiratory system limit exercise in mild chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2013;187(12): 1315-23
80. LeBlanc P, Summers E, Inman MD, et al. Inspiratory muscles during exercise: a problem of supply and demand. J Appl Physiol 1988;64(6):2482-9
81. Decramer M. Response of the respiratory muscles to rehabilitation in COPD. J Appl Physiol 2009;107(3):971-6
82. Polkey MI, Hamnegard CH, Hughes PD, et al. Influence of acute lung volume change on contractile properties of human diaphragm. J Appl Physiol 1998;85(4): 1322-8
83. Mador MJ, Kufel TJ, Pineda LA, Sharma GK. Diaphragmatic fatigue and high-intensity exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161(1):118-23
84. Polkey MI, Kyroussis D, Keilty SE, et al. Exhaustive treadmill exercise does not reduce twitch transdiaphragmatic pressure in patients with COPD. Am J Respir Crit Care Med 1995;152(3):959-64
85. Hamilton N, Killian KJ, Summers E, Jones NL. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 1995;152:2021-31
86. Bernard S, LeBlanc P, Whittom F, et al. Peripheral muscle weakness in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158(2):629-34
87. Gosselink R, Troosters T, Decramer M. Peripheral muscle weakness contributes to exercise limitation in COPD. Am J Respir Crit Care Med 1996;153(3):976-80
88. Seymour JM, Spruit MA, Hopkinson NS, et al. The prevalence of quadriceps weakness in COPD and the relationship with disease severity. Eur Respir J 2010;36(1):81-8
89. Borghi-Silva A, Carrascosa C, Oliveira CC, et al. Effects of respiratory muscle unloading on leg muscle oxygenation and blood volume during high-intensity exercise in chronic heart failure. Am J Physiol Heart Circ Physiol 2008;294(6):H2465-72
90. Louvaris Z, Zakynthinos S, Aliverti A, et al. Heliox increases quadriceps muscle oxygen delivery during exercise in COPD patients with and without dynamic hyperinflation. J Appl Physiol 2012;113(7):1012-23
91. Dempsey JA, Romer L, Rodman J, et al. Consequences of exercise-induced respiratory muscle work. Respir Physiol Neurobiol 2006;151(2-3):242-50
92. Dempsey JA. Limits to ventilation (for sure!) and exercise (maybe?) in mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187(12):1282-3
93. Scharf SM. Effects of normal and stressed inspiration on cardiovascular function. In: Scharf M, Cassidy SS, editors. Heart-lung interactions in health and disease S. Marcel Dekker; New York, NY, USA: 1989. p. 427-62
94. Lloyd TC. Mechanical heart-lung interaction. In: Scharf M, Cassidy SS, editors. Heart-lung interactions in health and disease S. Marcel Dekker; New York, NY, USA: 1989. p. 309-38
95. Light RW, Mintz HM, Linden GS, Brown SE. Hemodynamics of patients with severe chronic obstructive pulmonary disease during progressive upright exercise. Am Rev Respir Dis 1984;130(3):391-5
96. Vizza CD, Lynch JP, Ochoa LL, et al. Right and left ventricular dysfunction in patients with severe pulmonary disease. Chest 1998;113(3):576-83
97. Morrison DA, Adcock K, Collins CM, et al. Right ventricular dysfunction and the exercise limitation of chronic obstructive pulmonary disease. J Am Coll Cardiol 1987;9(6):1219-29
98. Vasilopoulou MK, Vogiatzis I, Nasis I, et al. On- and off-exercise kinetics of cardiac output in response to cycling and walking in COPD patients with GOLD Stages I-IV. Respir Physiol Neurobiol 2012; 181(3):351-8
99. Louvaris Z, Kortianou EA, Spetsioti S, et al. Intensity of daily physical activity is associated with central hemodynamic and leg muscle oxygen availability in COPD. J Appl Physiol 2013;115(6):794-802
100. Kortianou EA, Louvaris Z, Vasilopoulou M, et al. Activity monitoring reflects cardiovascular and metabolic variations in COPD patients across GOLD stages II to IV. Respir Physiol Neurobiol 2013;189(3): 513-20
101. Berton DC, Barbosa PB, Takara LS, et al. Bronchodilators accelerate the dynamics of muscle O2 delivery and utilisation during exercise in COPD. Thorax 2010;65(7): 588-93
102. Bronstad E, Tjonna AE, Rognmo O, et al. Aerobic exercise training improves rightand left ventricular systolic function in patients with COPD. COPD 2013;10(3): 300-6
103. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012;185(4): 435-52
104. Gandevia B, Hugh JP. Terminology for measurements of ventilatory capacity; a report to the thoracic society. Thorax 1957; 12(4):290-3
105. Moxham J, Jolley C. Breathlessness, fatigue and the respiratory muscles. Clin Med 2009;9(5):448-52
106. Sinderby C, Spahija J, Beck J, et al. Diaphragm activation during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163(7):1637-41
107. Luo YM, Hopkinson NS, Polkey MI. Tough at the top: must end-expiratory lung volume make way for end-inspiratory lung volume? Eur Respir J 2012;40(2):283-5
108. O'Donnell DE, Hong HH, Webb KA. Respiratory sensation during chest wall restriction and dead space loading in exercising men. J Appl Physiol 2000;88(5): 1859-69
109. Schwartzstein RM, Simon PM, Weiss JW, et al. Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 1989;139(5):1231-7
110. Harty HR, Corfield DR, Schwartzstein RM, Adams L. External thoracic restriction, respiratory sensation, and ventilation during exercise in men. J Appl Physiol 1999;86(4): 1142-50
111. Banzett RB, Pedersen SH, Schwartzstein RM, Lansing RW. The affective dimension of laboratory dyspnea: air hunger is more unpleasant than work/ effort. Am J Respir Crit Care Med 2008; 177(12):1384-90
112. Evans KC, Banzett RB, Adams L, et al. BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 2002;88(3):1500-11
113. Davenport PW, Vovk A. Cortical and subcortical central neural pathways in respiratory sensations. Respir Physiol Neurobiol 2009;167(1):72-86
114. Evans KC, Banzett RB, Adams L, et al. BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 2002;88(3):1500-11
115. Peiffer C, Poline JB, Thivard L, et al. Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med 2001;163(4):951-7
116. Von Leupoldt A, Sommer T, Kegat S, et al. The unpleasantness of perceived dyspnea is processed in the anterior insula and amygdala. Am J Respir Crit Care Med 2008;177(9):1026-32
117. Von Leupoldt A, Sommer T, Kegat S, et al. Down-regulation of insular cortex responses to dyspnea and pain in asthma. Am J Respir Crit Care Med 2009;180(3):232-8
118. Von Leupoldt A, Brassen S, Baumann HJ, et al. Structural brain changes related to disease duration in patients with asthma. PLoS One 2011;6(8):e23739
119. Lung function and patient preference with QVA149 vs. tiotropium in COPD patients (FAVOR). Available from: http:// clinicaltrials.gov/show/NCT02125734
120. The purpose of the this study is to evaluate the spirometric effect (trough FEV1) of umeclidinium/vilanterol 62.5/25 mcg once daily compared with tiotropium 18mcg once daily over a 12-week treatment period in subjects with COPD who continue to have symptoms on tiotropium. Available from: http://clinicaltrials.gov/show/ NCT01899742
121. Efficacy and safety of PT003, PT005, and PT001 in subjects with moderate to very severe COPD (PINNACLE 1). Available from: http://clinicaltrials.gov/show/ NCT01854645
122. Multi-center study to assess the efficacy and safety of PT003, PT005, and PT001 in subjects with moderate to very severe COPD (PINNACLE 2). Available from:
123. Effect of glycopyrronium on morning symptoms and pulmonary function in patients with moderate to severe COPD. Available from: http://clinicaltrials.gov/show/ NCT01959516
124. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996;153(3): 967-75
125. O'Donnell DE, Fluge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004; 23(6):832-40
126. Cooper CB, Celli BR, Jardim JR, et al. Treadmill endurance during 2-year treatment with tiotropium in patients with COPD: a randomized trial. Chest 2013; 144(2):490-7
127. RELOVAIR Lung Deflation Study. Available from: http://clinicaltrials.gov/show/ NCT01691885
128. De Backer W, Devolder A, Poli G, et al. Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients. J Aerosol Med Pulm Drug Deliv 2010;23(3):137-48
129. Tzani P, Crisafulli E, Nicolini G, et al. Effects of beclomethasone/formoterol fixed combination on lung hyperinflation and dyspnea in COPD patients. Int J Chron Obstruct Pulmon Dis 2011;6:503-9
130. Singh D, Nicolini G, Bindi E, et al. Extrafine Beclomethasone/formoterol compared to Fluticasone/salmeterol Combination Therapy in COPD. BMC Pulm Med 2014;14:43
131. Calverley PM, Kuna P, Monso E, et al. Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. Respir Med 2010;104(12): 1858-68
132. Maltais F, Hamilton A, Marciniuk D, et al. Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Chest 2005;128(3):1168-78
133. Scuarcialupi ME, Berton DC, Cordoni PK, et al. Can bronchodilators improve exercise tolerance in COPD patients without dynamic hyperinflation? J Bras Pneumol 2014;40(2):111-18
134. O'Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24(1):86-94
135. Peters MM, Webb KA, O'Donnell DE. Combined physiological effects of bronchodilators and hyperoxia on exertional dyspnoea in normoxic COPD. Thorax 2006;61(7):559-67
136. Effect of a new combination bronchodilator on exercise in GOLD STage II moderate COPD. Available from: http://clinicaltrials. gov/show/NCT01491802
137. To Evaluate the Effect of Inhaled Medication Together With Exercise and Activity Training on Exercise Capacity and Daily Activities in Patients With Chronic Lung Disease With Obstruction of Airways. Available from: http://clinicaltrials.gov/show/ NCT02085161
138. Effect on exercise endurance and lung hyperinflation of tiotropium + olodaterol in COPD patients. Available from:
139. van 't Hul A, Kwakkel G, Gosselink R. The acute effects of noninvasive ventilatory support during exercise on exercise endurance and dyspnea in patients with chronic obstructive pulmonary disease: a systematic review. J Cardiopulm Rehabil 2002;22(4):290-7
140. van 't Hul A, Gosselink R, Hollander P, et al. Acute effects of inspiratory pressure support during exercise in patients with COPD. Eur Respir J 2004;23(1):34-40
141. O'Donnell DE. Ventilatory limitations in chronic obstructive pulmonary disease. Med Sci Sports Exerc 2001;33(7 Suppl):S647-55
142. O'Donnell DE, Sanii R, Younes M. Improvement in exercise endurance in patients with chronic airflow limitation using continuous positive airway pressure. Am Rev Respir Dis 1988;138(6):1510-14
143. Petrof BJ, Calderini E, Gottfried SB. Effect of CPAP on respiratory effort and dyspnea during exercise in severe COPD. J Appl Physiol 1990;69(1):179-88
144. Polkey MI, Kyroussis D, Mills GH, et al. Inspiratory pressure support reduces slowing of inspiratory muscle relaxation rate during exhaustive treadmill walking in severe COPD. Am J Respir Crit Care Med 1996; 154(4 Pt 1):1146-50
145. Maltais F, Reissmann H, Gottfried SB. Pressure support reduces inspiratory effort and dyspnea during exercise in chronic airflow obstruction. Am J Respir Crit Care Med 1995;151(4):1027-33
146. Ambrosino N, Strambi S. New strategies to improve exercise tolerance in chronic obstructive pulmonary disease. Eur Respir J 2004;24(2):313-22
147. Harms CA, Babcock MA, McClaran SR, et al. Respiratory muscle work compromises leg blood flow during maximal exercise. J Appl Physiol 1997;82(5):1573-83
148. Harms CA, Wetter TJ, St Croix CM, et al. Effects of respiratory muscle work on exercise performance. J Appl Physiol 2000; 89(1):131-8
149. Bradley JM, Lasserson T, Elborn S, et al. A systematic review of randomized controlled trials examining the short-term benefit of ambulatory oxygen in COPD. Chest 2007;131(1):278-85
150. Dolmage TE, Evans RA, Goldstein RS. Defining hyperinflation as 'dynamic': moving toward the slope. Respir Med 2013; 107(7):953-8
151. Eves ND, Petersen SR, Haykowsky MJ, et al. Helium-hyperoxia, exercise, and respiratory mechanics in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174(7):763-71
152. O'Donnell DE, D'Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163(4):892-8
153. Somfay A, Porszasz J, Lee SM, Casaburi R. Dose-response effect of oxygen on hyperinflation and exercise endurance in nonhypoxaemic COPD patients. Eur Respir J 2001;18(1):77-84
154. Gagnon P, Bussieres JS, Ribeiro F, et al. Influences of spinal anesthesia on exercise tolerance in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186(7):606-15
155. Palange P, Valli G, Onorati P, et al. Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients. J Appl Physiol 2004;97(5): 1637-42
156. Hunt T, Williams MT, Frith P, Schembri D. Heliox, dyspnoea and exercise in COPD. Eur Respir Rev 2010;19(115): 30-8
157. Queiroga F Jr, Nunes M, Meda E, et al. Exercise tolerance with helium-hyperoxia versus hyperoxia in hypoxaemic patients with COPD. Eur Respir J 2013;42(2): 362-70
158. Hussain O, Collins EG, Adiguzel N, et al. Contrasting pressure-support ventilation and helium-oxygen during exercise in severe COPD. Respir Med 2011;105(3):494-505
159. Benditt JO, Wood DE, McCool FD, et al. Changes in breathing and ventilatory muscle recruitment patterns induced by lung volume reduction surgery. Am J Respir Crit Care Med 1997;155(1):279-84
160. Laghi F, Jubran A, Topeli A, et al. Effect of lung volume reduction surgery on neuromechanical coupling of the diaphragm. Am J Respir Crit Care Med 1998;157(2):475-83
161. Martinez FJ, de Oca MM, Whyte RI, et al. Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 1997;155(6):1984-90
162. O'Donnell DE, Webb KA, Bertley JC, et al. Mechanisms of relief of exertional breathlessness following unilateral bullectomy and lung volume reduction surgery in emphysema. Chest 1996;110(1): 18-27
163. Benditt JO, Lewis S, Wood DE, et al. Lung volume reduction surgery improves maximal O2 consumption, maximal minute ventilation, O2 pulse, and dead space-to-tidal volume ratio during leg cycle ergometry. Am J Respir Crit Care Med 1997;156(2 Pt 1):561-6
164. Cordova F, O'Brien G, Furukawa S, et al. Stability of improvements in exercise performance and quality of life following bilateral lung volume reduction surgery in severe COPD. Chest 1997;112(4):907-15
165. Keller CA, Ruppel G, Hibbett A, et al. Thoracoscopic lung volume reduction surgery reduces dyspnea and improves exercise capacity in patients with emphysema. Am J Respir Crit Care Med 1997;156(1):60-7
166. Marchand E, Gayan-Ramirez G, De Leyn P, Decramer M. Physiological basis of improvement after lung volume reduction surgery for severe emphysema: where are we? Eur Respir J 1999;13(3):686-96
167. Lacasse Y, Guyatt GH, Goldstein RS. The components of a respiratory rehabilitation program: a systematic overview. Chest 1997; 111(4):1077-88
168. Casaburi R, Porszasz J. Reduction of hyperinflation by pharmacologic and other interventions. Proc Am Thorac Soc 2006; 3(2):185-9
169. Casaburi R, Zuwallack R. Pulmonary rehabilitation for management of chronic obstructive pulmonary disease. N Engl J Med 2009;360(13):1329-35
170. O'Donnell DE, Ora J, Webb KA, et al. Mechanisms of activity-related dyspnea in pulmonary diseases. Respir Physiol Neurobiol 2009;167(1):116-32
171. Troosters T, Gosselink R, Janssens W, Decramer M. Exercise training and pulmonary rehabilitation: new insights and remaining challenges. Eur Respir Rev 2010; 19(115):24-9
172. Porszasz J, Emtner M, Goto S, et al. Exercise training decreases ventilatory requirements and exercise-induced hyperinflation at submaximal intensities in patients with COPD. Chest 2005;128(4): 2025-34
173. Puente-Maestu L, Abad YM, Pedraza F, et al. A controlled trial of the effects of leg training on breathing pattern and dynamic hyperinflation in severe COPD. Lung 2006; 184(3):159-67
174. Casaburi R, Porszasz J, Burns MR, et al. Physiologic benefits of exercise training in rehabilitation of patients with severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1997;155(5):1541-51
175. Wadell K, Webb KA, Preston ME, et al. Impact of pulmonary rehabilitation on the major dimensions of dyspnea in COPD. COPD 2013;10(4):425-35
176. Casaburi R, Kukafka D, Cooper CB, et al. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest 2005;127(3):809-17
177. Spahija J, Marchie M, Ghezzo H, Grassino A. Factors discriminating spontaneous pursed-lips breathing use in patients with COPD. COPD 2010;7(4): 254-61
178. Casciari RJ, Fairshter RD, Harrison A, et al. Effects of breathing retraining in patients with chronic obstructive pulmonary disease. Chest 1981;79(4):393-8
179. Garrod R, Dallimore K, Cook J, et al. An evaluation of the acute impact of pursed lips breathing on walking distance in nonspontaneous pursed lips breathing chronic obstructive pulmonary disease patients. Chron Respir Dis 2005;2(2):67-72
180. Nield MA, Soo Hoo GW, Roper JM, Santiago S. Efficacy of pursed-lips breathing: a breathing pattern retraining strategy for dyspnea reduction. J Cardiopulm Rehabil Prev 2007;27(4): 237-44
181. Pomidori L, Campigotto F, Amatya TM, et al. Efficacy and tolerability of yoga breathing in patients with chronic obstructive pulmonary disease: a pilot study. J Cardiopulm Rehabil Prev 2009;29(2): 133-7
182. Collins EG, Langbein WE, Fehr L, et al. Can ventilation-feedback training augment exercise tolerance in patients with chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2008;177(8):844-52
183. Gosselink R, De Vos J, van den Heuvel SP, et al. Impact of inspiratory muscle training in patients with COPD: what is the evidence? Eur Respir J 2011;37(2):416-25
184. Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med 2013;188(8): e13-64
185. O'Donnell DE, Sanii R, Giesbrecht G, Younes M. Effect of continuous positive airway pressure on respiratory sensation in patients with chronic obstructive pulmonary disease during submaximal exercise. Am Rev Respir Dis 1988;138(5):1185-91
186. Petrovic M, Reiter M, Zipko H, et al. Effects of inspiratory muscle training on dynamic hyperinflation in patients with COPD. Int J Chron Obstruct Pulmon Dis 2012;7:797-805
187. Ramirez-Sarmiento A, Orozco-Levi M, Guell R, et al. Inspiratory muscle training in patients with chronic obstructive pulmonary disease: structural adaptation and physiologic outcomes. Am J Respir Crit Care Med 2002;166(11):1491-7
188. Villafranca C, Borzone G, Leiva A, Lisboa C. Effect of inspiratory muscle training with an intermediate load on inspiratory power output in COPD. Eur Respir J 1998;11(1):28-33
189. O'Donnell DE. Impacting patient-centred outcomes in COPD: breathlessness and exercise tolerance. Eur Respir Rev 2006; 15(99):37-41
190. Man WD, Mustfa N, Nikoletou D, et al. Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD. Thorax 2004;59:471-6
191. O'Donnell DE, Sciurba F, Celli B, et al. Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest 2006;130: 647-56
192. Neder JA, Fuld JP, Overend T, et al. Effects of formoterol on exercise tolerance in severely disabled patients with COPD. Respir Med 2007;101:2056-64
193. Worth H, Forster K, Eriksson G, et al. Budesonide added to formoterol contributes to improved exercise tolerance in patients with COPD. Respir Med 2010;104:1450-9
194. O'Donnell DE, Casaburi R, Vincken W, et al. on behalf of INABLE study investigators. Effect of indacaterol on exercise endurance and lung hyperinflation in COPD. Respir Med 2011;105(7):1030-6
195. Beeh KM, Wagner F, Khindri S, Drollmann AF. Effect of indacaterol on dynamic lung hyperinflation and breathlessness in hyperinflated patients with COPD. COPD 2011;8:340-5
196. O'Donnell DE, Flüge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004; 23(6):832-40
197. Maltais F, Celli B, Casaburi R, et al. Aclidinium bromide improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. Respir Med 2011;105(4):580-7
198. Beeh KM, Sing D, Di Scala L, Drollmann A. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial. Int J COPD 2012;7:503-13
199. Beeh KM, Korn S, Beier J, et al. Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Respir Med 2014;108(4):584-92