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.
Pumar MI, Gray CR, Walsh JR, Yang IA, Rolls TA, Ward DL. Anxiety and depression-important psychological comorbidities of COPD. J Thorac Dis. 2014;6(11):1615–31.
Maltais F, Decramer M, Casaburi R, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189(9):e15–62.
Jones NL. The ins and outs of breathing: how we learnt about the body’s most vital function. Bloomington: iUniverse; 2011.
Jensen D, Ofir D, O’Donnell DE. Effects of pregnancy, obesity and aging on the intensity of perceived breathlessness during exercise in healthy humans. Respir Physiol Neurobiol. 2009;167:87–100.
Killian KJ, Gandevia SC, Summers E, Campbell EJ. Effect of increased lung volume on perception of breathlessness, effort, and tension. J Appl Physiol. 1984;57(3):686–91.
El-Manshawi A, Killian KJ, Summers E, Jones NL. Breathlessness during exercise with and without resistive loading. J Appl Physiol. 1986;61(3):896–905.
Lane R, Adams L, Guz A. Is low-level respiratory resistive loading during exercise perceived as breathlessness? Clin Sci. 1987;73:627–34.
Campbell EJ, Gandevia SC, Killian KJ, Mahutte CK, Rigg JR. Changes in the perception of inspiratory resistive loads during partial curarization. J Physiol. 1980;309:93–100.
Moosavi SH, Topulos GP, Hafter A, et al. Acute partial paralysis alters perceptions of air hunger, work and effort at constant P(CO(2)) and V(E). Respir Physiol. 2000;122:45–60.
Banzett RB, Lansing RW, Brown R, et al. ‘Air hunger’ from increased PCO2 persists after complete neuromuscular block in humans. Respir Physiol. 1990;81(1):1–17.
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.
Chen Z, Eldridge FL, Wagner PG. Respiratory-associated thalamic activity is related to level of respiratory drive. Respir Physiol. 1992;90(1):99–113.
Chen Z, Eldridge FL, Wagner PG. Respiratory-associated rhythmic firing of midbrain neurones in cats: relation to level of respiratory drive. J Physiol. 1991;437:305–25.
Eldridge FL, Millhorn DE, Waldrop TG. Exercise hyperpnea and locomotion: parallel activation from the hypothalamus. Science. 1981;211(4484):844–6.
Gandevia SC, Killian K, McKenzie DK, et al. Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during paralysis in humans. J Physiol. 1993;470:85–107.
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.
Stoeckel MC, Esser RW, Gamer M, Buchel C, von Leupoldt A. Brain responses during the anticipation of dyspnea. Neural Plast. 2016;2016:6434987.
Jolley CJ, Luo YM, Steier J, Rafferty GF, Polkey MI, Moxham J. Neural respiratory drive and breathlessness in COPD. Eur Respir J. 2015;45(2):355–64.
Jolley CJ, Luo YM, Steier J, et al. Neural respiratory drive in healthy subjects and in COPD. Eur Respir J. 2009;33(2):289–97.
Lou YM, Hart N, Mustfa N, Lyall RA, Polkey MI, Moxham J. Effect of diaphragm fatigue on neural respiratory drive. J Appl Physiol. 2001;90(5):1691–9.
Lou YM, Lyall RA, Harris ML, et al. Effect of lung volume on the oesophageal diaphragm EMG assessed by magnetic phrenic nerve stimulation. Eur Respir J. 2000;15(6):1033–8.
Lou YM, Moxham J. Measurment of neural respiratory drive in patients with COPD. Respir Physiol Neurobiol. 2005;146(2–3):165–74.
Faisal A, Alghamdi BJ, Ciavaglia CE, et al. Common mechanisms of dyspnea in chronic interstitial and obstructive lung disorders. Am J Respir Crit Care Med. 2016;193(3):299–309.
Guenette JA, Chin RC, Cheng S, et al. Mechanisms of exercise intolerance in Global Initiative for Chronic Obstructive Lung Disease grade 1 COPD. Eur Respir J. 2014;44(5):1177–87.
Elbehairy AF, Guenette JA, Faisal A, et al. Mechanisms of exertional dyspnoea in symptomatic smokers without COPD. Eur Respir J. 2016;48(3):694–705.
Elbehairy AF, Ciavaglia CE, Webb KA, et al. Pulmonary gas exchange abnormalities in mild chronic obstructive pulmonary disease: implications for dyspnea and exercise intolerance. Am J Respir Crit Care Med. 2015;191(12):1384–94.
Neder JA, Berton DC, Muller PT, et al. Ventilatory inefficiency and exertional dyspnea in early chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2017;14(Supplement_1):S22–9.
Hueper K, Vogel-Claussen J, Parikh MA, et al. Pulmonary microvascular blood flow in mild chronic obstructive pulmonary disease and emphysema: the MESA COPD study. Am J Respir Crit Care Med. 2015;192(5):570–80.
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.
Ofir D, Laveneziana P, Webb KA, Lam YM, O’Donnell DE. 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.
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):314–24.
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.
Ponikowski PP, Chua TP, Francis DP, Capucci A, Coats AJ, Piepoli MF. Muscle ergoreceptor overactivity reflects deterioration in clinical status and cardiorespiratory reflex control in chronic heart failure. Circulation. 2001;104(19):2324–30.
Porszasz J, Emtner M, Goto S, Somfay A, Whipp BJ, Casaburi R. Exercise training decreases ventilatory requirements and exercise-induced hyperinflation at submaximal intensities in patients with COPD. Chest. 2005;128(4):2025–34.
Ward SA, Whipp BJ. Kinetics of the ventilatory and metabolic responses to moderate-intensity exercise in humans following prior exercise-induced metabolic acidaemia. New Front Respir Control. 2009;669:323–6.
Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner CF, Wasserman K. Reductions in exercise lactic acidosis and ventilation as a result of exercise training in patients with obstructive lung disease. Am Rev Respir Dis. 1991;143(1):9–18.
Patessio A, Casaburi R, Carone M, Appendini L, Donner CF, Wasserman K. Comparison of gas exchange, lactate, and lactic acidosis thresholds in patients with chronic obstructive pulmonary disease. Am RevRespir Dis. 1993;148(3):622–6.
Maltais F, Leblanc P, Simard C, et al. Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1996;154(2):442–7.
Maltais F, Simard AA, Simard C, Jobin J, Desgagnés P, Leblanc P. Oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with COPD. Am J Respir Crit Care Med. 1996;153(1):288–93.
Sue DY, Chung MM, Grosvenor M, Wasserman K. Effect of altering the proportion of dietary fat and carbohydrate on exercise gas exchange in normal subjects. Am Rev Respir Dis. 1989;139(6):1430–4.
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.
O’Donnell DE. Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006;3(2):180–4.
Olafsson S, Hyatt RE. Ventilatory mechanics and expiratory flow limitation during exercise in normal subjects. J Clin Invest. 1969;48(3):564–73.
Dodd DS, Brancatisano T, Engel LA. Chest wall mechanics during exercise in patients with severe chronic air-flow obstruction. Am Rev Respir Dis. 1984;129(1):33–8.
Stubbing DG, Pengelly LD, Morse JLC, Jones NL. Pulmonary mechanics during exercise in subjects with chronic airflow obstruction. J Appl Physiol. 1980;49:511–5.
Similowski T, Yan S, Gauthier AP, Macklem PT, Bellemare F. Contractile properties of the human diaphragm during chronic hyperinflation. N Engl J Med. 1991;325(13):917–23.
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.
Puente-Maestu L, Palange P, Casaburi R, et al. Use of exercise testing in the evaluation of interventional efficacy: an official ERS statement. Eur Respir J. 2016;47(2):429–60.
Palange P, Ward SA, Carlsen KH, et al. Recommendations on the use of exercise testing in clinical practice. Eur Respir J. 2007;29(1):185–209.
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.
Laveneziana P, Webb KA, Ora J, Wadell K, O’Donnell DE. 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.
Laveneziana P, Palange P, Ora J, Martolini D, O’Donnell DE. Bronchodilator effect on ventilatory, pulmonary gas exchange, and heart rate kinetics during high-intensity exercise in COPD. Eur J Appl Physiol. 2009;107(6):633–43.
Laveneziana P, Valli G, Onorati P, Paoletti P, Ferrazza AM, Palange P. Effect of heliox on heart rate kinetics and dynamic hyperinflation during high-intensity exercise in COPD. Eur J Appl Physiol. 2011;111(2):225–34.
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.
Berton DC, Barbosa PB, Takara LS, et al. Bronchodilators accelerate the dynamics of muscle O2 delivery and utlisation during exercise in COPD. Thorax. 2010;65(7):588–93.
Elbehairy AF, Webb KA, Laveneziana P, Domnik NJ, Neder JA, O’Donnell DE. Acute bronchodilator therapy does not reduce wasted ventilation during exercise in COPD. Respir Physiol Neurobiol. 2018;252–253:64–71.
Vogel-Claussen J, Schönfeld C-O, Kaireit TF, et al. Effect of indacaterol/glycopyrronium on pulmonary perfusion and ventilation in hyperinflated COPD patients (CLAIM): a double-blind, randomised, crossover trial. Am J Respir Crit Care Med. 2019;199:1086–96.
Estepar RS, Kinney GL, Black-Shinn JL, et al. Computed tomographic measures of pulmonary vascular morphology in smokers and their clinical implications. Am J Respir Crit Care Med. 2013;188(2):231–9.
Iyer KS, Newell J, Jin D, et al. Quantitative dual-energy computed tomography supports a vascular etiology of smoking-induced inflammatory lung disease. Am J Respir Crit Care Med. 2016;193(6):652–61.
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.
O’Donnell DE, Bain DJ, Webb KA. Factors contributing to relief of exertional breathlessness during hyperoxia in chronic airflow limitation. Am J Respir Crit Care Med. 1997;155(2):530–5.
Ekström M, Ahmadi Z, Bornefalk‐Hermansson A, Abernethy A, Currow D. Oxygen for breathlessness in patients with chronic obstructive pulmonary disease who do not qualify for home oxygen therapy. Cochrane Database Syst Rev 2016;(11):CD006429.
Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med. 1980;93(3):391–8.
Stuart-Harris C, Bishop JM, Clark TJH, et al. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema: report of the Medical Research Council working party. Lancet. 1981;317(8222):681–6.
Vozoris NT, Wang X, Austin PC, et al. Adverse cardiac events associated with incident opioid drug use among older adults with COPD. Eur J Clin Pharmacol. 2017;73(10):1287–95.
Vozoris NT, Wang X, Fischer HD, et al. Incident opioid drug use and adverse respiratory outcomes among older adults with COPD. Eur Respir J. 2016;48(3):683–93.
Vozoris NT, Wang X, Fischer HD, et al. Incident opioid drug use among older adults with chronic obstructive pulmonary disease: a population-based cohort study. Br J Clin Pharmacol. 2016;81(1):161–70.
Jensen D, Alsuhail A, Viola R, Dudgeon DJ, Webb KA, O’Donnell DE. Inhaled fentanyl citrate improves exercise endurance during high-intensity constant work rate cycle exercise in chronic obstructive pulmonary disease. J Pain Symptom Manag. 2012;43(4):706–19.
Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Opioids for chronic refractory breathlessness: patient predictors of beneficial response. Eur Respir J. 2013;42(3):758–66.
Rocker GM, Simpson AC, Horton R, et al. Opioid therapy for refractory dyspnea in patients with advanced chronic obstructive pulmonary disease: patients’ experiences and outcomes. CMAJ Open. 2013;1(1):E27–36.
Ekstrom M, Nilsson F, Abernethy AA, Currow DC. Effects of opioids on breathlessness and exercise capacity in chronic obstructive pulmonary disease: a systematic review. Ann Am Thorac Soc. 2015;12(7):1079–92.
Abdallah SJ, Wilkinson-Maitland C, Saad N, et al. Effect of morphine on breathlessness and exercise endurance in advanced COPD: a randomised crossover study. Eur Respir J. 2017;50(4):1701235.
Barnes H, McDonald J, Smallwood N, Manser R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database Syst Rev. 2016;3(3):CD011008.
Currow D, Louw S, McCloud P, et al. Regular, sustained-release morphine for chronic breathlessness: a multicentre, double-blind, randomised, placebo-controlled trial. Thorax. 2019. https://doi.org/10.1136/thoraxjnl-2019-213681.
O’Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation: the role of lung hyperinflation. Am Rev Respir Dis. 1993;148(5):1351–7.
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.
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.
Laveneziana P, Webb KA, Wadell K, Neder JA, O’Donnell DE. Does expiratory muscle activity influence dynamic hyperinflation and exertional dyspnea in COPD? Respir Physiol Neurobiol. 2014;199:24–33.
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.
Gordon CS, Waller JW, Cook RM, Cavalera SL, Lim WT, Osadnik CR. Effect of pulmonary rehabilitation on symptoms of anxiety and depression in COPD: a systematic review and meta-analysis. Chest. 2019;156(1):80–91.
Herigstad M, Faull OK, Hayen A, et al. Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation. Eur Respir J. 2017;50(3):1701029.
McCarthy B, Casey D, Devane D, Murphy K, Murphy E, Lacasse Y. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;2:CD003793.
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2019 report). 2019. https://goldcopd.org/. Accessed 5 Sept 2019.
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.
O’Donnell DE, Laveneziana P. The clinical importance of dynamic lung hyperinflation in COPD. COPD. 2006;3:219–32.
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.
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(3):647–56.
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.
Calzetta L, Ora J, Cavalli F, Rogliani P, O’Donnell DE, Cazzola M. Impact of LABA/LAMA combination on exercise endurance and lung hyperinflation in COPD: a pair-wise and network meta-analysis. Respir Med. 2017;129:189–98.
Calzetta L, Rogliani P, Matera MG, Cazzola M. A systematic review with meta-analysis of dual bronchodilation with LAMA/LABA for the treatment of stable COPD. Chest. 2016;149(5):1181–96.
Oba Y, Keeney E, Ghatehorde N, Dias S. Dual combination therapy versus long‐acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta‐analysis. Cochrane Database Syst Rev 2018;(12):CD012620.
O’Donnell DE, Aaron S, Bourbeau J, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2007 update. Can Respir J. 2007;14:5B–32B.
Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265.
Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179–91.
Langer D, Ciavaglia CE, Faisal A, et al. Inspiratory muscle training reduces diaphragm activation and dyspnea during exercise in COPD. J Appl Physiol. 2018;125:381–92.
Gosselink R, De Vos J, van den Heuvel SP, Segers J, Decramer M, Kwakkel G. Impact of inspiratory muscle training in patients with COPD: what is the evidence? Eur Respir J. 2011;37(2):416–25.
Mahler DA, Waterman LA, Ward J, McCusker C, ZuWallack R, Baird JC. Validity and responsiveness of the self-administered computerized versions of the baseline and transition dyspnea indexes. Chest. 2007;132(4):1283–90.
Beaumont M, Forget P, Couturaud F, Reychler G. Effects of inspiratory muscle training in COPD patients: a systematic review and meta-analysis. Clin Respir J. 2018;12(7):2178–88.
Banzett RB, O’Donnell CR, Guilfoyle TE, et al. Multidimensional dyspnea profile: an instrument for clinical and laboratory research. Eur Respir J. 2015;45(6):1681–91.
Banzett RB, Moosavi SH. Measuring dyspnoea: new multidimensional instruments to match our 21st century understanding. Eur Respir J. 2017;49(3):1602473.
Kochovska S, Fazekas B, Hensley M, Wheatley J, Allcroft P, Currow DC. A randomized, double-blind, multisite, pilot, placebo-controlled trial of regular, low-dose morphine on outcomes of pulmonary rehabilitation in COPD. J Pain Symptom Manag. 2019. https://doi.org/10.1016/j.jpainsymman.2019.07.026.
Means JH. Dyspnea: medical monograph, vol. 5. Baltimore: Williams & Wilkins; 1924.
Cournand A, Richards DW. Pulmonary insufficiency, Part IL discussion of a physiological classification and presentation of clinical tests. Am Rev Tuberc. 1941;44:26–41.
Bradley TD, Chartrand DA, Fitting JW, Killian KJ, Grassino A. The relation of inspiratory effort sensation to fatiguing patterns of the diaphragm. Am Rev Respir Dis. 1986;134(6):1119–24.
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.
Jacobs SS, Lederer DJ, Garvey CM, et al. Optimizing home oxygen therapy: an official American Thoracic Society workshop report. Ann Am Thorac Soc. 2018;15(12):1369–81.
Vogiatzis I, Nanas S, Roussos C. Interval training as an alternative modality to continuous exercise in patients with COPD. Eur Respir J. 2002;20(1):12–9.
O’Donnell DE, McGuire M, Samis L, Webb KA. General exercise training improves ventilatory and peripheral muscle strength and endurance in chronic airflow limitation. Am J Respir Crit Care Med. 1998;157(5 Pt 1):1489–97.
Rochester CL, Vogiatzis I, Holland AE, et al. An official American Thoracic Society/European Respiratory Society policy statement: enhancing implementation, use, and delivery of pulmonary rehabilitation. Am J Respir Crit Care Med. 2015;192(11):1373–86.