Skip to main content
Log in

Exercise Limitation in IPF Patients: A Randomized Trial of Pulmonary Rehabilitation

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Background

Patients with idiopathic pulmonary fibrosis (IPF) have severely limited exercise capacity due to dyspnea, hypoxemia, and abnormal lung mechanics. This pilot study was designed to determine whether pulmonary rehabilitation were efficacious in improving the 6-min walk test (6-MWT) distance, exercise oxygen uptake, respiratory muscle strength [maximum inspiratory pressure (MIP)], and dyspnea in patients with IPF. Underlying physiological mechanisms and effects of the intervention were investigated.

Methods

Subjects were randomly assigned to a 3-month pulmonary rehabilitation program (n = 11) or to a control group (n = 10). All subjects initially underwent the 6-MWT and constant load exercise gas exchange studies.

Results

Subjects in the rehabilitation group increased treadmill exercise [metabolic equivalent of task-minutes] over the first 14 sessions. Beneficial effects on physical function resulted in those who completed rehabilitation. Subjects who completed the program increased cycle ergometer time and maintained exercise oxygen consumption (exercise VO2) at the baseline level over 3 months, while the control group suffered a significant decrease in exercise VO2. Rehabilitation subjects also increased their MIP. Plasma lactate doubled and brain natriuretic peptide levels increased significantly after exercise, as did the plasma amino acids glutamic acid, arginine, histidine, and methionine. These changes were associated with significant decreases in arterial oxygen saturation and increases in 15-F2t-isoprostanes after exercise.

Conclusions

Pulmonary rehabilitation effectively maintained exercise oxygen uptake over 3 months and lengthened constant load exercise time in patients with moderately severe IPF. Exercise endurance on cycle ergometry testing was limited by dyspnea and severe hypoxemia associated with systemic oxidant stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. King T, Pardo A, Selman M (2011) Idiopathic pulmonary fibrosis. Lancet 378:1949–1961

    Article  PubMed  Google Scholar 

  2. Christie J, Edwards L, Kucheryavaya A, Aurora P, Dobbels F, Kirk R, Rahmel A, Stehlik J, Hertz M (2010) The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart–lung transplantation report-2010. J Heart Lung Transplant 29:1103–1118

    Google Scholar 

  3. O’Donnell D, Laveneziana D (2007) Patterns of cardiopulmonary response to exercise in lung disease. Eur Respir Monogr 12:69–92

    Google Scholar 

  4. Jones N, Killian K (2000) Exercise limitation in health and disease. N Engl J Med 343:632–641

    Article  CAS  PubMed  Google Scholar 

  5. Shorr A, Wainright J, Cors C, Lettieri C, Nathan S (2007) Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J 30:715–721

    Article  CAS  PubMed  Google Scholar 

  6. Jackson R, Ramos C, Glassberg M, Bejarano P, Gómez-Marin O (2010) Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung 188:115–123

    Article  CAS  PubMed  Google Scholar 

  7. Clanton T (2007) Hypoxia-induced reactive oxygen species formation in skeletal muscle. J Appl Physiol 102:2379–2388

    Article  CAS  PubMed  Google Scholar 

  8. Jackson R, Ramos C, Gupta C, Gómez-Marin O (2010) Exercise decreases plasma antioxidant capacity and increases urinary isoprostanes in IPF. Respir Med 104:1919–1928

    Article  CAS  PubMed  Google Scholar 

  9. Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J, Carone M, Celli B, Engelen M, Fahy B, Garvey C, Goldstein R, Gosselink R, Lareau S, MacIntyre N, Maltais F, Morgan M, O’Donnell D, Prefault C, Reardon J, Rochester C, Schols A, Singh S, Troosters T, ATS, ERS Pulmonary Rehabilitation Writing Committee (2006) American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med 173:1390–1413

    Article  PubMed  Google Scholar 

  10. Holland A, Hill C (2008) Physical training for interstitial lung disease. Cochrane Database Syst Rev (4):CD006322. doi:10.1002/14651858.CD006322.pub2

  11. Nishiyama O, Kondoh Y, Kimura T, Kato K, Kataoke K, Ogawa T, Watanabe F, Arizono S, Nishimura K, Taniguchi H (2008) Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis. Respirology 13:354–399

    Article  Google Scholar 

  12. Salhi B, Troosters T, Behaegel M, Joos G, Derom E (2010) Effects of pulmonary rehabilitation in patients with restrictive lung diseases. Chest 137:273–279

    Article  PubMed  Google Scholar 

  13. Huppman P, Sczepansk B, Boensch M, Winterkamp Schonheit-Kenn U, Neurohr C, Behr J, Kenn K (2013) Effects of inpatient pulmonary rehabilitation in patients with interstitial lung disease. Eur Respir J 42:444–453

    Article  Google Scholar 

  14. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ, ATS, ERS, JRS, ALAT Committee on Idiopathic Pulmonary Fibrosis (2011) An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183:788–824

    Article  PubMed  Google Scholar 

  15. Arcasoy S, Christie J, Ferrari V, St. John Sutton M, Zisman D, Blumenthal N, Pochettino A, Kotloff R (2003) Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 167:735–740

    Article  PubMed  Google Scholar 

  16. Lynch D, Godwin D, Safrin S, Starko K, Hormel P, Brown K, Raghu G, King T, Bradford W, Schwartz D, Webb W (2005) High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 172:488–493

    Article  PubMed  Google Scholar 

  17. Rosdahl H, Gullstrand L, Salier-Eriksson J, Johansson P, Schantz P (2010) Evaluation of the Oxycon mobile metabolic system against the Douglas bag method. Eur J Appl Physiol 109:159–171

    Article  PubMed  Google Scholar 

  18. Puente-Maestu L, Sanz M, Sanz P, Ruiz de Ona J, Rodriguez-Hermosa J, Whipp B (2000) Effects of two types of training on pulmonary and cardiac responses to moderate exercise in patients with COPD. Eur Respir J 15:1026–1032

    Article  CAS  PubMed  Google Scholar 

  19. Puente-Maestu L, Sanz M, Sanz P, Cubillo J, Mayol J, Casaburi R (2000) Comparison of effects of supervised versus self-monitored training programmes in patients with chronic obstructive pulmonary disease. Eur Respir J 15:517–525

    Article  CAS  PubMed  Google Scholar 

  20. Palange P, Galassetti P, Mannix E, Farber M, Manfredi F, Serra P, Carlone S (1995) Oxygen effect on O2 deficit and VO2 kinetics during exercise in obstructive pulmonary disease. J Appl Physiol 78:2228–2234

    CAS  PubMed  Google Scholar 

  21. Solberg G, Robstad B, Skjonsberg O, Borchsenius F (2005) Respiratory gas exchange indices for estimating the anaerobic threshold. J Sports Sci Med 4:29–36

    PubMed Central  PubMed  Google Scholar 

  22. American Thoracic Society/European Respiratory Society (2002) ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med 166:518–624

    Article  Google Scholar 

  23. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories (2002) ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 166:111–117

    Article  Google Scholar 

  24. American Thoracic Society (1999) Dyspnea. Mechanisms, assessments and management: a consensus statement. Am J Resp Crit Care Med 159:321–340

    Article  Google Scholar 

  25. Byrne N, Hills A, Hunter G, Weinsier R, Schutz Y (2005) Metabolic equivalent: one size does not fit all. J Appl Physiol 99:1112–1119

    Article  PubMed  Google Scholar 

  26. Haschke M, Zhang Y, Kahle C, Klawitter J, Korecka M, Shaw L, Christians U (2007) HPLC-atmospheric pressure chemical ionization MS/MS for quantification of 15-F2-isoprostane in human urine and plasma. Clin Chem 53:1–9

    Article  Google Scholar 

  27. Klawitter J, Haschke M, Shokati T, Klawitter J, Christians U (2011) Quantification of 15-F2-isoprostane in human plasma and urine: Results from enzyme-linked immunoassay and liquid chromatography cannot be compared. Rapid Commun Mass Spectrom 25:463–468

    Article  CAS  PubMed  Google Scholar 

  28. Lundholm L, Mohme-Lundholm E, Vamos N (1963) Lactic acid assay with L(+) lactic acid dehydrogenase from rabbit muscle. Acta Physiol Scand 58:243–249

    Article  CAS  PubMed  Google Scholar 

  29. Elin R, Winter W (2004) Laboratory and clinical aspects of b-type natriuretic peptides. Arch Pathol Lab Med 128:669–697

    Google Scholar 

  30. Cnaan A, Laird N, Slasor P (1997) Using the general linear mixed model to analyze unbalanced repeated measures and longitudinal data. Stat Med 16:2349–2380

    Article  CAS  PubMed  Google Scholar 

  31. Powers S, Nelson W, Hudson M (2011) Exercise-induced oxidative stress in humans: causes and consequences. Free Radical Biol Med 51:942–950

    Article  CAS  Google Scholar 

  32. Basu S (2008) F2-isoprostanes in human health and diseases: from molecular mechanisms to clinical implications. Antioxid Redox Signal 10:1405–1434

    Article  CAS  PubMed  Google Scholar 

  33. Leuchte H, Neurohr C, Baumgartner R, Holzapfel M, Giehrl W, Vogeser M, Behr J (2004) Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 170:360–365

    Article  PubMed  Google Scholar 

  34. Blanco I, Ribas J, Xaubet A, Gómez F, Roca J, Rodriguez-Roisin R, Barberà J (2011) Effects of inhaled nitric oxide at rest and during exercise in idiopathic pulmonary fibrosis. J Appl Physiol 110:138–145

    Article  Google Scholar 

  35. Henriksson J (1991) Effect of exercise on amino acid concentrations in skeletal muscle and plasma. J Exp Biol 160:149–165

    CAS  PubMed  Google Scholar 

  36. Engelen M, Wouters E, Does J, Schols A (2001) Effects of exercise on amino acid metabolism in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 161:859–864

    Article  Google Scholar 

  37. Pisarenko O, Solomatina E, Ivanov V, Studneva I, Kapelko V, Smirnov V (1985) On the mechanism of enhanced ATP formation in hypoxic myocardium caused by glutamic acid. Basic Res Cardiol 80:126–134

    Article  CAS  PubMed  Google Scholar 

  38. Mitani Y, Maruyama K, Sakurai M (1997) Prolonged administration of l-arginine ameliorates chronic pulmonary hypertension and pulmonary vascular remodeling in rats. Circulation 96:689–697

    Article  CAS  PubMed  Google Scholar 

  39. du Bois R, Weycker D, Albera C, Bradford W, Costabel U, Karteshev A, Lancaster L, Noble P, Sahn S, Swarcberg J, Thomer M, Veleye D, King T (2011) Six-minute-walk tests in idiopathic pulmonary fibrosis. Test validation and minimal clinically important difference. Am J Respir Crit Care Med 183:1231–1237

    Article  PubMed  Google Scholar 

  40. Bolton C, Bevan-Smith E, Blakely J, Crowe P, Elkin S, Garrod R, Greening N, Heslop K, Hull J, Man W, Morgan M, Proud D, Roberts M, Sewell L, Singh S, Walker P, Walmsley S (2013) British Thoracic Society guideline on pulmonary rehabilitation in adults. Thorax 68:ii1–ii30

    PubMed  Google Scholar 

  41. Ferreira A, Garvey C, Connors G, Hilling L, Rigler J, Ferrell S, Cayou C, Shoriat C, Collard H (2009) Pulmonary rehabilitation in interstitial lung disease. Benefits and predictors of response. Chest 135:442–447

    Article  PubMed  Google Scholar 

  42. Cahalin L, Pappagianopoulus P, Prevost S, Wain J, Ginns L (1995) The relationship of the 6-minute walk test to maximal oxygen consumption in transplant candidates with end stage lung disease. Chest 108:452–459

    Article  CAS  PubMed  Google Scholar 

  43. Fell C, Liu L, Motika C, Kaserooni E, Gross B, Travis W, Colby T, Murray S, Toews G, Martinez F, Flaherty K (2009) The prognostic value of cardiopulmonary exercise testing in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 179:402–407

    Article  PubMed Central  PubMed  Google Scholar 

  44. Yorke J, Jones P, Swigris J (2010) Development and validity testing of an IPF specific version of the St George’s respiratory questionnaire. Thorax 65:921–926

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Rafael Valenzuela and Mr. Roman Miguel for assaying lactate and NT-proBNP. We also thank Drs. Uwe Christians and Jelena Klawitter of Integrated Solutions in Clinical Research and Development, University of Colorado, Aurora, CO, for assaying 15-F2t-isoprostanes. This study was supported by a Merit Review Award from the VA Research Service.

Conflict of interest

The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert M. Jackson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jackson, R.M., Gómez-Marín, O.W., Ramos, C.F. et al. Exercise Limitation in IPF Patients: A Randomized Trial of Pulmonary Rehabilitation. Lung 192, 367–376 (2014). https://doi.org/10.1007/s00408-014-9566-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-014-9566-9

Keywords

Navigation