European Journal of Applied Physiology

, Volume 112, Issue 3, pp 1059–1065 | Cite as

Acute short-term hyperoxia followed by mild hypoxia does not increase EPO production: resolving the “normobaric oxygen paradox”

  • Tadej Debevec
  • Michail E. Keramidas
  • Barbara Norman
  • Thomas Gustafsson
  • Ola Eiken
  • Igor B. Mekjavic
Original Article


Recent findings suggest that besides renal tissue hypoxia, relative decrements in tissue oxygenation, using a transition of the breathing mixture from hyperoxic to normoxic, can also stimulate erythropoietin (EPO) production. To further clarify the importance of the relative change in tissue oxygenation on plasma EPO concentration [EPO], we investigated the effect of a consecutive hyperoxic and hypoxic breathing intervention. Eighteen healthy male subjects were assigned to either IHH (N = 10) or CON (N = 8) group. The IHH group breathed pure oxygen (FiO2 ~ 1.0) for 1 h, followed by a 1-h period of breathing a hypoxic gas mixture (FiO2 ~ 0.15). The CON group breathed a normoxic gas mixture (FiO2 ~ 0.21) for the same duration (2 h). Blood samples were taken just before, after 60 min, and immediately after the 2-h exposure period. Thereafter, samples were taken at 3, 5, 8, 24, 32, and 48 h after the exposure. During the breathing interventions, subjects remained in supine position. There were significant increases in absolute [EPO] within groups at 8 and 32 h in the CON and at 32 h only in the IHH group. No significant differences in absolute [EPO] were observed between groups following the intervention. Relative (∆[EPO]) levels were significantly lower in the IHH than in the CON group, 5 and 8 h following exposure. The tested protocol of consecutive hyperoxic-hypoxic gas mixture breathing did not induce [EPO] synthesis stimulation. Moreover, the transient attenuation in ∆[EPO] in the IHH group was most likely due to a hyperoxic suppression. Hence, our findings provide further evidence against the “normobaric O2 paradox” theory.


Erythropoiesis Hyperoxemia Individual variation Diurnal variation 



The authors wish to thank the dedicated participants. Our thanks are also extended to Dr. Alenka Nemec-Svete and Miro Vrhovec for their technical support. This study was founded, in part, by grants from the Slovene Research Agency (grant no. L7-2413) and b-Cat (The Netherlands) to Igor B. Mekjavic and Ola Eiken. Tadej Debevec and Michail E. Keramidas are recipients of Young Researcher Scholarships from the Slovene Research Agency

Conflict of interest

No conflict of interest is declared.


  1. Balestra C, Germonpre P, Poortmans J, Marroni A, Schiettecatte J, Collard JF, Snoeck T (2004) Erythropoietin production can be enhanced by normobaric oxygen breathing in healthy humans. Undersea Hyperb Med 31:53–57PubMedGoogle Scholar
  2. Balestra C, Germonpre P, Poortmans JR, Marroni A (2006) Serum erythropoietin levels in healthy humans after a short period of normobaric and hyperbaric oxygen breathing: the “normobaric oxygen paradox. J Appl Physiol 100:512–518PubMedCrossRefGoogle Scholar
  3. Burk R (2007) Oxygen breathing may be a cheaper and safer alternative to exogenous erythropoietin (EPO). Med Hypotheses 69:1200–1204PubMedCrossRefGoogle Scholar
  4. Chapman RF, Stray-Gundersen J, Levine BD (1998) Individual variation in response to altitude training. J Appl Physiol 85:1448–1456PubMedGoogle Scholar
  5. De Bels D, Corazza F, Germonpre P, Balestra C (2011) The normobaric oxygen paradox: a novel way to administer oxygen as an adjuvant treatment for cancer? Med Hypotheses 76:467–470PubMedCrossRefGoogle Scholar
  6. Eckardt KU, Kurtz A (2005) Regulation of erythropoietin production. Eur J Clin Invest 35(Suppl 3):13–19PubMedCrossRefGoogle Scholar
  7. Eckardt KU, Boutellier U, Kurtz A, Schopen M, Koller EA, Bauer C (1989) Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol 66:1785–1788PubMedGoogle Scholar
  8. Erslev AJ (1997) Clinical erythrokinetics: a critical review. Blood Rev 11:160–167PubMedCrossRefGoogle Scholar
  9. Faura J, Ramos J, Reynafarje C, English E, Finne P, Finch CA (1969) Effect of altitude on erythropoiesis. Blood 33:668–676PubMedGoogle Scholar
  10. Ge RL, Witkowski S, Zhang Y, Alfrey C, Sivieri M, Karlsen T, Resaland GK, Harber M, Stray-Gundersen J, Levine BD (2002) Determinants of erythropoietin release in response to short-term hypobaric hypoxia. J Appl Physiol 92:2361–2367PubMedGoogle Scholar
  11. Gunga HC, Kirsch KA, Roecker L, Kohlberg E, Tiedemann J, Steinach M, Schobersberger W (2007) Erythropoietin regulations in humans under different environmental and experimental conditions. Respir Physiol Neurobiol 158:287–297PubMedCrossRefGoogle Scholar
  12. Haddad JJ, Olver RE, Land SC (2000) Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells. J Biol Chem 275:21130–21139PubMedCrossRefGoogle Scholar
  13. Hofso D, Ulvik RJ, Segadal K, Hope A, Thorsen E (2005) Changes in erythropoietin and haemoglobin concentrations in response to saturation diving. Eur J Appl Physiol 95:191–196PubMedCrossRefGoogle Scholar
  14. Jelkmann W (2007) Erythropoietin after a century of research: younger than ever. Eur J Haematol 78:183–205PubMedCrossRefGoogle Scholar
  15. Keramidas ME, Kounalakis SN, Debevec T, Norman B, Gustafsson T, Eiken O, Mekjavic IB (2011) Acute normobaric hyperoxia transiently attenuates plasma erythropoietin concentration in healthy males: evidence against the ‘normobaric oxygen paradox’ theory. Acta Physiol (Oxf) 202:91–98CrossRefGoogle Scholar
  16. Klausen T, Dela F, Hippe E, Galbo H (1993) Diurnal variations of serum erythropoietin in trained and untrained subjects. Eur J Appl Physiol Occup Physiol 67:545–548PubMedCrossRefGoogle Scholar
  17. Knaupp W, Khilnani S, Sherwood J, Scharf S, Steinberg H (1992) Erythropoietin response to acute normobaric hypoxia in humans. J Appl Physiol 73:837–840PubMedGoogle Scholar
  18. Kokot F, Franek E, Kokot M, Wiecek A (1994a) Erythropoietin secretion in patients with chronic renal failure after pure oxygen breathing. Nephron 67:436–440PubMedCrossRefGoogle Scholar
  19. Kokot M, Kokot F, Franek E, Wiecek A, Nowicki M, Dulawa J (1994b) Effect of isobaric hyperoxemia on erythropoietin secretion in hypertensive patients. Hypertension 24:486–490PubMedGoogle Scholar
  20. Levine BD (2002) Intermittent hypoxic training: fact and fancy. High Alt Med Biol 3:177–193PubMedCrossRefGoogle Scholar
  21. Levine BD, Stray-Gundersen J (1997) Living high-training low: effect of moderate-altitude acclimatization with low-altitude training on performance. J Appl Physiol 83:102–112PubMedGoogle Scholar
  22. Mackenzie RW, Watt PW, Maxwell NS (2008) Acute normobaric hypoxia stimulates erythropoietin release. High Alt Med Biol 9:28–37PubMedCrossRefGoogle Scholar
  23. McGuire A, Querido J, Fedoruk M, Wang P, Rupert J, McKenzie D (2006) Plasma erythropoietin concentration following normobaric hyperoxia. Appl Physiol Nutr Metab 31:S58Google Scholar
  24. Momeni M, De Kock M, Devuyst O, Liistro G (2011) Effect of N-acetyl-cysteine and hyperoxia on erythropoietin production. Eur J Appl Physiol doi: 10.1007/s00421-011-1893-4
  25. Ou LC, Salceda S, Schuster SJ, Dunnack LM, Brink-Johnsen T, Chen J, Leiter JC (1998) Polycythemic responses to hypoxia: molecular and genetic mechanisms of chronic mountain sickness. J Appl Physiol 84:1242–1251PubMedGoogle Scholar
  26. Paliege A, Rosenberger C, Bondke A, Sciesielski L, Shina A, Heyman SN, Flippin LA, Arend M, Klaus SJ, Bachmann S (2010) Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization. Kidney Int 77:312–318PubMedCrossRefGoogle Scholar
  27. Patel TV, Singh AK (2010) Anemia in chronic kidney disease: new advances. Heart Fail Clin 6:347–357PubMedCrossRefGoogle Scholar
  28. Roberts D, Smith DJ (1996) Erythropoietin does not demonstrate circadian rhythm in healthy men. J Appl Physiol 80:847–851PubMedGoogle Scholar
  29. Rodriguez FA, Ventura JL, Casas M, Casas H, Pages T, Rama R, Ricart A, Palacios L, Viscor G (2000) Erythropoietin acute reaction and haematological adaptations to short, intermittent hypobaric hypoxia. Eur J Appl Physiol 82:170–177PubMedCrossRefGoogle Scholar
  30. Samaja M (2001) Hypoxia-dependent protein expression: erythropoietin. High Alt Med Biol 2:155–163PubMedCrossRefGoogle Scholar
  31. Saunders PU, Pyne DB, Gore CJ (2009) Endurance training at altitude. High Alt Med Biol 10:135–148PubMedCrossRefGoogle Scholar
  32. Savourey G, Launay JC, Besnard Y, Guinet A, Bourrilhon C, Cabane D, Martin S, Caravel JP, Pequignot JM, Cottet-Emard JM (2004) Control of erythropoiesis after high altitude acclimatization. Eur J Appl Physiol 93:47–56PubMedCrossRefGoogle Scholar
  33. Stray-Gundersen J, Chapman RF, Levine BD (2001) Living high-training low altitude training improves sea level performance in male and female elite runners. J Appl Physiol 91:1113–1120PubMedGoogle Scholar
  34. Tanabe N, Ohnishi K, Fukui H, Ohno R (1997) Effect of smoking on the serum concentration of erythropoietin and granulocyte-colony stimulating factor. Intern Med 36:680–684PubMedCrossRefGoogle Scholar
  35. Westenbrink BD, Voors AA, de Boer RA, Schuringa JJ, Klinkenberg T, van der Harst P, Vellenga E, van Veldhuisen DJ, van Gilst WH (2010) Bone marrow dysfunction in chronic heart failure patients. Eur J Heart Fail 12:676–684PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Tadej Debevec
    • 1
    • 2
  • Michail E. Keramidas
    • 1
    • 2
  • Barbara Norman
    • 3
  • Thomas Gustafsson
    • 3
  • Ola Eiken
    • 4
  • Igor B. Mekjavic
    • 1
  1. 1.Department of Automation, Biocybernetics and RoboticsJozef Stefan InstituteLjubljanaSlovenia
  2. 2.Jozef Stefan International Postgraduate SchoolLjubljanaSlovenia
  3. 3.Division of Clinical Physiology, Department of Laboratory MedicineKarolinska InstituteStockholmSweden
  4. 4.Department of Environmental Physiology, School of Technology and HealthRoyal Institute of TechnologyStockholmSweden

Personalised recommendations