Sports Medicine

, Volume 46, Issue 11, pp 1753–1766 | Cite as

Sub-anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial

  • Christian StoppeEmail author
  • Julia Ney
  • Martin Brenke
  • Andreas Goetzenich
  • Christoph Emontzpohl
  • Gereon Schälte
  • Oliver Grottke
  • Manfred Moeller
  • Rolf Rossaint
  • Mark Coburn
Original Research Article



The licensed anesthetic xenon, which exerts organ protective properties, was recently added by the World Anti-Doping Agency to the list of prohibited substances. Xenon is supposed to trigger the production of hypoxia-inducible factor 1α (HIF-1α) and subsequently erythropoietin, but data are limited to in vivo experimental work. Therefore we evaluated the effect of xenon on erythropoietin levels in healthy persons.


Twenty-four healthy volunteers were randomly assigned either to a group spontaneously breathing xenon 30 % (Xe/O2 30 %/60 %) or a group breathing control gas (N2/O2 40 %/60 %) for 45 min. Primary outcome parameters were erythropoietin levels at several time-points after exposure. Secondary outcome parameters were serum levels of testosterone, cytokines, and growth factors as well as concentrations of xenon in blood and exhalation samples measured at several time-points after exposure. In addition, hemodynamic safety parameters were monitored during exposure.


The administration of xenon significantly increased erythropoietin levels 8 h after exposure (1.34 [±0.368]; p = 0.008), peaking at 24 h compared to the baseline values (1.45 [±0.498]; p = 0.01) and remained traceable in blood and exhalation probes until 24 h after exposure. In contrast, no significant change was observed in the control group. Measurement of stromal cell-derived factor 1 (SDF-1) revealed a significant increase of SDF-1 levels (p = 0.005), whereas no differences were observed with respect to growth factors, cytokines, or androgens. In an in vitro chemotaxis assay, endothelial progenitor cells (EPCs) showed a trend towards increased migration in serum samples received from participants after xenon exposure (p = 0.080).


The present study presents first evidence about a xenon-induced effect on increased erythropoietin levels in healthy volunteers.

The study was registered at the European Medicines Agency (EudraCT-number: 2014-000973-38) and at (NCT number: 02129400).



RR, MC, CS,together with JN conceived the study and drafted the manuscript. JN, MB, MM, AG, GS, and CE carried out the experiments and data acquisition. AG and OG analyzed the blood samples with respect to the measured cytokines, EPO, and hemoglobin (OG). CE performed the in vitro analysis. MM carried out gas chromatographic analyses (blood probes and exhaled air probes). MC, CS, and JN analyzed the received data. JN and CS designed the artwork (Fig. 7). GS and OG revised the manuscript, emphasizing the relevance of EPO and resulting effects on sportsmen. All authors revised and approved the final version of the manuscript. All authors agree to be accountable for all aspects of the work and ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

We thank Bernd Simon for construction of the respirator set-up and for the artwork (Online resource 1). Furthermore we would like to thank Mrs Hiltrud Niggemann (Jena, Germany) for statistical support.

Compliance with Ethical Standards

Declaration of interests and funding

All authors read and completed the conflict of interest form. Christian Stoppe, Julia Ney, Martin Brenke, Andreas Goetzenich, Christoph Emontzpohl, Gereon Schälte, Oliver Grottke, Manfred Möller, Rolf Rossaint, and Mark Coburn declare that they have no conflicts of interest. No conflicts of interest relevant to this article were reported. All costs to conduct this trial were covered by the Department of Anesthesiology. No grants were received for this project.

Ethical approval

All procedures performed in the study involving human participants received approval by the local institutional review board (EK 059/14) and the German Federal Drug Administration (BfArM) and were in accordance with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individual participants included in the study. The study was registered at the European Medicines Agency (EudraCT-number: 2014-000973-38) and at (NCT number: 02129400).

Supplementary material

40279_2016_505_MOESM1_ESM.docx (443 kb)
Supplementary material 1 (DOCX 443 kb)


  1. 1.
  2. 2.
    Koh B, Neef M. Xenon gas as a performance-enhancing drug: doping or just hot air? CyclingTips 2014. Accessed 12 May 2015.
  3. 3.
    Seppelt H. Geheimsache Doping—Wie Russland seine Sieger macht, ARD. 2014: Dec 3rd. Accessed 13 May 2015.
  4. 4.
    Pound W, McLaren RH, Younger G, Robertson J, et al. The Independent Commission Report #1. 9th November 2015.Google Scholar
  5. 5.
    Bukhtiyarov IV, Kalmanov AS, Kislyakov UU, Nikiforov DA, Chistov SD, Shvetskiy FM, Bubeyev UA. Studying of xenon adaptility within training process for functional state correction in sportsmen. НАУЧНО&ПРАКТИЧЕСКИЙ ЖУРНАЛ. 2010;6 (78):22.Google Scholar
  6. 6.
    Kalmanov AS, Yu A, Bubeev, Kotrovskaya TI. Course application effect of oxygen-xenon gas mixture inhalation on functional status of mountaineers. НАУЧНО&ПРАКТИЧЕСКИЙ ЖУРНАЛ. 2011;3(87):28.Google Scholar
  7. 7.
    Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA. 2005;293:90–5.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chong ZZ, Kang J-Q, Maiese K. Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation. 2002;106:2973–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Gao D, Ning N, Niu X, Dang Y, Dong X, Wei J, Zhu C. Erythropoietin treatment in patients with acute myocardial infarction: a meta-analysis of randomized controlled trials. Am Heart J. 2012;164(715–727):e1.Google Scholar
  10. 10.
    Derwall M, Coburn M, Rex S, Hein M, Rossaint R, Fries M. Xenon: recent developments and future perspectives. Minerva Anestesiol. 2009;75:37–45.PubMedGoogle Scholar
  11. 11.
    Stoppe C, Fahlenkamp AV, Rex S, Veeck NC, Gozdowsky SC, Schälte G, Autschbach R, Rossaint R, Coburn M. Feasibility and safety of xenon compared with sevoflurane anaesthesia in coronary surgical patients: a randomized controlled pilot study. Br J Anaesth. 2013;111:406–16.CrossRefPubMedGoogle Scholar
  12. 12.
    Ma D, Lim T, Xu J, Tang H, Wan Y, Zhao H, Hossain M, Maxwell PH, Maze M. Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. J Am Soc Nephrol. 2009;20:713–20.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tanaka, et al. General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain. Plos One. 2011; 6(12):e29378.Google Scholar
  14. 14.
    Baugh JA, Gantier M, Li L, Byrne A, Buckley A, Donnelly SC. Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1. Biochem Biophys Res Commun. 2006;347:895–903.CrossRefPubMedGoogle Scholar
  15. 15.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10:858–64.CrossRefPubMedGoogle Scholar
  16. 16.
    Stoppe C, Rimek A, Rossaint R, Rex S, Stevanovic A, Schälte G, Fahlenkamp A, Czaplik M, Bruells CS, Daviet C, Coburn M. Xenon consumption during general surgery: a retrospective observational study. Med Gas Res. 2013;3:12.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Stoppe C, Fries M, Rossaint R, Grieb G, Coburn M, Simons D, Brücken D, Bernhagen J, Pallua N, Rex S. Blood levels of macrophage migration inhibitory factor after successful resuscitation from cardiac arrest. PLoS One. 2012;7:e33512.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kolb B, Ettre LS. Theory and practice of multiple headspace extraction. Chromatographia. 1991;32(11–12):505–13.CrossRefGoogle Scholar
  19. 19.
    Coburn M, Kunitz O, Apfel CC, Hein M, Fries M, Rossaint R. Incidence of postoperative nausea and emetic episodes after xenon anaesthesia compared with propofol-based anaesthesia. Br J Anaesth. 2008;100:787–91.CrossRefPubMedGoogle Scholar
  20. 20.
    Coburn M, Kunitz O, Baumert J-H, Hecker K, Haaf S, Zühlsdorff A, Beeker T, Rossaint R. Randomized controlled trial of the haemodynamic and recovery effects of xenon or propofol anaesthesia. Br J Anaesth. 2005;94:198–202.CrossRefPubMedGoogle Scholar
  21. 21.
    Rishpon-Meyerstein N, Kilbridge T, Simone J, Fried W. The effect of testosterone on erythropoietin levels in anemic patients. Blood. 1968;31:453–60.PubMedGoogle Scholar
  22. 22.
    Axelsson J, Ingre M, Akerstedt T, Holmbäck U. Effects of acutely displaced sleep on testosterone. J Clin Endocrinol Metab. 2005;90:4530–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Bromage DI, Davidson SM, Yellon DM. Stromal derived factor 1α: a chemokine that delivers a two-pronged defence of the myocardium. Pharmacol Ther. 2014;143:305–15.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Davidson SM, Selvaraj P, He D, Boi-Doku C, Yellon RL, Vicencio JM, Yellon DM. Remote ischaemic preconditioning involves signalling through the SDF-1α/CXCR4 signalling axis. Basic Res Cardiol. 2013;108:377.CrossRefPubMedGoogle Scholar
  25. 25.
    Meganathan K, Sotiriadou I, Natarajan K, Hescheler J, Sachinidis A. Signaling molecules, transcription growth factors and other regulators revealed from in vivo and in vitro models for the regulation of cardiac development. Int J Cardiol. 2015;183C:117–28.CrossRefGoogle Scholar
  26. 26.
    Papaloucas M, Kyriazi K, Kouloulias V. Pheromones: a new ergogenic aid in sport? Int J Sports Physiol Perform. 2015;. doi: 10.1123/ijspp.2014-0226.PubMedGoogle Scholar
  27. 27.
    Déry M-AC, Michaud MD, Richard DE. Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol. 2005;37:535–40.CrossRefPubMedGoogle Scholar
  28. 28.
    Fahlenkamp AV, Coburn M, Haase H, Kipp M, Ryang Y-M, Rossaint R, Beyer C. Xenon enhances LPS-induced IL-1β expression in microglia via the extracellular signal-regulated kinase 1/2 pathway. J Mol Neurosci. 2011;45:48–59.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhang Q, Oh CK, Messadi DV, Duong HS, Kelly AP, Soo C, Wang L, Le AD. Hypoxia-induced HIF-1 alpha accumulation is augmented in a co-culture of keloid fibroblasts and human mast cells: involvement of ERK1/2 and PI-3K/Akt. Exp Cell Res. 2006;312:145–55.CrossRefPubMedGoogle Scholar
  30. 30.
    Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Stoppe C, Coburn M, Fahlenkamp A, Ney J, Kraemer S, Rossaint R, Goetzenich A. Elevated serum concentrations of erythropoietin after xenon anaesthesia in cardiac surgery: secondary analysis of a randomized controlled trial. Br J Anaesth. 2015;114:701–3.CrossRefPubMedGoogle Scholar
  32. 32.
    Eltzschig HK, Bratton DL, Colgan SP. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov. 2014;13:852–69.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ferrario M, Arbustini E, Massa M, Rosti V, Marziliano N, Raineri C, Campanelli R, Bertoletti A, De Ferrari GM, Klersy C, Angoli L, Bramucci E, Marinoni B, Ferlini M, Moretti E, Raisaro A, Repetto A, Schwartz PJ, Tavazzi L. High-dose erythropoietin in patients with acute myocardial infarction: a pilot, randomised, placebo-controlled study. Int J Cardiol. 2011;147:124–31.CrossRefPubMedGoogle Scholar
  34. 34.
    Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther. 2007;116:173–91.CrossRefPubMedGoogle Scholar
  35. 35.
    Debevec T, Keramidas ME, Norman B, Gustafsson T, Eiken O, Mekjavic IB. Acute short-term hyperoxia followed by mild hypoxia does not increase EPO production: resolving the “normobaric oxygen paradox”. Eur J Appl Physiol. 2012;112:1059–65.CrossRefPubMedGoogle Scholar
  36. 36.
    Ludman AJ, Yellon DM, Hasleton J, Ariti C, Babu GG, Boston-Griffiths E, Venugopal V, Walker M, Holdright D, Swanton H, Crake T, Brull D, Moon JC, Puranik R, Muthurangu V, Mutharangu V, Taylor A, Hausenloy DJ. Effect of erythropoietin as an adjunct to primary percutaneous coronary intervention: a randomised controlled clinical trial. Heart. 2011;97:1560–5.CrossRefPubMedGoogle Scholar
  37. 37.
    Najjar SS, Rao SV, Melloni C, Raman SV, Povsic TJ, Melton L, Barsness GW, Prather K, Heitner JF, Kilaru R, Gruberg L, Hasselblad V, Greenbaum AB, Patel M, Kim RJ, Talan M, Ferrucci L, Longo DL, Lakatta EG, Harrington RA, REVEAL Investigators. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA. 2011;305:1863–72.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Macdougall IC, Gray SJ, Elston O, Breen C, Jenkins B, Browne J, Egrie J. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol. 1999;10:2392–5.PubMedGoogle Scholar
  39. 39.
    Yelkmann W. Regulation of erythropoietin production. J Physiol. 2011;589(Pt 6):1251–8.CrossRefGoogle Scholar
  40. 40.
    Durussel J, et al. Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men. Plos One. 2013;8(2):e56151.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Epoetin alfa. Medscape. Accessed 21 June 2015.
  42. 42.
    Meloni EG, Gillis TE, Manoukian J, Kaufman MJ. Xenon impairs reconsolidation of fear memories in a rat model of post-traumatic stress disorder (PTSD). PLoS One. 2014;9(8):e106189.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Giacalone M, Abramo A, Giunta F, Forfori F. Xenon-related analgesia: a new target for pain treatment. Clin J Pain. 2013;29(7):639–43.CrossRefPubMedGoogle Scholar
  44. 44.
    Thevis M, Piper T, Geyer H, Thomas A, Schaefer MS, Kienbaum P, Schänzer W. Measuring xenon in human plasma and blood by gas chromatography/mass spectrometry. Rapid Commun Mass Spectrom. 2014;28(13):1501–6.CrossRefPubMedGoogle Scholar
  45. 45.
    Goto T, Suwa K, Uezono S, Ichinose F, Uchiyama M, Morita S. The blood-gas partition coefficient of xenon may be lower than generally accepted. Br J Anaesth. 1998;80(2):255–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Balestra C, Germonpré P, Poortmans JR, Marroni A. Serum erythropoietin levels in healthy humans after a short period of normobaric and hyperbaric oxygen breathing: the “normobaric oxygen paradox”. J Appl Physiol. 2006;100:512–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Keramidas ME, Kounalakis SN, Debevec T, Norman B, Gustafsson T, Eiken O, Mekjavic IB. Acute normobaric hyperoxia transiently attenuates plasma erythropoietin concentration in healthy males: evidence against the “normobaric oxygen paradox” theory. Acta Physiol (Oxf). 2011;202:91–8.CrossRefGoogle Scholar
  48. 48.
    Momeni M, De Kock M, Devuyst O, Liistro G. Effect of N-acetyl-cysteine and hyperoxia on erythropoietin production. Eur J Appl Physiol. 2011;111:2681–6.CrossRefPubMedGoogle Scholar
  49. 49.
    Miller ME, Cronkite EP, Garcia JF. Plasma levels of immunoreactive erythropoietin after acute blood loss in man. Br J Haematol. 1982;52(4):545–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Liu W, Liu Y, Chen H, Liu K, Tao H, Sun X. Xenon preconditioning: molecular mechanisms and biological effects. Med Gas Res. 2013;3:3.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Christian Stoppe
    • 1
    • 3
    Email author
  • Julia Ney
    • 1
  • Martin Brenke
    • 1
  • Andreas Goetzenich
    • 2
  • Christoph Emontzpohl
    • 3
  • Gereon Schälte
    • 1
  • Oliver Grottke
    • 1
  • Manfred Moeller
    • 4
  • Rolf Rossaint
    • 1
  • Mark Coburn
    • 1
  1. 1.Department of AnaesthesiologyUniversity Hospital RWTHAachenGermany
  2. 2.Department of Thoracic, Cardiac and Vascular SurgeryUniversity Hospital RWTH AachenAachenGermany
  3. 3.Institute of Biochemistry and Molecular Cell BiologyUniversity Hospital RWTH AachenAachenGermany
  4. 4.Institute of Hygiene and Environmental MedicineUniversity Hospital RWTH AachenAachenGermany

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