Sub-anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial
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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 ClinicalTrials.gov (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.
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 ClinicalTrials.gov (NCT number: 02129400).
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