Sports Medicine

, Volume 47, Issue 2, pp 381–382 | Cite as

Authors’ Reply to Anoop Balachandran et al.: Comment on “Sub-Anesthetic Xenon Increases Erythropoietin Levels in Humans: A Randomized Controlled Trial”

  • Christian StoppeEmail author
  • Julia Ney
  • Rolf Rossaint
  • Mark Coburn
  • Andreas Goetzenich
Letter to the Editor

We would like to thank Dr. Balachandran and colleagues for their interesting letter [1], which opens the discussion about the overall value and importance of statistical tests in explorative pilot studies, the primary aim of which is to uncover possible problems in implementing and assessing an intervention. In addition, a pilot study is conducted in order to address questions that are important for the design and conduct of the full-scale trial and is therefore often called a feasibility or vanguard study.

We agree with Bland and Altman that a missing comparison between groups may be misleading and should be interpreted with caution [2]. However, in apparent contrast, Tukey previously stated that exploratory analyses per se should emphasize graphical or numerical descriptions, whereas, subsequently, classical confirmatory analyses should emphasize significant versus non-significant results [3]. For this reason, further results of our analysis were not provided in the present study [4], although our statistical analysis revealed a significant difference when comparing the increase in erythropoietin levels from baseline to maximum levels between the Xenon and control groups (median 9.00 [25th–75th percentile 4.3–11.4] vs. 2.95 [25th–75th percentile 2.02–8.32]; p = 0.016). We decided not to report these results but to demonstrate that there is a visual biological effect, which is based on a sound underlying scientific rationale and convincing preclinical data [5, 6, 7]. These concerns about reporting results from pilot studies are supported by Friedman et al. who claimed that we need to have confidence that those who read, interpret, and use the reports are smart enough to understand their limitations [8].

However, we agree with Balachandran et al. that the observed findings should receive more careful investigation in following confirmatory studies as it remains unclear what aspects of treatments should be measured and what measure of response will be favorable to demonstrate a clinical or functionally relevant effect. Therefore, our findings should be seen and interpreted in light of the study by Friedman et al. who strongly support the publication of early-phase pilot studies, irrespective of the statistical significance [8]. Both exploratory and confirmatory data analyses are obviously needed as both types approach different aims.


Compliance with Ethical Standards

Conflict of interest

Christian Stoppe, Julia Ney, Rolf Rossaint, Mark Coburn and Andreas Goetzenich declare that they have no conflicts of interest relevant to the content of this letter.


No financial support was received for the preparation of this letter.


  1. 1.
    Balachandran A. Comment on “Sub-anesthetic xenon increases erythropoietin levels in humans: a randomized controlled trial.” Sports Med. 2016. doi: 10.1007/s40279-016-0659-x PubMedGoogle Scholar
  2. 2.
    Bland JM, Altman DG. Comparisons against baseline within randomised groups are often used and can be highly misleading. Trials. 2011;12:264.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Tukey JW. Exploratory data analysis: past, present and future. Technical report. Princeton: Princeton University; 1993.Google Scholar
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    Stoppe C, Ney J, Brenke M, Goetzenich A, Emontzpohl C, Schälte G, et al. Sub-anesthetic xenon increases erythropoietin levels in humans: a randomized controlled trial. Sports Med. 2016;46(11):1753–66.CrossRefPubMedGoogle Scholar
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    Ma D, Lim T, Xu J, Tang H, Wan Y, Zhao H, et al. Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. J Am Soc Nephrol. 2009;20:713–20.CrossRefPubMedPubMedCentralGoogle Scholar
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    Goetzenich A, Hatam N, Preuss S, Moza A, Bleilevens C, Roehl AB, et al. The role of hypoxia-inducible factor-1α and vascular endothelial growth factor in late-phase preconditioning with xenon, isoflurane and levosimendan in rat cardiomyocytes. Interact Cardiovasc Thorac Surg. 2014;18:321–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Stoppe C, Coburn M, Fahlenkamp A, Ney J, Kraemer S, Rossaint R, et al. 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
  8. 8.
    Friedman L. Commentary: why we should report results from clinical trial pilot studies. Trials. 2013;14:14.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Christian Stoppe
    • 1
    Email author
  • Julia Ney
    • 2
  • Rolf Rossaint
    • 2
  • Mark Coburn
    • 2
  • Andreas Goetzenich
    • 3
  1. 1.Department of Intensive Care MedicineUniversity Hospital RWTH AachenAachenGermany
  2. 2.Department of AnaesthesiologyUniversity Hospital RWTH AachenAachenGermany
  3. 3.Department of Thoracic, Cardiac and Vascular SurgeryUniversity Hospital RWTH AachenAachenGermany

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