Prevailing evidence contradicts the notion of a “normobaric oxygen paradox”

Abstract

The “normobaric oxygen paradox” originates from the serendipitous Wnding of a marked increase in the endogenous erythropoietin concentration 24 and 36 h after the cessation of a single 2-h intervention of normobaric oxygen breathing; Balestra et al. (2006) suggested that a “relative hypoxic stimulus”, such as the transition from a high to a normal oxygen partial pressure (PO2) constitutes a powerful erythropoietic stimulus. Although intriguing, this single observation appears to be irreconcilable with prevailing evidence. Namely, prior to the introduction of the “normobaric oxygen paradox” notion, a number of studies had demonstrated that an acute exposure to normobaric hyperoxia suppresses erythropoiesis both in animals (Fletcher et al. 1973; Morshchakova et al. 1980) and humans (Kokot et al. 1994a, b). In addition, three recent independent studies in healthy individuals using an experimental design similar to that of Balestra et al. (2006) failed to reproduce their Wndings. Thus, neither McGuire et al. (2006) nor Momeni et al. (2011) observed any signiWcant diVerence in erythropoietin levels after an episode of breathing pure oxygen, whereas Keramidas et al. (2011) actually detected a suppression of plasma erythropoietin 3–5 h after a 2-h normobaric oxygen breathing in a single-blinded counterbalanced crossover investigation. Notwithstanding the lack of evidence corroborating the initial Wnding by Balestra et al. (2006) and the implausible premise of the erythropoietic potential of hyperoxia, the “normobaric oxygen paradox” is being submitted to justify advocating oxygen as a treatment for anaemia (Balestra et al. 2010; Calzia et al. 2010; Ciccarella et al. 2011; De Bels et al. 2011). This contention is not based on well-controlled and blinded studies, but rather on anecdotal evidence either in single anaemic individuals (Balestra et al. 2010; Burk 2007) or in postoperative patients (Ciccarella et al. 2011), in whom potentially confounding factors (e.g., pre-hospitalized status, drugs, sleep apnoea etc.) were not taken account of. The “normobaric oxygen paradox” is also being referred to when oxygen breathing is being recommended as an adjuvant treatment to stimulate erythropoiesis in patients with cancer (De Bels et al. 2011) and sepsis (Calzia et al. 2010), and as an ergogenic method for enhancement of endurance exercise performance (Balestra and Germonpre 2010). It appears that the bases for recommending oxygen breathing in these cases are solely preand mis-conceptions, since there are no investigations supporting the notion that repeated oxygen breathing increases erythropoiesis for any of these populations. By contrast, the suppressive role of normobaric hyperoxia in erythropoiesis has been conWrmed by long-term exposure to oxygen both continuously (Embury et al. 1984; Tsangaris et al. 1999) and intermittently (Keramidas et al. 2012). According to Balestra and coworkers, the sudden and sustained decrease in tissue PO2 on the transition from hyperoxicto normoxicor from normoxicto hypoxicbreathing conditions (Balestra et al. 2006; Balestra and Germonpre 2012) constitutes a key element for erythropoietin Communicated by Susan A. Ward.