Hemoglobin mass response to simulated hypoxia "blinded" by noisy measurement?

TO THE EDITOR: Siebenmann and colleagues (13) found that 4 wk of simulated altitude (16 hr/day, 3,000 m) failed to increase Hbmass. We believe their methodology to quantify Hbmass was suboptimal, which confounds interpretation. In the mid-1990s, Finnish scientists reported increased red cell mass following 3– 4 wk of simulated altitude (8). Subsequent attempts by our group failed to reproduce these findings (2). In 2004, Rusko (11) suggested that an adequate hypoxic stimulus required 12 hr/day, 2,000 m, 3 wk. Indeed, since 2006, using the optimized CO-rebreathing technique (9), we have consistently observed mean increases in Hbmass of 3–5% after exposures of 14 hr/day, 3,000 m, 21 days in elite athletes (3, 6, 10, 12) and furthermore demonstrated this response as reproducible (10). We also quantified that individual variation of the Hbmass response to this hypoxic dose is of similar magnitude to the mean increase (10). We therefore disagree with the assertion of Siebenmann that “the presence of an effect on Hbmass crucially depends on the random composition of the subject groups,” as our nonresponders can usually be explained by illness, injury, or training stress. By using duplicate measures, we have demonstrated a mean increase in Hbmass of 1% per 100 h to both simulated (3, 6) and natural altitude (4). On the basis of these findings we would expect a 4 –5% increase in Siebenmann’s study. It is difficult to directly compare initial Hbmass values to other recently published studies in elite athletes (4, 10), because the CO-rebreathing method used by Siebenmann, results in an 2% overestimation of Hbmass because CO loss to myoglobin is unaccounted for (5). We consider it unlikely that the lack of increase is due to high baseline values. We are also concerned by Siebenmann’s relatively high typical error of 2.6% and contend that a likely explanation for the absence of an Hbmass response is a relatively poor signal-to-noise ratio. We have published extensively on ways to reduce error in Hbmass measurement (1, 5, 7) and suggest that the optimized method is superior for minimizing measurement error (5). We encourage all researchers to adopt this methodology. Specifically, in regard to Siebenmann’s method, HbCO% values of venous blood must be corrected for oxygen saturation and CO mixed completely throughout all vascular compartments before sampling (5). HbCO content of venous blood rises slowly following the onset of rebreathing and does not converge to a plateau until 10 min. Additionally, if venous blood is sampled prematurely (i.e., at 8 min as described by Siebenmann), this method may yield spuriously high Hbmass values (5). In our experience, on the basis of many Hbmass measurements of elite athletes using the optimized CO-rebreathing method, most athletes who are sufficiently fueled, iron supplemented, not sick or injured, and appropriately trained, typically show an increased Hbmass following an adequate hypoxic stimulus. More research is required to understand why some athletes fail to increase Hbmass. However, insights into this topic are best made when Hbmass is quantified with the highest precision technique available. Unlike Siebenmann’s approach, the optimized CO-rebreathing method (9), with recent refinements (5), holds more promise for quantifying small mean effects and individual responses to altitude.