Send letter to journal:
Re: Increase in Hb mass after alitude training in elite junior athletes

Dear Editors,

Dres. Gore and Hahn suggest that the significant mean increase of 6% in total haemoglobin mass (tHbmass) which we observed after altitude training in elite junior swimmers might to a major extend be attributed to few erroneous measurements after altitude training. As already discussed in the paper, we agree that an increase of about 24% is astonishingly high. However, as pointed out, we were not the first to observe a wide inter-individual variability in the erythropoietic response to altitude exposure. Large inter-individual differences in the hypoxia-induced increase in erythropoietin are well known [1-3] and a wide inter- individual variation has also been described for the increase in red blood cell volume after altitude training leading to the hypothesis that there might be “responders” and “non-responders” to altitude training [1].

Furthermore, measurements with Evans Blue dye [1] and with technetium labelling (cited in 4) yielded comparable significant increases in tHbmass or total red blood cell volume, respectively, when differences in time and altitude of exposure are taken into account. It was the aim of our study to find out if changes in tHbmass after altitude training might be predicted by the erythropoietin response after short exposure to moderate normobaric hypoxia. We did not want to provide an answer to the question whether or not 3 weeks of training at moderate altitude leads to an increase in the tHbmass of elite junior swimmers. Therefore, we did not include a control group of elite junior swimmers performing equivalent training at sea level.

We thank Dres. Gore and Hahn for drawing our attention to the paper of Parisotto et al. [5] reporting changes in tHbmass after administration of r-HuEPO. This paper, unfortunately, escaped our attention because title, abstract and key words did not refer to tHbmass. Two major differences between this paper and our study might account for the considerably larger variability in tHbmass in our subjects: First, Parisotto et al. injected doses of erythropoietin based on body weight which results in a much smaller inter-individual variability in plasma levels of erythropoietin than natural exposure to altitude.

Secondly, we studied elite junior athletes, who might increase total haemoglobin more than adult elite athletes and might also show greater variability when subjected to endurance training at altitude as they still experience growth and maturation. To our knowledge, the erythropoietic response of adolescent athletes to altitude training has not been studied so far.

We are well aware of the fact that any leak in the CO-rebreathing system would result in erroneously high values for blood volume. Therefore, we performed our measurements with great care to avoid such leakages. Should nevertheless any leakage have occurred in some measurements, it can be expected to be distributed randomly between baseline and post-exposure measurements. Therefore, the reported average increase in tHbmass of 6% should not have been affected substantially, while erroneous measurements could at least in part account for a lack of correlation between the increase in plasma erythropoietin levels and tHbmass. However, as mentioned in our paper, there are other investigations that could not find a significant correlation between tHbmass and erythropoietin response under comparable circumstances.

Furthermore, C.J Gore and A. G. Hahn refer to the study of Burge and Skinner [6] and state that the small dose of CO used in our study and the larger rebreathing volume are suboptimal. Burge and Skinner recommend an increase in COHb of at least 6.5 % to achieve a good degree of sensitivity and precision for the determination of tHbmass. However, they also admit that in another study of Thomsen et al. [7] changes in COHb > 5% reduced the coefficient of variation only marginally and that an increase of COHb of about 5 % also produces acceptable results in the measurement of tHbmass. The CO-volume of 0.85 ml • kg-1 in our study induced a mean increase in COHb of 5.2% which thus cannot be considered as “suboptimal”.

In summary, we conclude that the mean 6 % increase in tHbmass, which is in agreement with increases reported by other investigators [1,4], cannot be explained by erroneous measurements.

References

1. Chapman RF, Stray-Gundersen J, Levine BD. Individual variation in response to altitude training. J Appl Physiol 1998; 85: 1448-1456.

2. Richalet J-P, Souberbielle J-C, Antezana A-M, et al. Control of erythropoiesis in humans during prolonged exposure to the altitude of 6542 m. Am J Physiol 1994; 266: R756-R764.

3. Ge RL, Witkowski S, Zhang Y, et al. Determinants of erythropoietin release in response to short-term hypobaric hypoxia. J Appl Physiol 2002; 92:2361-2367.

4. Rusko HK, Tikkanen HO, Peltonen JE: Altitude and endurance training. J. Sports Science 2004; 22: 928-945.

5. Parisotto R, Gore CJ, Emslie KR, et al. A novel method utilising markers of altered erythropoiesis for the detection of recombinant human erythropoietin abuse in athletes. Haematologica 2000; 85: 564-572.

6. Burge CM, Skinner S. Determination of haemoglobin mass and blood volume with CO: evaluation and application of a method. J Appl Physiol 1995; 79: 623-631.

7. Thomsen JK, Fogh-Andersen N, BĂĽlow K, Devantier A. Blood and plasma volumes determined by carbon monoxide gas, 99m Tc-labelled erythrocytes, 125 I-albumin and the T 1824 technique. Scand J Clin Lab Invest 1991; 51: 185-190.

Send letter to journal:
Re: Why such large increases in Hb mass?

Dear Editors,

The altitude training study of Friedmann et al. reported a 6% increase in haemoglobin mass (Hbmass), but this result warrants close scrutiny, particularly without a corroborating measure of augmented VO2max, nor of corresponding measures in a matched control group. The authors’ contend that “there exist no studies in which the changes in total haemoglobin mass following treatment with recombinant human were measured…”. But in 2001, we reported increased Hbmass after 4 weeks of injections with recombinant human EPO (r HuEPO) at doses of 50 IU/kg, thrice weekly [1]. When combined with weekly iron supplements either intra-muscularly or orally, the mean (SD) increase in Hbmass was 7 (2)% and 12 (2)%, respectively [1]. In comparison, by interpolating from Friedmann’s Figure 2A, we calculate a mean (SD) expansion of Hbmass of 6 (7)%, reinforcing the authors’ conclusion of large individual variability.

Although we commend the authors for providing individual percent changes in Hbmass, rises of 24, 18 and even 13% (interpolation from their Figure 2A) after 3 weeks at 2100-2300m are disconcerting. Collectively, these three subjects contribute more than half of the overall group increase in Hbmass. Moreover, perturbations as large as these are extreme given the relatively attenuated EPO response of altitude compared with r HuEPO injections [2]. What else might contribute to such large increase in Hbmass? From our experience, the most common source of error with the CO- method is a leak by a subject around the mouthpiece or noseclip, or a leak in the rebreathing apparatus itself. An inadvertent leak substantially increases, never decreases, the estimated Hbmass. Secondly, a small rebreathing volume and large dose of CO (~1.5 ml.kg-1 for men and 1.25 ml.kg-1 for women) ameliorate the magnitude of error for Hbmass, but the smaller dose used by Friedmann (0.85 ml.kg-1) and the larger rebreathing volume (5L) are sub-optimal [3].

References

1. Parisotto R, Gore CJ, Emslie KR, et al. A novel method utilising markers of altered erythropoiesis for the detection of recombinant human erythropoietin abuse in athletes. Haematologica 2000;85:564-72.

2. Ashenden MJ, Hahn AG, Martin DT, et al. A comparison of the physiological response to simulated altitude exposure and r-HuEpo administration. J Sports Sci 2001;19:831-7.

3. Burge CM, Skinner SL. Determination of hemoglobin mass and blood volume with CO: evaluation and application of a method. J Appl Physiol 1995;79:623-31.