Flat beer vs. physiological improvement: effect of acetazolamide during hypoxic exercise

The paper by Jonk et al. (2007) in the current issue of The Journal of Physiology addresses an important matter related to exercise at altitude by studying the effects of the commonly used drug acetazolamide (ACZ) in normal individuals. ACZ is a relatively simple drug, a carbonic anhydrase inhibitor, though the mechanisms of action may be complex in the whole animal (Swenson & Teppema, 2007). One curious and common side-effect is that carbonated beverages like beer taste ‘flat’ after ingestion of ACZ (Graber & Kelleher, 1988; McMurdo et al. 1990). Is it worth suffering flat beer for improvement in physiology when ascending to altitude? In the Introduction, the authors address the questions of gas exchange and fluid balance in the lungs with the combined stress of altitude and exercise, which they simulate using normobaric hypoxia and exercise. The results of this investigation provide important new data regarding the effects of ACZ on lung gas exchange, though it is important to put this issue into context.

The basic mechanism for relief of high altitude symptoms by ACZ is thought to be an increase in ventilation from drug induced acidaemia, though ACZ may also attenuate hypoxic pulmonary vasoconstriction, which could improve gas exchange in the lungs under hypoxic stress. Jonk et al. (2007) explored the effects of ACZ on gas exchange in both lung and skeletal muscle by studying relatively fit normal volunteers under four conditions, all during bouts of cycle exercise tailored to the subject's own exercise capacity (30%, 50% and 90% of ). The four conditions allowed the group to compare hypoxic with normoxic exercise, with and without treatment with ACZ. Gas exchange in the lungs was quantified with the multiple inert gas elimination technique (MIGET), which is the current standard for quantifying lung gas exchange. The results showed that there were no effects of ACZ on leg blood flow, but there was a significant improvement in lung gas exchange efficiency with ACZ. Under ACZ treatment, subjects had a higher $P_{{\text{a},\text{O}}_2}$, and lower A-a $D_{{\text{O}}_2}$. In gas exchange theory, higher $P_{{\text{a},\text{O}}_2}$ and lowered A-a $D_{{\text{O}}_2}$ could result from a number of mechanisms, though the MIGET results specifically support an improved mismatching with a narrowing of the recovered logSDQ distribution. Although their study did not further explore mechanisms for these changes, the authors provide a nice review of potential mechanisms for the narrowing of the logSDQ distribution, which include a relative acidaemia in the presence of ACZ, and possible reduction in intensity of hypoxic pulmonary vasoconstriction by ACZ.

To address a possible increase in lung water on exposure to either hypoxia or exercise, the authors use the calculated A-a $D_{{\text{O}}_2}$ compared to measured A-a $D_{{\text{O}}_2}$ to estimate lung diffusing capacity for O₂, and found no statistically significant change in this parameter. A reduction in diffusion capacity would have implicated a change in the alveolar–capillary exchange barrier, possibly by changing the volume of interstitial lung fluid. However, comparing the predicted with measured A-a $D_{{\text{O}}_2}$ is one of the weaker applications of the MIGET technique. MIGET cannot quantify all sources of right to left shunting, and efforts to back-calculate the A-a $D_{{\text{O}}_2}$ using MIGET data often result in unphysiologically negative values, as was found in this study. This is a potentially important point, since there is continued debate as to whether there are subtle changes in lung water after exposure to either hypoxia or exercise alone, or exercise in hypoxia (see below). Because of the limitations in MIGET pointed out above, these conclusions need further experimental support.

Are short-term bouts of exercise in normobaric hypoxia a good model for exercise at altitude? In animals, there is evidence that lung lymphatic flow increases as cardiac output increases during relatively short-term exercise (Newman et al. 1988) and that lung water is not affected by short bouts of exercise (Coates et al. 1984; Marshall et al. 1975). These two findings suggest that lung lymph flow increases during exercise without expansion of the lung interstitial fluid space, or that any increase in lung fluid during exercise is transient and rapidly cleared after exercise. In humans, short duration exercise likewise does not appear to increase interstitial fluid when measured after exercise (Hanel et al. 1994) though measurements in humans are less direct than in animal studies that use direct, post mortem measures of lung water. Longer duration exercise may result in subclinical oedema after a triathalon (Caillaud et al. 1995). These findings in humans are consistent with data comparing shorter with longer duration exercise in sheep, though the evidence is still somewhat indirect: lymph flow remains high in recovery after longer duration exercise, suggesting a persistent increase in lung fluid that is slower to clear compared to shorter bouts of exercise (Newman et al. 1988).

The data of Jonk et al. (2007) only report lung function during hypoxia, which may be different from exposure to altitude. A recent study documented an increase in alveolar–capillary conductance and reduction in imaging measures of lung water on exposure of subjects to 17 h of normobaric hypoxia and exercise (Snyder et al. 2006) consistent with the study of Jonk et al. (2007) and the literature cited above for short-term exercise. Combining exercise with ascent to altitude, Cremona et al. (2002) provided reasonable evidence using relatively indirect measures that a surprisingly high fraction of climbers making a single-day ascent to 4559 m altitude experience increases in lung water. Setting aside methodological issues, whether the increase in lung water during exercise on ascent to altitude is due to hypobaric conditions, the hypoxia, or the longer duration exercise is currently unknown and also needs further investigation. Further studies using more direct measures of changes in lung water, or measurements of gas exchange efficiency with MIGET, would certainly be helpful to define changes in lung physiology under the combined stress of exercise and hypobaric hypoxia (altitude).

In conclusion, it appears that short-term exercise and normobaric hypoxia may not induce the changes in lung interstitium that would simulate altitude related illnesses. Longer term exercise or hypobaric hypoxia or both may combine to present more severe stresses to the lungs. It appears that the shorter duration exercise or nomobaric hypoxia used by Jonk et al. (2007) may limit application of their results to real-life altitude illness. Though the results of Jonk et al. make an important contribution to our understanding of exercise, hypoxia and effects of ACZ, different results may well be obtained with more realistic situations or more severe physiological stresses.

So, is it worth suffering flat beer after ingestion of ACZ to prevent symptoms at altitude? Probably, though the complete physiological mechanisms are yet to be determined.