Response to letter from Teppema and Berendsen concerning Fan <i>et al.</i> (2012): ‘Acetazolamide and cerebrovascular function at high altitude’

In their recent Letter to the Editor Teppema and Berendsen (2012) address a recent article by Fan et al. (2012) and raise two questions concerning the use of my modified rebreathing method at altitude. The authors state the first question as follows: ‘One of the features of Duffin's modified rebreathing is the initial hyperventilation lasting 5 min. At sea level this resulted in a mean and of 22 and 135 mmHg, respectively; at 5050 m these values were 17 and 63 mmHg (see Fan et al. 2010). In other words, in contrast to sea level, modified rebreathing at high altitude started with a sudden transient from a hypoxic to a hyperoxic condition. Despite the low , does this lead to a sudden reduction in carotid body output (and central chemoreceptor output if there is a crosstalk between them as recently suggested)? Note that in acclimatized subjects carotid body sensitivity is greatly enhanced (references in Teppema & Dahan, 2010) raising the question if hyperventilation down to a of 17 mmHg simply eliminates carotid body activity in these ‘sensitized’ subjects.’ The possibility of ‘crosstalk’ or central–peripheral interaction has been addressed in the past (St Croix et al. 1996) and was also examined using a new technique in a recent paper (Cui et al. 2011), and shown to be absent in humans, although present in animals (Blain et al. 2010; Tin et al. 2012). With respect to hyperventilation to a of 17 mmHg eliminating carotid body activity, this is indeed the purpose of the hyperventilation phase to lower the below chemoreceptor thresholds (Mohan & Duffin, 1997; Duffin et al. 2000), which are reduced during altitude acclimatisation (Somogyi et al. 2005; Fan et al. 2012). The second question is stated as follows: ‘During the course of modified rebreathing both the and ventilation rise. A crucial assumption underlying the Duffin type of rebreathing is that, due to the hyperventilation, the in all tissues decreases, which is followed by an equilibration of the arterial and central chemoreceptor during the rebreathing. Brain tissue () is closely linked to , but if cerebral blood flow (CBF) reaches saturation at a of 40–45 mmHg (a consistent observation by Battisti-Charbonney et al. 2011), the slope of the – relationship must change because the further rise is now solely dictated by the tissue CO2 buffering capacity. Does this lead to an altered ventilation– relationship?’ The second question is based on a misreading of Battisti-Charbonney et al. (2011); CBF reaches a vasodilatation threshold of about 50 mmHg as rises in hyperoxia, but continues to rise above that due to increasing perfusion pressure. This point is well illustrated in Zhang et al. (2011). Nevertheless, the question of whether the CBF response to affects the ventilation– relationship or more accurately the ventilation–brain tissue relationship is one that often arises when explaining the rebreathing approach. There is a general misconception that during rebreathing, brain tissue is driven by the rise in as it is in steady-state experiments. However, during rebreathing brain tissue rises due to the metabolic production of CO2, not due to the rising ; the latter is driven by the rise in tissue , not the reverse. Thus, rebreathing avoids the effect of CBF on the central arterial gradient, a problem that affects steady-state methods (Duffin, 2011). A caveat to these considerations is the recognition that the central chemoreceptors monitor [H+] (Gourine & Kasparov, 2011) and so changes in the relationship between and [H+] will affect the ventilation– relationship (Duffin, 2005).

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