Rebuttal from Luc J. Teppema and Curtis A. Smith



Duffin & Mateika (2013) state that their rebreathing data could also be fitted to a parabola. If they consider a parabolic shape an indication of hyper-additive interaction, it is surprising that they did not compare the quality of the fits of linear regression vs. parabolic or hyperbolic fits in order to decide which interaction mode would fit their data best. Apart from this, we have doubts about several assumptions underlying the modified rebreathing technique: (1) the absence of carotid body activity in hyperoxia; (2) that the hypoxic response would be a modified acidic response; (3) due to variable changes in CBF during the manouevre, the tissue–arterial inline image relationship cannot be constant (Battisti-Charbonney et al. 2011); and (4) absence of cortical influences on ventilation following 5 min of voluntary hyperventilation.

As explained by Robbins (1988), a linear inline imageinline image relationship is not inconsistent with multiplicative interaction. As outlined previously (Teppema & Berendsen, 2012), we do not agree with the claim of simple addition in humans by Cui et al. (2012) because they ignored the O2–CO2 interaction within the carotid bodies.

The fact that increasing carotid body output decreases the central CO2 threshold (Wilson & Day, 2013) is not inconsistent with (hyper)addition. By itself, it does not indicate hypoaddition.

In the dog model, blood pressure changes in the carotid sinus did not change ventilation despite potential cross-talk between brainstem sympathetic and respiratory neurons (Saupe et al. 1995). There was no evidence of retrogradely perfused blood affecting ventilation via the brainstem.

In dogs and goats, unilateral CBD has no functional implications (Smith et al. 1995). Reversing the stimulus order in steady-state conditions has no effect (Adams et al. 1978). The presentation order of changes in stimuli is not always peripheral and then central. Ischaemia or changes in CBF will first increase brain inline image. During an apnoea, inline image will rise first but thereafter it no longer depends on ventilation and tissue inline image will rise faster than inline image. Changes in metabolism may also cause changes in tissue inline image/pH, to be followed later by changes in the arterial blood.

The hybrid model (Wilson & Day, 2013) is inconsistent with data from dogs during the hyperventilation secondary to hypoxic exposure in non-REM sleep which showed an increased propensity for apnoea due to a steeper, not shallower, ventilatory response slope (Nakayama et al. 2002).

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