Maturation of respiratory control and the propensity for breathing instability in a sheep model

Limited evidence suggests that the ventilatory interaction between O(2) and CO(2) is additive after birth and becomes multiplicative with postnatal development. Such a switch may be linked to the propensity for periodic breathing (PB) in infancy. To test this idea, we characterized the maturation of the respiratory controller and its effect on breathing stability in approximately 10-day-old lambs and 6-mo-old sheep. We measured 1) carotid body sensitivity via dynamic ventilatory responses to step changes in O(2) and CO(2), 2) steady-state ventilatory sensitivity to CO(2) under hypoxic and hyperoxic conditions, 3) the dependence of the apneic threshold on arterial Po(2), and 4) the effect of hypoxic or hypercapnic gas inhalation during induced PB. Stability of the system was assessed using surrogate measures of loop gain. Peripheral sensitivity to O(2) was higher in newborn than in older animals (P < 0.05), but peripheral CO(2) sensitivity was unchanged. Central CO(2) sensitivity was reduced with age, but the slopes of the ventilatory responses to CO(2) were the same in hypoxia and hyperoxia. Reduced arterial Po(2) caused a leftward shift in the apneic threshold at both ages. Inspiration of hypoxic gas during PB immediately halted PB, whereas hypercapnia stopped PB only after one or two further PB cycles. We conclude that the controller in the sheep remains additive over the first 6 mo of life. Our results also show that the loop gain of the respiratory control system is reduced with age, possibly as a result of a reduction of peripheral O(2) sensitivity.