Running Title: Respiratory instability in lambs Address for proofs and correspondence:

We examined the effect of hypoxia and hypercapnia administered during deliberately induced periodic breathing (PB) in 7 lambs following post-hyperventilation apnea. Based on our theoretical analysis the sensitivity or loop gain (LG) of the respiratory control system of the lamb is directly proportional to the difference between alveolar PO2 and inspired PO2. This analysis indicates that during PB, when by necessity LG is> 1, replacement of the inspired gas with one of reduced PO2 lowers LG; if we made PIO2 approximate alveolar PO2, we predict LG would be approximately zero, and breathing would promptly stabilize. In 6 lambs we switched the inspired gas from FIO2 = 0.4 to FIO2 = 0.12 during an epoch of PB; PB was immediately suppressed supporting the view that the peripheral chemoreceptors play a pivotal role in the genesis and control of unstable breathing in the lamb. In the 6 lambs in which we administered hypercapnic gas during PB, breathing instability was also suppressed, but only after a considerable time lag, indicating the CO2 effect is likely to have been mediated through the central chemoreceptors. When we simulated both interventions in a published model of the adult respiratory controller, PB wa