Yokhana SS, Gerst DG 3rd, Lee DS, Badr MS, Qureshi T, Mateika JH. Impact of repeated daily exposure to intermittent hypoxia and mild sustained hypercapnia on apnea severity. J Appl Physiol 112: 367-377, 2012. First published November 3, 2011; doi: 10.1152/japplphysiol.00702.2011.-We examined whether exposure to intermittent hypoxia (IH) during wakefulness impacted on the apnea/hypopnea index (AHI) during sleep in individuals with sleep apnea. Participants were exposed to twelve 4-min episodes of hypoxia in the presence of sustained mild hypercapnia each day for 10 days. A control group was exposed to sustained mild hypercapnia for a similar duration. The intermittent hypoxia protocol was completed in the evening on day 1 and 10 and was followed by a sleep study. During all sleep studies, the change in esophageal pressure (Delta Pes) from the beginning to the end of an apnea and the tidal volume immediately following apneic events were used to measure respiratory drive. Following exposure to IH on day 1 and 10, the AHI increased above baseline measures (day 1: 1.95 +/- 0.42 fraction of baseline, P <= 0.01, vs. day 10: 1.53 +/- 0.24 fraction of baseline, P < 0.06). The indexes were correlated to the hypoxic ventilatory response (HVR) measured during the IH protocol but were not correlated to the magnitude of ventilatory long-term facilitation (vLTF). Likewise, Delta Pes and tidal volume measures were greater on day 1 and 10 compared with baseline (Delta Pes: - 8.37 +/- 0.84 vs. -5.90 +/- 1.30 cmH(2)0, P <= 0.04; tidal volume: 1,193.36 +/- 101.85 vs. 1,015.14 +/- 119.83 ml, P <= 0.01). This was not the case in the control group. Interestingly, the AHI on day 10 (0.78 +/- 0.13 fraction of baseline, P <= 0.01) was significantly less than measures obtained during baseline and day 1 in the mild hypercapnia control group. We conclude that enhancement of the HVR initiated by exposure to IH may lead to increases in the AHI during sleep and that initiation of vLTF did not appear to impact on breathing stability. Lastly, our results suggest that repeated daily exposure to mild sustained hypercapnia may lead to a decrease in breathing events.