The impact of arousal state, sex, and sleep apnea on the magnitude of progressive augmentation and ventilatory long-term facilitation

Abstract

We examined the impact of arousal state, sex, and obstructive sleep apnea (OSA) on the magnitude of progressive augmentation of the hypoxic ventilatory response and ventilatory long-term facilitation (vLTF). We also examined whether exposure to intermittent hypoxia during sleep has an impact on the apnea-hypopnea index (AHI) in individuals with OSA. Ten men and seven women with OSA, along with ten healthy men and ten healthy women, were exposed to twelve 2-min episodes of hypoxia (end-tidal PO(2): 50 Torr) in the presence of sustained hypercapnia (end-tidal PCO(2): 3 Torr above baseline), followed by a 30-min recovery period during wakefulness and sleep. The OSA participants completed an additional sham study during sleep. The AHI during the first hour of sleep following the intermittent hypoxia and sham protocols were compared. Progressive augmentation was only evident during wakefulness and was enhanced in the OSA participants. vLTF was evident during wakefulness and sleep. When standardized to baseline, vLTF was greater during wakefulness and was enhanced in the OSA group (men: wakefulness 1.39 ± 0.08 vs. sleep 1.14 ± 0.03; women: wakefulness 1.35 ± 0.03 vs. sleep 1.16 ± 0.05 fraction of baseline; P ≤ 0.001) compared with control (men: wakefulness 1.19 ± 0.03 vs. sleep 1.09 ± 0.03; women: wakefulness 1.26 ± 0.05 vs. sleep 1.08 ± 0.04 fraction of baseline; P ≤ 0.001). The AHI following exposure to intermittent hypoxia was increased (intermittent hypoxia 72.8 ± 7.3 vs. sham 56.5 ± 7.0 events/h; P ≤ 0.01). Sex-related differences were not observed for the primary measures. We conclude that progressive augmentation is not evident, and the magnitude of vLTF is diminished during sleep compared with wakefulness in men and women. However, when present, the phenomena are enhanced in individuals with OSA. The AHI data indicate that, under the prevailing experimental conditions, vLTF did not serve to mitigate apnea severity.

Figures

Fig. 1.

Experimental design and intermittent hypoxia and sham protocols. A schematic diagram shows the experimental design (A), and the intermittent hypoxia (B) and sham (C) protocols. Breathing events were recorded for 1 h following the intermittent hypoxia and sham protocol during sleep in the obstructive sleep apnea (OSA) participants. CPAP, continuous positive airway pressure; PetCO2, partial pressure of end-tidal carbon dioxide; PetO2, partial pressure of end-tidal oxygen; B1, initial baseline period measured under normoxic conditions; B2, second baseline period measured under hypercapnic conditions.

Fig. 2.

Measures of the hypoxic ventilatory response (HVR) during the intermittent hypoxia protocol completed during wakefulness and sleep. Average values of the HVR determined for the initial two episodes and the final two episodes of the intermittent hypoxia protocol in men and women of the OSA and control groups are shown. Note that the HVR was greater during wakefulness compared with sleep. Moreover, note that there was a progressive increase in the HVR from the initial two episodes to the final two episodes during wakefulness but not sleep. Furthermore, note that progressive augmentation of the HVR was greater in the OSA group compared with control in both men and women. SaO2, Arterial oxygen saturation. Values are means ± SE. ‡Significantly different from initial episodes. †Significantly different from sleep.

Fig. 3.

Measures of minute ventilation (top), PetCO2 (middle), and PetO2 (bottom) during completion of the intermittent hypoxia protocol during wakefulness and sleep. A raw record of breath-by-breath minute ventilation recorded from one participant exposed to intermittent hypoxia is shown. The dotted lines represent baseline values specific to each state. Note that minute ventilation during the end-recovery period was greater than baseline during wakefulness as well as during sleep. B1, last 5 min of the initial normocapnic 10 min baseline period; B2, last 5 min of the second baseline period during which PetCO2 was elevated 3 Torr above B1 measures.

Fig. 4.

Minute ventilation during the end-recovery period expressed as a fraction of baseline measured during wakefulness and sleep. Note that ventilatory long-term facilitation (vLTF) was elicited during both wakefulness and sleep in both OSA and control groups; however, the magnitude of vLTF was greater during wakefulness compared with sleep. Also note that the magnitude of vLTF was more enhanced in the OSA group compared with control during both wakefulness and sleep. Values are means ± SE. †Significantly different from sleep. ΦSignificantly different from control.

Fig. 5.

The relative contribution of tidal volume (top) and breathing frequency (bottom) toward minute ventilation during the end-recovery period expressed as a fraction of baseline. Note that tidal volume during the end-recovery period contributed to vLTF during both wakefulness and sleep, whereas the contributions of breathing frequency to vLTF were significant during wakefulness only. Values are means ± SE. †Significantly different from sleep. ΦSignificantly different from control.

Fig. 6.

Minute ventilation during the end-recovery period expressed as a fraction of baseline following exposure to the intermittent hypoxia and sham protocols during sleep in the OSA group. Note that minute ventilation was significantly greater than baseline following exposure to intermittent hypoxia compared with sham exposure. Values are means ± SE. δSignificantly different from sham.

Fig. 7.

Measures of tidal volume (top) and breathing frequency (bottom) during the end-recovery period expressed as a fraction of baseline in the OSA group following exposure to the intermittent hypoxia and sham protocols during sleep. Note that tidal volume is significantly greater following exposure to intermittent hypoxia compared with sham exposure, while breathing frequency is similar following exposure to both protocols. Values are means ± SE. δSignificantly different from sham.

Fig. 8.

Measures of the apnea-hypopnea index obtained from 1 h following exposure to the intermittent hypoxia and sham protocols during sleep in the OSA participants. Note that the number of respiratory events increased following exposure to intermittent hypoxia compared with sham exposure. Values are means ± SE. δSignificantly different from sham.