Effect of episodic hypoxia on the susceptibility to hypocapnic central apnea during NREM sleep

Abstract

We hypothesized that episodic hypoxia (EH) leads to alterations in chemoreflex characteristics that might promote the development of central apnea in sleeping humans. We used nasal noninvasive positive pressure mechanical ventilation to induce hypocapnic central apnea in 11 healthy participants during stable nonrapid eye movement sleep before and after an exposure to EH, which consisted of fifteen 1-min episodes of isocapnic hypoxia (mean O(2) saturation/episode: 87.0 +/- 0.5%). The apneic threshold (AT) was defined as the absolute measured end-tidal PCO(2) (Pet(CO(2))) demarcating the central apnea. The difference between the AT and baseline Pet(CO(2)) measured immediately before the onset of mechanical ventilation was defined as the CO(2) reserve. The change in minute ventilation (V(I)) for a change in Pet(CO(2)) (DeltaV(I)/ DeltaPet(CO(2))) was defined as the hypocapnic ventilatory response. We studied the eupneic Pet(CO(2)), AT Pet(CO(2)), CO(2) reserve, and hypocapnic ventilatory response before and after the exposure to EH. We also measured the hypoxic ventilatory response, defined as the change in V(I) for a corresponding change in arterial O(2) saturation (DeltaV(I)/DeltaSa(O(2))) during the EH trials. V(I) increased from 6.2 +/- 0.4 l/min during the pre-EH control to 7.9 +/- 0.5 l/min during EH and remained elevated at 6.7 +/- 0.4 l/min the during post-EH recovery period (P < 0.05), indicative of long-term facilitation. The AT was unchanged after EH, but the CO(2) reserve declined significantly from -3.1 +/- 0.5 mmHg pre-EH to -2.3 +/- 0.4 mmHg post-EH (P < 0.001). In the post-EH recovery period, DeltaV(I)/DeltaPet(CO(2)) was higher compared with the baseline (3.3 +/- 0.6 vs. 1.8 +/- 0.3 l x min(-1) x mmHg(-1), P < 0.001), indicative of an increased hypocapnic ventilatory response. However, there was no significant change in the hypoxic ventilatory response (DeltaV(I)/DeltaSa(O(2))) during the EH period itself. In conclusion, despite the presence of ventilatory long-term facilitation, the increase in the hypocapnic ventilatory response after the exposure to EH induced a significant decrease in the CO(2) reserve. This form of respiratory plasticity may destabilize breathing and promote central apneas.

Fig. 1.

Representative polygraph segment from a subject during stable nonrapid eye movement (NREM) sleep at different time points: room air control condition (C) and mechanical ventilation (MV) leading to central apnea (A) after the cessation of MV. Note the 10-s central apnea [absence of respiratory effort on the supraglottic pressure (P_SG) tracing]. EOG, electrooculogram; EEG, electroencephalogram; P_mask: mask pressure.

Fig. 2.

Representative compressed polygraph segment from a subject showing the hypoxia protocol, including the control room air period (A), the beginning (Hx1) and end of the hypoxia episodes (Hx12–Hx15) (B), and the recovery period (C). Note that isocapnia was maintained during the hypoxia episodes. Also note that the tidal volume (V_T) was elevated during each hypoxia episode and remained elevated during recovery. The dotted line represents the control V_T. Pet_CO2, end-tidal Pco₂; Sa_O2, arterial O₂ saturation.

Fig. 3.

Acute and net hypoxic ventilatory response (HVR) expressed as the change in minute ventilation (V̇_I) for a corresponding change in Sa_O2 (see text). No significant changes were noted between the first 3 hypoxia episodes (solid bar) and the last 3 hypoxia episodes (shaded bar). NS, not significant.

Fig. 4.

Schematic representation of the observed eupneic CO₂, apneic threshold (AT) Pet_CO2, and CO₂ reserve (eupneic Pet_CO2 minus AT Pet_CO2) during the pre-episodic hypoxia (pre-EH; solid bars) and post-EH (grey bars) periods (n = 11). The top horizontal line represents the eupneic CO₂, the bottom horizontal line represents the AT, and boxes between these two lines represent the CO₂ reserve [pre-EH (solid box) and post-EH (shaded box)]. The CO₂ reserve was significantly smaller post-EH as a result of the significantly lower eupneic Pet_CO2, without a change in the AT.

Fig. 5.

Comparison of the hypocapnic ventilatory responses under the two conditions: 1) the EH protocol [pre-EH (solid bar) vs. post-EH (shaded bar)] and 2) the sham protocol [before (hatched bar) vs. after (cross-hatched bar) the sham intervention]. The major finding was that the hypocapnic ventilatory response was significantly increased after isocapnic EH but not after the sham protocol (see text for explanation).

Fig. 6.

Diagramatic representation of the relationship between V̇_I and Pet_CO2 along the isometabolic curve. A steeper slope post-EH (solid line) compared with the pre-EH exposure (dotted line) indicates a higher hyocapnic ventilatory chemoresponse post-EH. An increase in the slope decreased the magnitude of the CO₂ reserve below eupnea post-EH (solid arrow) versus the CO₂ reserve pre-EH (dotted arrow), thereby increasing the susceptibility to the development of apnea, despite hyperventilation and the reduced eupneic Pet_CO2, indicative of reduced plant gain (point A vs. point B) (see text for further explanation).