Increased Oxidative Stress, Loop Gain And The Arousal Threshold Are Clinical Predictors Of Increased Apnea Severity Following Exposure To Intermittent Hypoxia

Abstract

Gino S Panza,1,2,* Raichel M Alex,1,2,* Sanar S Yokhana,1,2 Dorothy S Lee Pioszak,1,2 M Safwan Badr,1–3 Jason H Mateika1–3 1Research and Development, John D. Dingell Veterans Affairs Medical Center, Detroit, MI 48201, USA; 2Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA; 3Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA*These authors contributed equally to this workCorrespondence: Jason H MateikaJohn D. Dingell VA Medical Center, 4646 John R (11R), Room 4333, Detroit, MI 48201, USATel [phone]Fax [phone]Email [email protected]: We determined if oxidative stress prior to sleep onset is correlated to loop gain (LG) and the arousal threshold (AT) during non‐rapid eye movement (NREM) sleep. We also explored if LG and AT are correlated with apnea severity and indices of upper airway collapsibility during NREM sleep.Methods: Thirteen male participants with obstructive sleep apnea (apnea–hypopnea index > 5 events/hr) were administered an antioxidant or placebo cocktail while exposed to mild intermittent hypoxia in the awake state. Thereafter, loop gain and measures of arousal, apnea severity and upper airway collapsibility were ascertained during NREM sleep.Results: Modification in oxidative stress (i.e., 8-hydroxy-2-deoxyguanosine) prior to sleep onset was correlated to LG (r = 0.8, P = 0.003), the number (r = 0.71, P = 0.01) and duration (r = 0.63, P = 0.04) of apneic events and the percentage of time breathing was stable (r = −0.66, P = 0.03) during sleep. Using a forward stepwise regression analysis, our results showed that LG, AT, the ventilatory response to arousal and nadir end-tidal carbon dioxide were determinants of the apnea–hypopnea index (P value range = 0.04–0.001). In addition, the AT was a predictor of measures of upper airway collapsibility, including the hypopnea/apnea + hypopnea ratio and the degree of flow reduction that accompanied hypopneic events (P < 0.001).Conclusion: Modifications in oxidative stress following exposure to intermittent hypoxia during wakefulness are positively associated with loop gain and apnea severity during NREM sleep. Moreover, an increase in the arousal threshold is a predictor of increased upper airway collapsibility.Keywords: mild intermittent hypoxia, non-rapid eye movement sleep, arousal, oxidative stress, loop gain

Keywords

• mild intermittent hypoxia
• non-rapid eye movement sleep
• arousal
• oxidative stress
• loop gain