Sleep Physiology Introduction Arousal from Sleep Is Considered One of the Most Important Protective Responses to Ad- Verse Respiratory Events Such as Obstructive

AROUSAL FROM SLEEP IS CONSIDERED ONE OF THE MOST IMPORTANT PROTECTIVE RESPONSES TO ADVERSE RESPIRATORY EVENTS SUCH AS OBSTRUCTIVE apnoea.1 Arousal produces intense cardiovascular and respiratory activation that rapidly reverses blood-gas disturbance associated with airway obstruction and likely promotes physiologic preparedness for subsequent “fight-or-flight” survival responses. In healthy individuals, airway obstruction invariably precipitates rapid arousal.2 Patients with obstructive sleep apnea (OSA) show less-consistent and delayed arousal consistent with an increased arousal threshold to respiratory stimuli.3 While some obstructive events appear to resolve without arousal, and airway reopening precedes arousal in approximately 20% of events, arousal is nonetheless elicited in the majority of events in OSA.4 Hypoxia is an invariable accompaniment of sleep-disordered breathing. Experimental acute hypoxia (e.g., 0.5 to 2-3 minutes) during sleep induces a rapid ventilatory response followed by arousal.5 In contrast, indirect evidence supports that, following more-sustained hypoxia or repeated brief hypoxia, there may be a relative suppression of arousal responses. Early studies showed that healthy subjects frequently fail to arouse in NREM sleep during slowly progressive hypoxia even when SaO2 was reduced to 70%.6 Similarly, clinical observations in patients with neuromuscular or chest wall disease show these patients frequently spend prolonged periods of sleep with severe hypoxemia and no arousal. Furthermore, prolonged isocapnic hypoxia has been shown to release a number of inhibitory neurotransmitters and neuromodulators in the central nervous system, such as gamma aminobutyric acid (GABA), adenosine, and endogenous opioids.7,8 These inhibitory neurochemicals are likely responsible for the decline or “roll-off” in ventilatory drive during sustained and repetitive isocapnic hypoxia9-12 and may also be responsible for suppression of respiratory load sensation,13,14 respiratory-related evoked responses,15 and more general neuropsychologic functioning.16 To the extent that sleep arousal in general is dependent on intact central nervous system functioning and that respiratoryrelated arousals may importantly depend on the quantum of respiratory drive and associated sensations,5 prolonged hypoxia thus has the potential to suppress arousal either in general or, more specifically, to respiratory stimuli via depression of afferent or efferent respiratory pathways. Hypoxic depression of arousal in general or specifically to respiratory load would promote greater inspiratory effort at arousal and potentially greater postarousal ventilatory overshoot and subsequent undershoot in individuals exposed to sustained hypoxia, such as at altitude and in diseases such as chronic obstructive pulmonary disease, OSA, and sleep hypoventilation syndromes. Therefore, while sustained hypoxia has other sleep-disruptive effects (e.g., periodic breathing) and may coexist with important disease-specific phenomena that may also influence arousal (e.g., increased breathing effort), blunted arousal with hypoxia nevertheless has the potential to further destabilize respiratory control during sleep. To test the hypothesis that hypoxia depresses neural mechanisms subserving arousal in general, we examined the susceptibility of normal subjects to arouse to auditory stimuli presented in Mild Hypoxia Does Not Suppress Auditory Arousal From NREM Sleep