Pathogenesis Of Central Apnea During Sleep

Breathing during non-rapid eye movement (NREM) sleep is critically dependent on chemical stimuli, especially Pco2 (6), owing to the removal of the wakefulness drive to breathe. NREM sleep unmasks a highly sensitive hypocapnic "apneic threshold." Thus, central apnea occurs if arterial Pco2 is lowered below the apneic threshold (6). Hypocapnia during sleep is the most ubiquitous and potent influence leading to the development of central apnea. Experimental paradigms used to produce hypocapnic central apnea include nasal mechanical ventilation (Fig. 1) and brief (3-5 minutes) hypoxic exposure. Both methods increase minute ventilation and alveolar ventilation and decrease arterial Pco2. Termination of hyperventilation would result in hypopnea or apnea depending on the degree of hypocapnia (7-10).

The effects of hypocapnia on ventilation are modulated by several mechanisms that mitigate the effect of hypocapnia on ventilatory motor output. For example, hypo-capnic central apnea has not been shown conclusively during rapid eye movement (REM) sleep. Most, but not all studies suggest that breathing during REM sleep is impervious to chemical influences (8). Likewise, the duration of hyperpnea is another important determinant of central apnea following hyperventilation, as brief hyperventilation is rarely followed by central apnea in sleeping humans (11,12), perhaps due to the insufficient reduction in Pco2 at the level of the chemoreceptors. Finally, intrinsic excitatory mechanisms may also mitigate the effects of hypocapnia. Specifically, brief hypoxic hyperventilation is associated with increased ventilatory motor output referred to as short-term potentiation (STP) (10,13,14). This results in persistent, but gradually diminishing hyperpnea upon cessation of the stimulus to breathe. The activation of STP may serve as a teleological purpose by mitigating the effects of transient hypoxia and hypocapnia, on subsequent ventilation during sleep (10).

Although hypocapnia is the most common influence leading to central apnea (3,6,11,15), other less common mechanisms include negative pressure-mediated upper airway reflexes (16,17) and normocapnic hyperpnea (18,19). However, the

FIGURE 1 An example of hypocapnic central apnea induced by passive mechanical ventilation for three minutes. Note absence of flow and effort. Control represents room air breathing prior to initiation of mechanical ventilation; MV represents three minutes of mechanical ventilation, last five breaths are shown. Note the occurrence of central apnea upon termination of MV in the recovery period. Abbreviations: EOG, electro-oculogram; EEG, electroencephalogram; Flow, airflow; Volume, tidal volume (VT); Psg, supraglottic pressure, note positive pressure during nasal mechanical ventilation; CO2, end-tidal Pco2 (PETCO2); Mask pressure (Pmask), note positive mask pressure during mechanical ventilation.

FIGURE 1 An example of hypocapnic central apnea induced by passive mechanical ventilation for three minutes. Note absence of flow and effort. Control represents room air breathing prior to initiation of mechanical ventilation; MV represents three minutes of mechanical ventilation, last five breaths are shown. Note the occurrence of central apnea upon termination of MV in the recovery period. Abbreviations: EOG, electro-oculogram; EEG, electroencephalogram; Flow, airflow; Volume, tidal volume (VT); Psg, supraglottic pressure, note positive pressure during nasal mechanical ventilation; CO2, end-tidal Pco2 (PETCO2); Mask pressure (Pmask), note positive mask pressure during mechanical ventilation.

relevance of these mechanisms to the pathogenesis of central apnea in sleeping humans is yet to be determined.

Central apnea does not occur as an isolated event but as periodic breathing consisting of cycles of recurrent apnea or hypopnea alternating with hyperpnea. While hypocapnia can produce the initial event, additional factors are required to sustain breathing instability and periodic breathing. Upper airway narrowing or occlusion may occur during central apnea requiring additional effort to overcome craniofacial gravitational forces or tissue adhesion forces. In addition, breathing does not resume until arterial Pco2 (PaCO2) is elevated by 4 to 6 mmHg above eupnea owing to the inertia of the ventilatory control system (18,20). Consequently, the magnitude of hypoxia is enhanced and transient arousal may occur, leading to ventilatory overshoot, subsequent hypocapnia, and further apnea/hypopnea.

DETERMINANTS OF CENTRAL APNEA: RISK FACTORS

Several physiologic and pathologic conditions influence the vulnerability to develop central apnea for a given perturbation. These include age, gender, sleep state, CHF, thyroid disease and acromegaly.

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