EFFECTS OF SLEEP ON VENTILATION

State-related changes in CNS activity associated with the transition from wakefulness to sleep exert complex effects on ventilatory control that profoundly affect the level and pattern of breathing. In general, withdrawal of cortical and higher CNS influences that provide excitatory inputs to the medullary respiratory neurons during wakefulness cause the chemical regulation of ventilation to assume greater importance.
The transition from wakefulness to slow-wave sleep (i.e., stages 1, 2, 3, and 4 non-REM) is associated with increases in PaCO2 and decreases in PO2, an increase in the threshold of the ventilatory response to CO2, and elimination of the “dog leg” in the ventilatory response to CO2 attributable to the wakefulness drive. In normal subjects, elimination of wakefulness drives and decreases in chemosensitivity typically increase PaCO2 and decrease PO2 by 4 to 8 mmHg. Small reductions in PCO2 in the order of 4 to 6 mmHg regularly induce apnea in normal subjects, in contrast to what occurs during wakefulness, when breathing persists despite marked hypocapnia. Steady-state changes in PCO2 during slow-wave sleep appear to be inversely related to the magnitude of the ventilatory response to CO2 during wakefulness.
Breathing during stages 1 and 2 of slow-wave (i.e., light) sleep is frequently periodic and often characterized by apnea (i.e., cessation of air flow for >10 seconds) with or without occlusion of the airway (see below). Periodic breathing resembles the Cheyne-Stokes respiration occurring during wakefulness. On the other hand, stages 3 and 4 of non-REM sleep are generally characterized by a slow, deep, regular pattern of breathing. Interestingly, this phase of sleep is associated with a greater depression of ventilatory responses to CO2 and O2 than are stages 1 and 2.
Breathing during REM sleep is rapid and irregular, with marked variation in the duration of inspiration and expiration, tidal volume, and average inspiratory air flow rate. Periods of hyperpnea appear to coincide with REM sleep. Electrical activity (EMG) of the rib cage and upper airway respiratory muscles is profoundly depressed in REM sleep, in keeping with the marked muscular atonia observed in the limb muscles. Diaphragmatic EMG activity is relatively spared, but abrupt, irregular periods of inhibition during inspiration may occur. A disproportionate reduction in intercostal relative to diaphragmatic activity in REM sleep leads to paradoxical inward movement of the rib cage on inspiration. Profound inhibition of upper airway muscle electrical activity considerably increases upper airway resistance. Ventilatory responses to CO2 and O2 are at their lowest during this stage of sleep. In subjects with underlying lung disease, the greatest disturbances in PaO2 and PaCO2 occur during this stage of sleep, presumably because of the rapid, shallow pattern of breathing, increased ratio of volume of dead space to tidal volume, and uncoordinated pattern of rib cage and abdominal movement.
Periodic Breathing During Sleep
Recent studies have suggested several possible mechanisms for the periodic breathing and airway occlusion that occur during the transition from wakefulness to light sleep, each of which causes instability in the ventilatory control system. First, removal of the wakefulness drive depresses ventilation, with concomitant large and rapid increases in PCO2 and reductions in PO2 that stimulate peripheral and central chemoreceptors. Second, alterations in blood gas tensions and mild reductions in metabolic activity that decrease CO2 production and O2 consumption increase plant gain—that is, the change in blood gas tensions induced by a given change in ventilation. Increased plant gains in stage 1 and stage 2 sleep may offset the mild reductions in ventilatory responses to CO2 and O2 that occur during these stages and increase controller gain. Third, progressive increases in respiratory effort during occlusive apnea lead to arousal, the primary mechanism whereby occlusive apnea is terminated. Collapse of the upper airway and arousal destabilize breathing by producing large and rapid changes in PCO2 and PO2. Fourth, arousal may be followed by a rapid return to sleep, removal of the wakefulness drive, and rapid deterioration in blood gases. Cycles of airway occlusion and arousal superimposed on sleep-related changes in controller gain may be mutually reinforcing and lead to sustained, progressively amplifying oscillations in breathing and blood gas tensions. Breathing in stages 3 and 4 of sleep is likely to be more stable than in stages 1 and 2, because overall controller gain may be diminished and because changes in ventilation caused by external stimuli are less likely than in stages 1 and 2. Depression of CO2 and O2 chemosensitivity in stages 3 and 4 may more than offset increases in plant gain.
Changes in respiration with periods of apnea, profound arterial desaturation, and disturbed sleep appear to be especially common in patients with congestive heart failure. Periodic breathing in these subjects may be explained by a prolongation in circulation time with information delays and increases in plant gain as a result of decreases in pulmonary stores of O2 related to pulmonary edema.
Airway Occlusion During Sleep
The pathogenesis of airway occlusion during sleep has now been elucidated. Patency of the upper airway during sleep depends on a balance between the subatmospheric “sucking” pressures in the posterior nasopharyngeal space generated by the inspiratory muscles of the chest wall and the opposing dilating forces generated by the upper inspiratory airway muscles, which tend to enlarge and “stiffen” the upper airway. In essence, collapse of the upper airway during inspiration occurs when there is an imbalance of forces in favor of the subpharyngeal pressures. Collapse of the upper airway therefore depends on three factors: (1) activity of the dilator muscles, (2) intraluminal airway pressure, and (3) mechanical properties of the passive upper airway.
The activity of the respiratory skeletal muscles of the upper airways, which originate on the mandible, tongue, larynx, and hyoid bone and dilate the upper airway (i.e., genioglossus, geniohyoid, sternohyoid, posterior arytenoids, cricothyroid), demonstrate a respiratory modulation—that is, the EMG and tension of these muscles increase during inspiration, thereby augmenting the caliber of the upper airway and its tendency to remain patent. Hypercapnic and hypoxic chemical stimuli to breathing increase upper airway muscle electrical activity (e.g., genioglossus, posterior arytenoids) in a manner qualitatively similar to that seen in the pump muscles of the chest wall. All stages of sleep are associated with depression of EMG activity of upper airway muscles at any given level of PO2 or PCO2 out of proportion to changes in chest-wall muscle EMG. REM sleep is associated with the greatest inhibition of upper airway muscle electrical activity, in keeping with the generalized muscular atonia that occurs during this stage of sleep. Airway collapse during sleep is favored, therefore, by depression of the electrical activity of dilating upper airway muscles. Re-establishment of airway patency in the setting of obstructive apnea requires arousal and increases in upper airway EMG activity. Of interest, administration of alcohol in amounts that have no effect on ventilation or pattern of breathing depress genioglossus EMG activity during eucapnia or hypercapnia. This finding may explain the greater tendency for obstructive sleep apnea to develop after alcohol ingestion or sedative use.
In addition, end-expiratory lung volume (FRC) oscillates during periodic breathing and demonstrates progressive reduction during the several breaths preceding occlusion. Reductions in lung volume per se reduce the cross-sectional area of the posterior nasopharynx and increase the mechanical advantage of the inspiratory muscles of the chest wall (i.e., the inspiratory pressure generated for a given EMG activity is increased).
Classic control system theory indicates that increased controller gain predisposes to control system instability and oscillation. However, it seems likely that the precise mechanisms by which periodic breathing with apnea develop during sleep vary from individual to individual and may depend on the magnitude of the wakefulness drive, the propensity to awaken and undergo rapid, state-related changes in ventilation, and the proclivity of the upper airway to collapse.