Effect of Sleep Stage on Breathing in Children with Central Hypoventilation

Abstract

The early literature suggests that hypoventilation in infants with congenital central hypoventilation syndrome (CHS) is less severe during rapid eye movement (REM) than during non-REM (NREM) sleep. However, this supposition has not been rigorously tested, and subjects older than infancy have not been studied. Given the differences in anatomy, physiology, and REM sleep distribution between infants and older children, and the reduced number of limb movements during REM sleep, we hypothesized that older subjects with CHS would have more severe hypoventilation during REM than NREM sleep. Nine subjects with CHS, aged (mean ± SD) 13 ± 7 yr, were studied. Spontaneous ventilation was evaluated by briefly disconnecting the ventilator under controlled circumstances. Arousal was common, occurring in 46% of REM vs. 38% of NREM trials [not significant (NS)]. Central apnea occurred during 31% of REM and 54% of NREM trials (NS). Although minute ventilation declined precipitously during both REM and NREM trials, hypoventilation was less severe during REM (drop in minute ventilation of 65 ± 23%) than NREM (drop of 87 ± 16%, P = 0.036). Despite large changes in gas exchange during trials, there was no significant change in heart rate during either REM or NREM sleep. We conclude that older patients with CHS frequently have arousal and central apnea, in addition to hypoventilation, when breathing spontaneously during sleep. The hypoventilation in CHS is more severe during NREM than REM sleep. We speculate that this may be due to increased excitatory inputs to the respiratory system during REM sleep.

CENTRAL HYPOVENTILATION SYNDROME (CHS) is a rare disorder of ventilatory control, characterized by generally adequate ventilation during wakefulness, but severe alveolar hypoventilation during sleep, to the point where patients require mechanical ventilation (2). The congenital form of CHS is now known to be due to mutations of the PHOX2B gene (3, 55), which promotes neuronal differentiation and development of the autonomic nervous system (54).

The early literature reported that infants with CHS breathed better during rapid eye movement (REM) than non-REM (NREM) sleep (12, 19), although this finding has never been tested systematically. REM sleep is characterized by hypotonia of skeletal muscles, with the exception of the extraocular muscles and the diaphragm. The finding of improved ventilation during REM sleep is surprising, as it is currently believed that patients with CHS breathe better during wakefulness than sleep because of limb mechanoreceptor input during wakefulness (17, 18, 45). However, limb movements are rare during REM sleep due to REM-related hypotonia. Furthermore, during REM sleep there is hypotonia of the accessory muscles of respiration and, although controversial (43, 44), some human studies suggest that the ventilatory drive is lowest during REM sleep (9). Thus most types of sleep-disordered breathing, such as obstructive sleep apnea, are worse during REM compared with NREM sleep (14).

There are many physiological differences in the respiratory system between infants and older subjects. Infants have a different configuration of the thorax, with ribs orientated more horizontally, as well as a very compliant chest wall. As a result, the rib cage contribution to breathing during sleep is less than in older subjects (22). Infants perform laryngeal braking (active glottic narrowing) to maintain their functional residual capacity, which is lower than that of adults. Muscle mass increases with age, and whereas infants can produce high inspiratory pressures, they tend to function close to the diaphragmatic fatigue threshold (41). Other physiological differences between infants and adults include a higher arousal threshold during sleep (37) and differences in ventilatory control (6, 33, 50). Furthermore, infants with CHS may initially hypoventilate during both wakefulness and sleep (2) but only require ventilatory support during sleep once they have matured. Thus breathing patterns in infants with CHS may differ from older patients. Furthermore, REM sleep changes with age. Infants typically enter sleep via REM and have shorter ultradian cycles with more REM sleep than older individuals. REM density also decreases with age (23). Therefore, it is possible that the breathing pattern during REM sleep in infants differs from REM breathing in older individuals.

In view of these differences in physiology between infants and older individuals, we thought it likely that spontaneous breathing during sleep in older individuals with CHS would differ from that of infants. Considering that sleep-disordered breathing in most conditions is typically worse during REM than NREM sleep and that limb movement is less common during REM, we hypothesized that subjects with CHS who were past infancy would have more severe hypoventilation during REM than NREM sleep. Further, we sought to resolve the controversy regarding whether arousal occurred in response to endogenous gas exchange abnormalities in CHS (2, 32).