Congenital central hypoventilation syndrome (CCHS) has been thought to be a disorder of central chemoreceptor responsiveness. Previous studies in CCHS have shown decreased or absent ventilatory responsiveness to both hypercarbia and hypoxia. However, hypoxic responsiveness during wakefulness has not been systematically studied. We studied hypoxic and hypercapnic ventilatory responses during wakefulness in five children with CCHS (6 to 11 yr of age). To measure the hypercapnic response, the children rebreathed a hyperoxic hypercapnic mixture until PaCO2 reached 56 to 69 mm Hg. For the hypoxic response, the children rebreathed a hypoxic gas mixture, at mixed venous PCO2, until SaO2 had fallen to less than 78%. We found that the ventilatory responses to hypercapnia and hypoxia were very variable (linear correlation coefficients ranging from -0.44 to +0.63 for hypercapnic responses and from -0.15 to +0.77 for hypoxic responses), with no significant change from baseline in response to either stimulus. There was no evidence of progressive ventilatory stimulation despite increasing stimulus. Additionally, these children had no subjective sensation of dyspnea or discomfort. This establishes that hypoxic and hypercapnic ventilatory control is absent during wakefulness. Chemoreceptor control (peripheral and central) is, therefore, defective in all states in children with CCHS. We speculate that the defect in CCHS lies in central integration of the central and peripheral chemoreceptor signals.

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The role of the central and peripheral chemoreceptors in the hyperpnea of exercise has been controversial. We studied five children, age 6 to 11 yr, with absent hypercapneic and hypoxic ventilatory responses during wakefulness (congenital central hypoventilation syndrome, CCHS). Each child performed an incremental treadmill exercise test. Maximal oxygen consumption (VO2) and minute ventilation (VE) at maximal exercise were lower than but not significantly different from these values in a group of nine normal control children of similar age, height, and weight (VO2/kg, 33.7 +/- 5.0 versus 45.4 +/- 2.9 ml/kg/min, mean +/- SEM, NS; VE 28.3 +/- 7.3 versus 43.8 +/- 3.9 L/min, NS). Oxygen tension and saturation fell and CO2 tension rose significantly at maximal exercise in CCHS but not in control subjects. In contrast to control subjects, CCHS subjects increased VE largely by increasing respiratory frequency (f) rather than tidal volume (VT). In the oldest child, submaximal exercise tests at 50% VO2, with varying pacing rate, showed a significant positive relation between pacing rate and f, but not VT. Thus, VE was higher at the faster pacing rate. Further incremental testing in the two oldest subjects with recording of the pacing rate showed positive linear relations between pacing frequency and breathing frequency and between pacing frequency and VE up to a maximum pacing rate of 48 to 50 paces per 15 s. VE beyond this level varied randomly around the maximum level. We conclude that exercise-induced hyperpnea can occur in the absence of chemoreceptor function. In the CCHS children, limb movement is an important determinant of the ventilatory response to exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

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