Ventilatory Response to CO₂ During Exercise in Patients With Congenital Central Hypoventilation Syndrome

Congenital central hypoventilation syndrome (CCHS) is characterized by a markedly impaired ventilatory response to CO₂ due to central chemoreceptor dysfunction. Although inadequate ventilation and hypercapnia during exercise have been reported, ventilatory response during exercise has not been quantitatively evaluated in CCHS. This study aimed to quantify ventilatory response during exercise and compare it with that at rest.

Ten patients with genetically confirmed CCHS underwent cardiopulmonary exercise test (CPET) using a stepwise incremental treadmill protocol with breath-by-breath respiratory gas analysis. CPET was terminated when end-tidal CO₂ (EtCO₂) increased by at least 2% (15.2 mmHg) from baseline. Ventilatory response to CO₂ (VRCO₂) was calculated as Δminute volume (MV)/ΔEtCO₂/body weight (mL/min/mmHg/kg). VRCO₂ at rest was measured using the CO₂ rebreathing method. Data are presented as median (interquartile range [IQR]).

Age was 13.5 (12.3-15.5) years, and exercise duration was 5 min 53 s (4 min 47 s-6 min 56 s). Although MV increased during exercise, SpO₂ decreased and EtCO₂ increased, indicating hypoventilation. VRCO₂ during exercise was 2.27 (1.61-3.16), not significantly different from VRCO₂ at rest, 1.56 (1.07-2.83) (p = 0.85). VRCO₂ was markedly lower than values in healthy children (34.6 (29.3-42.8)). No patients reported dyspnea, and no serious adverse events occurred.

VRCO₂ during exercise remains profoundly low in CCHS. No significant difference from VRCO₂ at rest was detected, suggesting persistent impairment of CO₂-driven ventilatory control despite increased metabolic demand. These findings provide insight into exercise-related hypoventilation in CCHS and underscore the importance of objective physiological assessment to support cautious and individualized clinical judgment rather than subjective symptoms.