Abnormalities of ventilatory control may play a significant role in the pathophysiology of sleep-disordered breathing in patients with the Prader-Willi syndrome (PWS). We measured rebreathing hypercapnic and hypoxic ventilatory responses (HCVR and HPVR, respectively) during wakefulness in 8 nonobese PWS (NOB-PWS) and 9 obese PWS (OB-PWS) patients and compared their results with those from 24 healthy nonobese control (NOB-CON) and 10 obese control (OB-CON) subjects. The slope of HCVR was similar in NOB-PWS patients and NOB-CON subjects (NS). However, HCVR was significantly lower in OB-PWS patients than in OB-CON subjects (P < 0.02). In PWS patients, the mean point of origin of the positive slope of HCVR occurred at a significantly higher end-tidal PCO2 than in either control group. During isocapnic hypoxic challenges, six PWS patients had no significant HPVR. In the remainder, mean slopes of HPVR were -0.80 +/- 0.06 l.min-1.%arterial O2 saturation-1 in five NOB-PWS patients and -0.68 +/- 0.15 l.min-1.%arterial O2 saturation-1 in six OB-PWS patients. These responses were significantly decreased compared with those in the control groups (P < 0.006). We conclude that NOB-PWS patients have normal HCVR, which is blunted in OB-PWS patients. Furthermore, isocapnic HPVR is either absent or markedly reduced in PWS patients. The severity of abnormality of the HPVR is independent of the degree of obesity. We postulate that the primary abnormality of ventilatory control in PWS affects peripheral chemoreceptor pathways.

Abnormalities in ventilatory control during wakefulness and sleep have been observed in patients with Prader-Willi syndrome (PWS). The role of peripheral chemoreceptors in the pathophysiology of abnormal ventilatory responses in PWS is unknown. We studied peripheral chemoreceptor function during wakefulness in 17 genetically confirmed PWS patients [age 27.0 +/- 2.5 (SE) yr; 7 males, 10 females; body mass index 31.1 +/- 1.4 kg/m2] and compared their responses with 17 control subjects matched for age, sex, and body mass index. All PWS and control subjects had normal resting end-tidal PCO2 and arterial O2 saturation while awake. Peripheral chemoreceptor function was assessed by the ventilatory responses to 100% O2 breathing, five tidal breaths of 100% N2, and vital capacity breaths of 15% CO2 in O2. Control subjects decreased minute ventilation (VE) by 15.5 +/- 3.6% during hyperoxia. However, PWS patients increased VE by 17.6 +/- 3.3%, indicating a paradoxical response to hyperoxia (P < 0.00001). After CO2 vital capacity breaths, PWS patients showed no significant change and control subjects showed a marked increase (P < 0.0001) in VE. During N2 breathing, again PWS patients showed no change and control subjects exhibited a marked increase (P < 0.00005) in VE. We conclude that PWS patients have absent peripheral chemoreceptor ventilatory responses. We speculate that the lack of ventilatory responses is due to primary peripheral chemoreceptor dysfunction and/or defective afferent pathways to central controllers.

During exercise, children with congenital central hypoventilation syndrome (CCHS) demonstrate coupling of VE to exercise load, despite the absence of a VE response to changes in FICO2. To assess the effect of movement on VE, we studied six CCHS patients and six matched controls during passive motion in a motor-driven ergocycle at pedaling frequencies (PF) of 6 to 60 rpm. VE, VO2, VCO2, VT, heart rate, respiratory rate, SPO2, and PETCO2 were measured. During steady-state conditions, VE was constant at PF of 0 to 30 rpm, but increased at PF > or = 40 rpm in both controls and CCHS patients (p < 0.005). The increase in respiratory rate in CCHS patients was greater than in controls (p < 0.05) whereas VT increased similarly in both groups. At 60 rpm, VO2 increased in both groups, but VE/VO2 and VE/VCO2 increased in the CCHS patients and remained constant in the controls (P < 0.03; p < 0.04). From PF of 0 to 60, PETCO2 decreased from 47 +/- 7 to 41 +/- 6 mm Hg in the CCHS patients (p < 0.001) but remained unchanged in the controls (38 +/- 3 mm Hg; p = NS). An analysis of on-transient responses at 60 rpm revealed that VE increased immediately with the first breath after onset of motion in both groups, and that comparable differences in ventilatory patterns persisted in the two groups. We conclude that passive leg motion at PF > or = 40 increases VE in both CCHS patients and controls. In controls, VE was tightly coupled to VO2 and VCO2. However, in CCHS patients, passive leg motion elicited normalization of PETCO2.

Obstructive sleep apnea (OSA) involves the interplay of several different factors such as an unfavorable upper airway anatomy, deficiencies in pharyngeal muscle responsiveness, a low arousal threshold, and ventilatory control instability. Although the stability of ventilatory control has been extensively studied in adults, little is known about its characteristics in the pediatric population. In this study, we developed a novel experimental setup that allowed us to perturb the respiratory system during natural non-rapid eye movement (NREM) sleep conditions by manipulating the inspiratory pressure, provided by a bilevel pressure ventilator, to induce sighs after upper airway stabilization. Furthermore, we present a modeling framework that utilizes the noninvasively measured ventilatory responses to the induced sighs and spontaneous breathing data to obtain representations of the processes involved in the chemical regulation of respiration and extract their stability characteristics. After validation with simulated data, the modeling technique was applied to data collected experimentally from 11 OSA and 15 non-OSA overweight adolescents. Statistical analysis of the model-derived stability parameters revealed a significantly higher plant gain and lower controller gain in the OSA group (P = 0.046 and P = 0.007, respectively); however, no differences were found in loop gain (LG) and circulatory time delay between the groups. OSA severity and LG, within the 0.03-0.04-Hz frequency band, were significantly negatively associated (r = -0.434, P = 0.026). Contrary to what has been found in adults, our results suggest that in overweight adolescents, OSA is unlikely to be initiated through ventilatory instability resulting from elevated chemical loop gain.