INTRODUCTION

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Central chemoreceptors are considered to be important controllers of ventilation during states associated with moment-to-moment changes in metabolic requirements such as exercise or sleep (1). Children with the congenital central hypoventilation syndrome (CCHS) have markedly abnormal central chemosensory function during sleep states (2), which persists during wakefulness (3, 4). More specifically, although alveolar hypoventilation will develop during any state, its severity will be greatest during non-rapid eye movement (NREM) sleep and improve during REM sleep and quiet wakefulness (5). This state dependency of ventilatory output may lead to relatively adequate spontaneous daytime ventilation in children with more mildly affected CCHS, who will, however, require mechanical ventilatory support during sleep.

In recent years, transition from invasive mechanical ventilation to nasal mask ventilation has been reported in older patients with CCHS who were selectively nocturnal ventilator-dependent (6). However, a recent report of a 9-mo-old infant who has received adequate noninvasive ventilatory support for > 2 yr suggests that nasal mask ventilation or other forms of noninvasive ventilation may be a viable option in selected cases at younger ages (10).

The observation of parents that children with CCHS develop significant hypoventilation during wakefulness when sustaining a motor quiescent state such as watching television has been further confirmed in the laboratory and shown to display dependencies on mental activity (11) and degree of limb motion (12, 13). The latter was shown to ameliorate gas exchange during exercise at intensities below the anaerobic threshold (13) as well as during passive limb motion at rest (12), possibly via activation of limb mechanoreceptors or respiratory entrainment.

In the present study, we hypothesized that activation of mechanoreceptors by passive motion of the extremities during quiet sleep would elicit increases in alveolar ventilation in children with CCHS.

	METHODS

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Patients

Patients with CCHS who were being clinically followed at the Tulane or Kosair Children's Hospital Comprehensive Sleep Medicine Center were invited to participate in the study, which received institutional experimental human subject committee approval. The diagnosis of CCHS was based on recently reviewed criteria (14) and included: (1) persistent evidence of sleep hypoventilation (Pa_CO2 > 60 mm Hg); (2) the onset of symptoms usually occurred during the first days of life and always before the first birthday; (3) absence of primary pulmonary disease or neuromuscular dysfunction, which could explain the hypoventilation; and (4) no evidence of cardiac disease. In addition, evidence for a markedly attenuated response to hypercapnia was obtained in all participating children days to months prior to their participation in the study. The hypercapnic ventilatory response was measured during quiet or NREM sleep using the hyperoxic rebreathing method. The cuff of the tracheostomy tube was inflated and the tube connected to a calibrated and heated pneumotachograph and a one-way rebreather valve (Hans Rudolph, Kansas City, MO) as previously described (17). In brief, end-tidal carbon dioxide tension (PET_CO2) was sampled continuously at the expiratory port and analyzed using an infrared microcapnometer (Columbus Intruments, Columbus, OH). Airflow was measured from a pressure transducer (Validyne Corp., Northridge, CA) connected to the pneumotachograph, and breath-by-breath VT was obtained by analog integration of the flow signal. Physiologic signals were digitally acquired into a MacIntosh PC at 125 Hz sampling frequency using MacLab Digital Acquisition Software (AD Instruments, Castle Hill, Australia), and a peak-trough detection algorithm (Wavemetrics, Lake Oswedo, OR) was subsequently applied for calculation of minute ventilation (E). Ventilatory responses to hypercapnia were expressed as the slope of E versus PET_CO2 corrected for body weight and are therefore expressed as ml/min/mm Hg/kg.

Children with CCHS were studied in the sleep laboratory. Studies were performed in a quiet dark room, and no sleep deprivation or sedation was used. The children were accompanied by a parent or legal caretaker who gave his or her informed consent, and the two older children also assented to participate. Polysomnographic signals were digitally acquired on a computerized polysomnography system (Alice 3; Healthdyne, Marietta, GA), and the following parameters were recorded: electroencephalogram (C3/A2; C4/A1; Cz/Oz); right and left electrooculogram (EOG); submental electromyogram (cEMG); electrocardiogram; chest and abdominal wall motion (piezoelectric transducers); airflow (thermistor) and PET_CO2 were measured at the tracheostomy by infrared capnometry (SC-300; Pryon, Menomonee Falls, WI); arterial oxygen saturation (Sa_O2) by pulse oximetry (Nellcor N-200, Nellcor, Van Nuys, CA), and the oximeter waveform; Transcutaneous PCO₂ (TcPCO₂) and PO₂ (TcPO₂) were also monitored throughout the night (Tina 3; Radiometer, Copenhagen, Denmark).

Protocol

Children were allowed to fall asleep while connected to their mechanical ventilator via a tracheotomy and using their routine ventilator settings. In the two patients in whom mechanical motion of the extremities was also performed, an electrically motorized mechanical device was strapped while the children were awake (see below).

Sleep state was visually monitored on screen, and Stages III-IV of NREM sleep were recognized by the presence of dominant delta wave activity as defined by Rechtschaffen and Kales (18). For infants, sleep was partitioned into quiet sleep (QS), active sleep, and undetermined sleep (19), and both passive motion of the lower extremities (PMLE) and control trials were always performed during QS. Arousals were defined as recommended by the American Sleep Disorders Association Task Force report (20).

When patients entered Stage III-IV of NREM sleep or QS, the ventilator was disconnected, and supplemental oxygen was administered to maintain Sa_O2 > 95% at all times. PET_CO2 was allowed to drift upwards until it reached values > 55 mm Hg, at which point in time PMLE was conducted for as long as 3 min, or discontinued if an arousal or a shift to a lower stage of NREM sleep occurred. As control, similar epochs were selected, but no motion was applied to the extremities. At the end of each trial, children were reconnected to the ventilator for at least 5 min. PMLE was performed by one of the investigators, moving the child's feet at the ankle level either manually (46 trials; up- and down-flexion of the foot in a total angle of ~ 45 degrees) or with a hydraulic electrically motorized device strapped to the child's feet prior to lights out (12 trials). The device consisted of a foot platform in which the subject's foot was positioned and strapped with velcro bands. The foot platform was lifted by one of two hydraulic pistons, such that the ankle and the distal portion of each foot would alternatively move upwards or downwards. In both instances, a frequency of > 40 but < 50 strokes/min was adopted as dictated by a light-emitting pacesetter. For control trials, the feet were held by the investigator with no motion being applied. The order of one PMLE and one control trial was randomized. If arousal occurred during any phase of the trial, the data were discarded. All children had at least one PMLE and one control trial for each night. However, because of the variable number nights that each child spent in the sleep laboratory (one to three nights) and the different number of Stage III-IV of NREM sleep epochs, the number of successful PMLE trials for each child ranged from four to 12.

Data Analysis

Results are presented as mean ± SEM. Changes in respiratory rate, PET_CO2, TcPCO₂ and TcPO₂ were quantitated before and after the onset of the experimental condition (PMLE or control) for at least 30 s. Measurements obtained during manual and mechanical PMLE were initially analyzed separately. Because the responses to manual and mechanical PMLE did not differ, the data were pooled for presentation purposes. Student's paired two-tailed t tests were applied for statistical comparisons of changes occurring within each experimental condition, whereas differences between the two experimental groups were compared by one-way analyses of variance followed by the Newman-Keuls post-hoc test. A p value of < 0.05 was considered to achieve statistical significance.

	RESULTS

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Six children with CCHS completed a total of 74 successful trials not associated with EEG changes compatible with arousal or shifts to Stage I-II, over a period of one to three nights. In addition, 16 trials had to be aborted because of EEG or behavioral arousal. The various clinical characteristics for these patients are shown in Table 1. All patients received ventilatory support via tracheostomy and positive pressure mechanical ventilation. All patients exhibited symptoms at or shortly after birth. However, the final diagnosis of CCHS was not reached in some children until several months later (Table 1).

An illustrative example of the effect of PMLE on ventilation in a child with CCHS is shown in Figure 1. Indeed, after patients with CCHS were disconnected from mechanical ventilatory support, PET_CO2 gradually increased from 33.8 ± 1.4 to 58.9 ± 3.5 mm Hg (p < 0.0001) over a period of 3 to 5 min, and despite the increase in PET_CO2, there were no discernible changes in ventilation or EEG-defined sleep state. Upon application of PMLE, PET_CO2 decreased to 40.9 ± 2.6 mm Hg in 58 trials (p < 0.001), whereas PET_CO2 increased from 58.8 ± 3.1 to 62.1 ± 3.7 mm Hg in the 16 trials in which no passive motion was applied (control versus PMLE: p < 0.001) (Figure 2). Similar changes in TcPCO₂ occurred during off-respirator periods and during either PMLE or control periods, thereby confirming PET_CO2 changes. Although no significant changes in oxyhemoglobin saturation by pulse oximetry were apparent during the trials because of concurrent administration of supplemental oxygen, TcPO₂ increased during PMLE, from 36 ± 2 to 49 ± 3 mm Hg (p < 0.001). Although tidal volume was not measured, PMLE was associated with substantial increases in respiratory rate, from 10.2 ± 1.9 to 21.2 ± 2.7 breaths/min (p < 0.0001) (Figure 2), which lasted throughout the duration of PMLE.

View larger version (46K): [in this window] [in a new window]   Figure 1.   Representative physiological tracing of a 5-mo-old male infant with central hypoventilation syndrome (CCHS) who was disconnected from his mechanical ventilator and allowed to increase PETCO2 to ~ 60 mm Hg. Upon initiation of passive motion of lower extremities (PMLE) (as indicated by the arrow), there was a rapid decline in both PETCO2 and TcPCO2, increased TcPO2 and respiratory frequency, and no changes in EEG or submental EMG activities. TcPCO2 = transcutaneous carbon dioxide tension; TcPO2 = transcutaneous oxygen tension; PETCO2 = end-tidal carbon dioxide tension; Abd = abdominal respiratory excusion; SpO2 = oxyhemoglobin saturation by pulse oximetry; ECG = electrocardiogram; cEMG = chin electromyogram; C4A1 and C3A2 = electroencephalogram leads; REOG and LEOG = right and left electrooculogram.

View larger version (22K): [in this window] [in a new window]   Figure 2.   Individual average changes in PETCO2 (upper panels) and respiratory frequency (f) (lower panels) from baseline (pre-PMLE or pre-C) and after application of PMLE (solid lines) or control (C) (dashed lines). As an indicator of intraindividual variability in the PMLE response, the standard deviation of pre-PMLE-PMLE ranged from 1.7 to 4.6 mm Hg across subjects.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

In this study, we have shown that passive motion of the extremities in sleeping children with CCHS elicited significant increases in alveolar ventilation as evidenced by reductions in PET_CO2 and TcPCO₂ and increases in respiratory frequency. The improvement in gas exchange lasted for the duration of PMLE.

In a previous study by Paton and coworkers (13), incremental exercise tests were conducted on a treadmill in children with CCHS. At peak exercise, oxygen consumption and E were lower in CCHS; however, CCHS primarily increased their ventilation by increasing breathing frequency rather than tidal volume. Further, breathing frequency and E increased proportionately to running frequency in CCHS, suggesting that respiratory entrainment, mechanoreceptor activation, and/or lactate-induced activation of type III/IV fibers in exercising muscle may underlie the ventilatory enhancements associated with exercise (21).

Both animal and human evidence support the concept that passive motion of limbs will induce increased ventilation via spinal afferent pathways (24). To assess whether peripheral neural feedback mechanisms are critical for motion-induced ventilatory responses, Weissman and coworkers (30) used a spinal lesion model in cats, whereas later, Brice and colleagues (31, 32) studied awake humans with clinically complete spinal lesions. Passive movements of lower extremities did not elicit E increases in the presence of complete spinal lesions (30). Thus, based on the premise that no evidence of spinal lesion or dysfunction is demonstrable in children with CCHS, we performed PMLE during wakefulness, and elicited significant increases in ventilation (12). However, the overall contribution of cortical activity (i.e., the wakefulness drive to breathe) to PMLE-associated ventilatory enhancements could not be determined. The present study performed in Stages 3-4 of NREM sleep would suggest that such cortical contribution is at most minimal, as evidenced by Ishida and colleagues (33), who demonstrated that increases in ventilation elicited by passive limb motion were actually greater in four of five healthy adult subjects tested during Stage 3-4 of NREM sleep.

Earlier observations on the coordination of breathing and movement seemed to support the assumption that synchronization of these two activities would be advantageous to decrease the work of respiratory muscles induced by exercise (21, 34) Thus, entrainment of respiration could be a learned behavior to facilitate ventilatory adjustments during transient changes in respiratory requirements. Indeed, unconscious entrainment of respiratory frequency to rhythmical events such as finger tapping (35), music (36), and walking or running (37), is frequently observed in awake humans. On the other hand, body movement could induce vestibular influences on breathing pattern, which would be operative during both awake and sleep states. In 18 premature infants, manual rocking at varying rates between 30 and 60 cycles/min showed coherence spectra > 0.85, indicative of strong entrainment to rocking in 15 babies (38). Infants born at postconceptional ages > 35 wk exhibited greater coherence to rocking than did more prematurely born infants, indicating that this vestibular-mediated reflex undergoes maturational changes (38). Thus, natural stimulation of rocking in newborns seemed to provide phasic inputs to the respiratory pattern generator that were capable of resetting the oscillatory pattern and entraining the respiratory rhythm (38). Furthermore, the rocking bed method was successfully implemented in adult patients with respiratory failure, and it elicited both increases in oxygen saturation and falls in PCO₂ (39). Notwithstanding the vestibular or visceral contributions to respiratory control by body rocking, it is unlikely that they played any role in our current experiments since the periodic motion applied to the patients with CCHS was restricted to their lower limbs, with no changes in head or body position throughout the trials.

In an interesting study, Ingersoll and Thoman (40) examined the effect of a "breathing" teddy bear on sleep states and regularity of respiration during sleep states in premature infants born at 33 wk gestational age. The bear, which provided a source for optional rhythmic stimulation, was associated with slower and more regular respiration during QS and more QS at 45 wk postconceptional age compared with infants who had a "nonbreathing" bear (40). These findings suggested that the rhythmic stimulation facilitated neurobehavioral development, as well as entrainment from an optional stimulation reflecting one of the infant's own biologic rhythms. It is therefore possible that children with CCHS, who lack central chemosensitivity and display deficient integration of afferent cardiorespiratory inputs, may have "learned" and further developed the locomotor-respiratory interdependencies that promote increased ventilatory outputs during physical activity. Thus, any maneuver that leads to increased mechanoreceptor activity or that will enhance entrainment of a priori separate rhythmicities (i.e., lower limb motion and respiration) could be associated with favorable increases in ventilatory outputs and improved gas homeostasis.

The central coupling between locomotion and respiration was further examined in the decerebrate and paralyzed rabbit preparation (41). In this experimental model, stimulation of the mesencephalic locomotor region evokes locomotor activities as recorded from hindlimb muscle nerves that are rarely coordinated with phrenic inspiratory activity. However, stimulation of the spinal locomotion generator situated caudal to C6-C7 resulted in enhanced coupling of respiratory and locomotor activity during ongoing mesencephalic stimulation (41). When transection was performed at C6-C7 but not at L1 (i.e., when the spinal locomotor centers became isolated from supraspinal regions), the 1/1 evoked locomotor-respiratory coupling was abolished (41). These experiments suggest that either a common supraspinal drive cannot entrain locomotion and respiration or that respiration is entrained at the locomotor rate by the spinal locomotion generators. Thus, extrapolation of such findings to our experiments would support the concept that passive motion of the lower limbs will activate spinal afferent pathways during both wakefulness (12, 13) and sleep (33), which, in turn, will lead to enhanced activation of those regions underlying the central pattern generator of respiration. In this context, the effect of sleep on these spinal reflexes is difficult to assess since these children were not the same children that we previously tested during wakefulness (12). Nevertheless, it is noteworthy pointing out that, in general, sleep exerts substantial attenuation of spinal reflexes and that such reduction is particularly prominent during NREM sleep (42). To what extent this effect of sleep applies to the respiratory system remains to be determined.

Within the limitations of current knowledge on the basic defect in CCHS, we present novel evidence, which indicates that the dysfunctional brain structures that mediate the abnormal ventilatory response to slowly evolving hypercapnia or hypoxia in CCHS do not disrupt the on-response of reflex ventilatory changes elicited by passive motion during NREM sleep. However, although the ventilatory response to passive motion was present for as long as passive movement was continued, we still do not know whether this mechanism will undergo some form of habituation and therefore will progressively decrease the effect of PMLE on ventilation during sleep. In two trials, PMLE was continued for 15 min and no attenuation of the ventilatory effect was noted (data not shown), suggesting that the effect of PMLE is sustained. However, this issue needs to be critically examined before any definitive conclusion can be drawn. In addition, the impact of CCHS phenotype variability on the magnitude and duration of the PMLE-induced ventilatory response remains undefined. Notwithstanding such shortcomes, PMLE may provide a useful interventional strategy for nocturnal, noninvasive ventilatory support in some children with CCHS.