A full-term newborn infant is described with recurrent episodes of oxygen desaturation and apnea on the day of birth. The apnea did not improve with continuous positive airway pressure (CPAP) and intermittent nasal ventilation, therefore intubation and mechanical ventilation were required. A preliminary diagnosis of congenital central hypoventilation syndrome (CCHS) was made with the use of simultaneous measurements of end-tidal CO2 (EtCO2) and a diaphragm electrical activity waveform that was detected using microsensors placed on the infant’s feeding tube. It was observed that during deep sleep, the diaphragm electrical activity waveform was close to 0 μV (central apnea) and EtCO2 levels rose accordingly (central hypoventilation). Genetic testing subsequently revealed a Phox2b mutation, establishing the diagnosis of CCHS. Simultaneously measuring diaphragm electrical activity and EtCO2 is feasible and may be a valuable bedside diagnostic tool in cases of suspected CCHS before the diagnosis is confirmed with genetic testing.
Congenital central hypoventilation syndrome (CCHS) is a rare disorder defined by impaired automatic control of breathing. Patients typically present with alveolar hypoventilation primarily while asleep.1 Sensitivity to hypercapnia and hypoxia is decreased, and ventilatory support is required in affected individuals. First symptoms are usually observed in the neonatal period. The paired-like homeobox 2B gene (Phox2b) was found to be the disease-defining gene for CCHS.1 Today, the control of breathing can be routinely and clinically monitored in infants requiring mechanical ventilation, via measurements of the diaphragm electrical activity (EAdi).2, 3 Miniaturized microsensors mounted on a naso/orogastric feeding tube detect the spontaneous breathing activity, and impose no additional invasiveness to infants being fed enterally while on mechanical ventilation. The EAdi waveform provides information about the neural respiratory effort,2 and in its absence, it is an indicator of central apnea.
A 4560-g female baby was born at 38 weeks of gestation by Cesarean section. The course of pregnancy was uneventful, but the decision regarding the mode of delivery was taken because of postnatal complications in a prior sibling who has cerebral palsy of unclear origin. The newborn in this case report was breathing spontaneously after birth, but presented with apnea in the third minute of life. Cord blood gases were normal (pH=7.37, base excess=–0.3). Because of recurrent episodes of desaturation and apnea associated with respiratory acidosis and hypercapnia (with PaCO2 reaching 90 mm Hg), the infant was treated with non-invasive ventilatory support (Infant Flow SiPAP, Carefusion, Yorba Linda, CA, USA). Nasal continuous positive airway pressure (CPAP) and intermittent nasal ventilation was insufficient to maintain a normal clinical- and pulmonary laboratory state. Hence, the baby required intubation and mechanical ventilation with synchronized intermittent mandatory ventilation (SIMV) combined with pressure support (PS) mode (Servo-I ventilator, Maquet, Solna, Sweden).
At 19 days after birth, the infant was extubated but required non-invasive respiratory support (BiPhasic mode of the Infant Flow SiPAP device) while asleep for reoccurring apnea. From birth, apneic episodes were observed whenever the baby went to sleep. While awake, the baby was breathing regularly without any clinical signs of increased work of breathing. No metabolic disorders were diagnosed in this patient. Cerebral anomalies and congenital heart defects were ruled out by ultrasound studies. The baby revealed no pathological findings on ophthalmic and neurological examinations. Electroencephalography recording was normal.
The older sister of this patient suffers from cerebral palsy. The child requires home mechanical ventilation using a tracheostomy, because apnea always occurs when she goes to sleep, a clinical characteristic shared by this index case. Based on these findings in the patient and the older sibling, a disorder involving the central regulation of breathing was suspected.
In order to assess the neural respiratory drive and respiratory control, the electrical activity of the diaphragm (EAdi) was measured. This was achieved by a commercially available sensor placed in the esophagus (NAVA catheter, Maquet Critical Care) at the level of the gastro-esophageal junction (Figure 1).4 The sensor also has the capability of feeding, similar to a standard naso-gastric feeding tube, and therefore, imposes no additional invasiveness. End-tidal CO2 (EtCO2) was simultaneously measured (CO2 Analyzer Module, Maquet Critical Care). During the period of simultaneous EtCO2 and EAdi monitoring (Figure 2), the following SIMV settings were used (SIMV+PSV mode): ventilator rate=30 per minute, PIP=18 cm H2O, PEEP=5 cm H2O, PS level=10 cm H2O, and FiO2=21%.
We observed that if the infant went into deep sleep (assessed by a physician using the Brazelton’s Neonatal Behavioral Assessment Scale definition), the following events occurred: (a) the EtCO2 concentration levels increased (maximum observed value was 70 mm Hg) despite assisted ventilation at the same time and (b) the EAdi signal was extremely low (if not absent) indicating central apnea. The simultaneous recordings of central respiratory drive (EAdi) during different states of consciousness and development of hypercapnia (EtCO2) are presented in Figure 2. During sleep depicted by the gray shadowed bars, EAdi decreased with more frequent ‘zero values’, and concurrently EtCO2 increased and remained elevated during deep sleep and persistent apnea. Life-threatening desaturation and hypercarbia occur if no intervention or nasal CPAP alone is utilized. Thus, some ventilatory assistance is mandated during the diagnostic testing. Upon return of more consistent and elevated EAdi values and breathing, the EtCO2 returned to normal values after ∼20 min.
Based on those findings, a preliminary diagnosis of CCHS was made. To confirm the diagnosis, a blood sample was sent to Embryology and Genetics Department of L'hôpital Necker-Enfants Malades in Paris, France. Phox2b direct sequencing showed a heterozygous variation of the stop codon leading to an extension of the Phox2b protein (c.945A>T, p.X315CextX41). This genetic mutation confirmed a diagnosis of CCHS for this patient. Genetic testing of the older sister identified the same mutation.
This is the first occurrence of CCHS in siblings with an identified Phox2b mutation in Poland. The diagnosis of CCHS in the index case was based on standard criteria: hypoventilation episodes during sleep, early age of onset, and absence of primary neuromuscular, lung, cardiac, metabolic disease or any brainstem pathology.1 The infant had persistent apnea when falling asleep and thus fulfilled the definition of CCHS.
Central hypoventilation was confirmed by monitoring diaphragmatic electrical activity in combination with EtCO2 measurements. Similar findings were recently reported.5 The EAdi is a signal that is representative of central respiratory drive.4 In its absence, it is an indication of central apnea2, assuming the catheter with the sensors is adequately positioned, and this was confirmed in the index case with the use of the built-in catheter positioning window. During central apnea, diaphragmatic activity signal was not detected in our patient during non-aroused sleep. The described methodology allows the distinction between central and obstructive apneas as obstructive pathophysiology always demonstrates diaphragmatic contractions.6 Occasional EAdi signals were observed during the apnea period in the index case (Figure 2). This monitoring disparity may be caused by changes in the state of consciousness of the infant (that is, deep sleep versus brief arousal events), although sporadic artifacts cannot be excluded.
Early diagnosis is crucial because CCHS that goes unrecognized in early infancy may result in sudden unexpected deaths or life-threatening episodes of apnea. Survivors often manifest different types of cerebral injury,7, 8 and hence an early diagnosis and treatment is needed to prevent these complications. The method of simultaneously measuring electrical activity of the diaphragm and EtCO2 presented here allows a tentative diagnosis of CCHS when genetic testing is not readily available.
Based on this case report, synchronized EAdi and EtCO2 monitoring is achievable and provides a valuable diagnostic tool in cases of suspected CCHS before the results of genetic tests return to the clinician. This method should facilitate the diagnosis of this rare disease.
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Dr Beck has made inventions related to neural control of mechanical ventilation that are patented. The license for these patents belongs to Maquet Critical Care. Future commercial uses of this technology may provide financial benefit to Dr Beck through royalties. Dr Beck owns 50% of Neurovent Research Inc (NVR). NVR is a research and development company that builds the equipment and catheters for research studies. NVR has a consulting agreement with Maquet Critical Care. The other authors declare no conflict of interest.
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Szczapa, T., Beck, J., Migdal, M. et al. Monitoring diaphragm electrical activity and the detection of congenital central hypoventilation syndrome in a newborn. J Perinatol 33, 905–907 (2013). https://doi.org/10.1038/jp.2013.89
- congenital central hypoventilation syndrome
- diaphragm electrical activity
- central apnea
- mechanical ventilation
- Phox2b mutation
Evaluation of respiratory center function in congenital central hypoventilation syndrome by monitoring electrical activity of the diaphragm
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