Hypercapnia and Hypoventilation in a Term Newborn

A term baby born by cesarean delivery develops respiratory distress soon after delivery. The baby is put on continuous positive airway pressure (CPAP) at +5 cm H2O; fraction of inspired oxygen (Fio2), 0.4. Chest radiography shows bilateral haziness. Early-onset sepsis/pneumonia is suspected, and a complete blood cell (CBC) count and blood cultures are drawn. She is started on ampicillin and gentamicin.The mother is a 34-year-old gravida 2, para 2-0-0-2 woman. She reported normal prenatal controls, although she smoked cigarettes and marijuana during pregnancy.With worsening respiratory distress, the baby is transferred to the NICU. On arrival in the NICU, she has subcostal retractions, mild nasal flaring, increased work of breathing, and tachypnea. On auscultation, the infant has diminished breath sounds at the bases and scattered rales. Surfactant is administered without improvement. CBC count is normal, without leukocytosis or anemia. CPAP pressure is increased to +6 cm H2O.An arterial blood gas (ABG) test shows respiratory acidosis with hypercapnia with pH 7.1; oxygen (O2) level, 82 mm Hg (10.91 kPa); carbon dioxide (CO2) level, 101 mEq/L (101 mmol/L); and base excess (BE), −9.6. With clinical deterioration and worsening hypoxemia/hypoventilation, the infant is intubated and placed on ventilatory support with initial settings of: tidal volume, 16 mL (5 mL/kg); rate, 30 breaths per minute; pressure support, 12 cm H2O; positive end-expiratory pressure, +5 cm H2O; and Fio2, 0.3.Clinical improvement is noted with a follow-up ABG test: pH 7.41; O2 level, 45 mm Hg (5.99 kPa); CO2 level, 49 mEq/L (49 mmol/L); and BE, 2.5. On day 3, the patient is extubated and placed on CPAP at +6 cm H2O; Fio2, 0.4. Her respiratory distress recurs with worsening acidosis and hypoventilation. An ABG test shows pH 6.96; O2 level, 139 mm Hg (18.49 kPa); CO2 level, 98 mEq/L (98 mmol/L); and BE, −12.5. The baby is reintubated and placed on mechanical ventilation, and the pulmonology team is consulted.Our patient presents with hypoventilation, hypercapnia, and respiratory distress. Hypoventilation is defined as the difficulty of CO2 elimination by the respiratory system. In the newborn, this can be caused by multiple etiologies, such as genetic syndromes, neuromuscular problems, congenital malformations in the central nervous system, adverse drug reactions, and pulmonary problems. (1)(2) It is also essential to consider primary respiratory, neurologic, and cardiovascular conditions that could lead to hypoventilation and secondary hypercapnia.Hypoplastic lung disease has an incidence of 1.4 per 1,000 births in the general population. (3) This pathology can cause a restrictive lung disease physiology and present as shallow breathing and, sometimes, tachypnea. Although a normal chest radiograph on a term baby without obvious anatomic congenital defects or neuromuscular deficits makes the possibility of hypoplastic lung disease and secondary restrictive lung disease physiology less likely, it should be considered anyway. In the ABG test it can show hypoxemia and hypercapnia. (4)Central sleep apnea can present in 70% to 80% of patients with Prader-Willi syndrome. (5)(6) This syndrome is characterized by severe hypotonia, feeding difficulties (poor suction), and aspiration in newborns. (6)Jeune syndrome (asphyxiating thoracic dystrophy) and Jarcho-Levin syndrome are congenital syndromes that present with chest wall deformities. Both will have a smaller rib cage and, therefore, a restrictive lung disease physiology. (7)Hypercapnia can also be caused by a problem in the central nervous system, such as myelomeningocele and Arnold-Chiari malformation, or congenital hydrocephalus. Midbrain tumors can cause compression with "apneic spells" or other rare disorders such as congenital Guillain-Barre syndrome with weakness and secondary poor respiratory effort. (2)(8)(9)Findings from brain magnetic resonance imaging, heart echocardiography, and chest computed tomography were normal. Genetic testing revealed a pathogenic mutation in the PHOX2B gene (paired-like homeobox 2B gene), p. Ala24125 PARM 20/25 (polyalanine repeat expansion mutation 20/25), confirming the diagnosis of congenital central hypoventilation syndrome (CCHS).CCHS is a rare genetic disease that usually presents in the newborn period, although it can present less commonly in older children and extremely rarely in adults (later-onset CCHS). (10) It frequently exhibits as alveolar hypoventilation and shallow breathing while asleep, awake, or both and as autonomic nervous system dysfunction (ANSD), but it can be as severe as sudden infant death. In these patients, there is an increased risk for Hirschsprung disease and tumors of neural crest origin. Older children present with alveolar hypoventilation while sleeping, altered cognitive performance, and attenuated manifestations of autonomic nervous system dysregulation such as heart rhythm disorders, temperature instability, constipation, abnormal pupillary responses to light, and other vagal dysfunction symptoms. (1)(2)(11)A heterozygous mutation of the PHOX2B gene located on chromosome 4p12 is found in most patients. (12) In 85% of cases, it is secondary to a polyalanine repeat mutation (PARM) of 5 to 13 amino acids; 10% of cases are due to a non-PARM (NPARM), and the remaining 5% can be caused by whole gene or exon 3 deletions. (1)(13)The 20/25 in our case indicates the number of alanine repeats from normal (numerator) and altered (denominator) alleles of the PHOX2B gene.Different genotypes of CCHS have been associated with different needs for ventilatory support, risk of cardiac arrhythmia (sinus pauses), and other ANSD symptoms. (13) Knowing the genotype can benefit the patient's management by targeting the specific symptoms of each genotype.Patients who present with short PARMs (20/24, 20/25) will usually require night-only mechanical ventilation; some of these patients may require mechanical ventilation all day initially, and later support can be weaned to only when sleeping. On the other hand, NPARMs and long PARMs (20/26–20/33) will frequently require 24-hour ventilation. Knowing this, patients with NPARMs and long PARMs might be candidates for a more aggressive approach with tracheostomy. (13)Infants with the 20/27 and 20/26 mutations are the most likely to have cardiac sinus pauses, and they should be evaluated with a Holter monitor; on rare occasions a pacemaker is needed. Children with the 20/25 genotype are very unlikely to have cardiac sinus pauses. (13)All infants with a CCHS diagnosis should be screened for ANSD every 12 months, including Hirschsprung disease according to the American Thoracic Society guidelines. Patients with 20/28 to 20/33 and NPARM genotypes should be monitored closely because these are more likely to develop neural crest tumors. Abdominal ultrasonography and as-needed abdominal and chest computed tomography are indicated. (13)In addition, all infants with CCHS should be screened yearly with a CBC count, an ABG test, electrolytes, echocardiography, neurocognitive assessment, evaluation of ANSD, and, as necessary, a sleep study for ventilation titration. (13) Individual manifestations should be treated by multidisciplinary specialists as they appear. (1)(13)Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder that usually presents in newborns as alveolar hypoventilation and hypopnea/apnea mainly while asleep.Genotype testing is recommended for clinically suspected CCHS. The most common mutation in CCHS is in the PHOX2B gene.Most patients will require long-term mechanical ventilation.It can be associated with Hirschsprung disease and neural crest tumors.Cognitive problems with lower IQs have been reported.Later-onset CCHS can happen in older children and adults.American Board of Pediatrics Neonatal-Perinatal Content SpecificationsKnow the concepts of insertion, deletion, inversion, and translocation.Know the frequency of minor congenital anomalies.Know the frequency of major congenital malformations.Recognize the pathologic features of respiratory distress syndrome.Know the management of respiratory distress syndrome, including surfactant replacement.Recognize the clinical features of extrapulmonary causes of respiratory distress.Know the clinical features and inheritance patterns of common syndromes or associations that can be recognized in the newborn period (eg, VATER association and DiGeorge syndrome).Know the basis for (including genetic), clinical, and laboratory features (including associated abnormalities), differential diagnosis, evaluation, management, and outcomes of neonatal hypotonia/neuromuscular weakness.Know the pathophysiology of apnea of prematurity.Know the pathogenesis, pathophysiology, and risk factors of transient tachypnea of the newborn infant.