Central Alveolar Hypoventilation

Failure of the automatic control of breathing that causes hypoventilation (raised PaCO2 and low PaO2) despite normal lungs, chest wall and respiratory muscles, worse in sleep.

• Congenital central hypoventilation syndrome (Ondine curse): caused by a mutation in the PHOX2B gene (about 90% have a polyalanine repeat expansion, genotypes 20/24 to 20/33; the remainder have non-polyalanine repeat mutations); autosomal dominant, with most cases arising de novo; incidence is about 1 in 150,000 to 200,000 live births; late-onset forms present in later childhood or adulthood.
• Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD): presents at age 2 to 7 years with rapid weight gain, then hypoventilation.
• Acquired causes: brainstem stroke, tumour, infarct or demyelination; Chiari malformation; encephalitis; bulbar poliomyelitis; neurosurgery or cervical cordotomy; severe hypothyroidism; chronic opioid and sedative use; and idiopathic cases.
• Mechanism: chemoreceptor and brainstem integration of carbon dioxide and oxygen sensing is impaired, so ventilation does not rise with hypercapnia or hypoxia, and falls during sleep (and, in severe disease, while awake).

Neonates: apnoea, cyanosis and shallow breathing during sleep (and sometimes awake), failure to breathe after birth, no distress with hypercapnia; infants may present after sedation, anaesthesia or respiratory infection.

• Features of autonomic dysfunction: reduced heart rate variability, sinus pauses, constipation or Hirschsprung disease (about 16 to 20% of those with congenital central hypoventilation syndrome), tumours of neural crest origin (neuroblastoma, ganglioneuroma, ganglioneuroblastoma in 1 to 6%), pupillary abnormalities, strabismus, temperature and sweat abnormalities, and reduced pain perception.
• Adults and older children: sleep-disordered breathing, morning headache, daytime sleepiness, cor pulmonale, polycythaemia, seizures from hypoxaemia, and neurodevelopmental delay.
• Differential diagnosis: obesity hypoventilation, neuromuscular disease, chest wall disease, lung disease, congenital heart disease, metabolic disorders (Leigh disease, pyruvate dehydrogenase deficiency), Prader-Willi syndrome, brainstem malformation, drug-induced hypoventilation, hypothyroidism, myasthenia.
• Complications: hypoxic brain injury and neurodevelopmental delay, pulmonary hypertension and cor pulmonale, seizures, arrhythmia and sudden death, tumours, Hirschsprung enterocolitis, and death with respiratory infection or sedatives.

Blood gas: PaCO2 of more than 6.0 kPa (45 mmHg) awake in severe disease, and raised in sleep (more than 6.7 kPa) with a high bicarbonate, but with normal lungs on chest imaging, normal respiratory muscle and neuromuscular tests, and no explanation from drugs.

• Polysomnography with carbon dioxide monitoring: hypoventilation worst in non-rapid eye movement sleep, with minimal arousal or ventilatory response.
• PHOX2B gene testing (the definitive test): polyalanine repeat expansion, or sequencing for non-polyalanine repeat mutations; parental testing for mosaicism.
• Ventilatory response testing to hypercapnia and hypoxia (specialist laboratories): absent or blunted response.
• Brain and brainstem MRI to exclude structural disease; neurology review; creatine kinase, thyroid function, metabolic screen (lactate, pyruvate, acylcarnitines, amino acids) when the picture is atypical.
• Associated disease screen: rectal suction biopsy for Hirschsprung disease when constipated; urine catecholamines and chest and abdominal imaging every 6 to 12 months for neural crest tumours; 72 hour Holter for pauses (more than 3 seconds); echocardiography; ophthalmology; endocrine tests (hypothalamic dysfunction in ROHHAD).

Lifelong ventilatory support is the mainstay; no drug restores the ventilatory drive, and respiratory stimulants are not effective.

• Aims: keep SpO2 at 95% or more and end-tidal carbon dioxide at 4.7 to 6.0 kPa (35 to 45 mmHg) during all sleep and any hypoventilating wake periods.
• Infants and young children: tracheostomy with home positive pressure ventilation (tidal volume 10 to 15 mL/kg, rate 20 to 30 per minute with pressure control at inspiratory pressure to reach an end-tidal carbon dioxide of 35 to 45 mmHg), 24 hours a day if apnoeic when awake, and at least all sleep.
• Older children with good awake breathing: non-invasive bilevel ventilation by mask with a backup rate; mask fit and skin care need constant review.
• Diaphragm pacing by phrenic nerve stimulation: in selected patients who need ventilation 24 hours a day and are able to be weaned for part of the day; used during the day, so that sleep ventilation continues by pressure support; complications are device failure, infection, and the need for backup ventilation.
• Home monitoring: continuous pulse oximetry and capnography during sleep, trained carers at all times (two carers trained in tracheostomy and resuscitation), home ventilators with backup battery and a second machine, suction, bag and mask.
• Avoid respiratory depressants (benzodiazepines, opioids, barbiturates, alcohol, anaesthetic agents); if anaesthesia is needed, use short-acting agents with ventilation and postoperative monitoring.
• Respiratory infections: early review, antibiotics (for example amoxicillin-clavulanate 25 to 30 mg/kg of the amoxicillin component three times daily in children, 625 mg three times daily in adults), and increased ventilatory support.
• Cardiac: implant a pacemaker for sinus pauses of 3 seconds or more; treat arrhythmia.
• Associated conditions: surgery for Hirschsprung disease; oncology treatment for neural crest tumours; vaccinations (annual influenza, pneumococcal conjugate vaccine, and routine childhood vaccines).
• Acquired central hypoventilation: treat the cause (resect Chiari malformation with decompression, tumour surgery, levothyroxine 50 micrograms rising to 100 to 150 micrograms for hypothyroidism, stop opioids); non-invasive ventilation at night; baclofen and other stimulants are not proven.
• Neurodevelopmental support, physiotherapy and school support; genetic counselling (50% risk to offspring of an affected person; testing of siblings and parents).
• Special groups: children (monitor growth, development and school progress; transition to adult care); pregnancy (continue ventilation, keep carbon dioxide in the normal range, deliver in a centre with respiratory and neonatal teams, plan anaesthesia and delivery with caution; the fetus has a 50% chance of inheriting the mutation); elderly (late onset; consider brainstem stroke); renal impairment (no change); infection (higher ventilatory support and an early ventilator review).
• Red flags: hypoxic or hypercapnic episodes, cyanosis, fever, tracheostomy blockage, ventilator failure, sinus pauses, seizures, distended abdomen or constipation, new mass.
• Follow-up: every 3 to 6 months in specialist centres with in-hospital sleep testing, ventilator settings and carbon dioxide monitoring; yearly echocardiogram, Holter monitor, neurocognitive testing and tumour screening (in the first years of life every 3 to 6 months).