Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn is failure of the normal fall in pulmonary vascular resistance after birth. Pulmonary arterial pressure stays at or over systemic level, blood shunts right to left across the foramen ovale and ductus arteriosus, and hypoxaemia is out of proportion to any lung disease. It affects mainly term and late preterm infants.

It occurs in about 1 to 2 of every 1000 live births. Mortality is about 5 to 10% where inhaled nitric oxide and extracorporeal support are available. A minority of survivors have neurodevelopmental impairment or sensorineural hearing loss.

Three patterns occur: maladaptation (meconium aspiration, pneumonia, sepsis, respiratory distress syndrome, perinatal asphyxia), maldevelopment (congenital diaphragmatic hernia, pulmonary hypoplasia from oligohydramnios, alveolar capillary dysplasia) and idiopathic disease with structurally normal lungs and muscularised arterioles.

Risk is higher with late preterm or post-term birth, caesarean delivery without labour, maternal diabetes, maternal obesity, male sex, and late pregnancy exposure to selective serotonin reuptake inhibitors or non-steroidal anti-inflammatory drugs (which can constrict the foetal ductus).

Oxygenation index equals mean airway pressure (cmH2O) multiplied by FiO2 multiplied by 100, divided by PaO2 (mmHg). A value over 15 is moderate, over 25 is severe, and 40 or more usually meets criteria for extracorporeal membrane oxygenation.

Pathophysiology.

In foetal life pulmonary resistance is high and most right ventricular output bypasses the lungs. At birth, lung expansion, oxygen and endogenous vasodilators (nitric oxide, prostacyclin) lower resistance rapidly.

In this condition the pulmonary vessels are over muscularised after chronic intrauterine stress, underdeveloped in hypoplasia, or constricted by hypoxia, acidosis, hypothermia and inflammation.

Right to left shunting produces a difference between preductal and postductal saturation. Right ventricular pressure overload reduces left ventricular filling, causing systemic hypotension, which worsens hypoxia and acidosis in a self-reinforcing cycle.

• Cyanosis and respiratory distress in the first hours of life, often with labile oxygenation and desaturation on handling.
• Preductal (right hand) saturation more than 10 percentage points higher than postductal (foot) saturation indicates a ductal shunt. A normal difference does not exclude disease when the shunt is atrial only.
• Single loud second heart sound, systolic murmur of tricuspid regurgitation, hepatomegaly in later presentations.
• Hypotension and poor peripheral perfusion.

Red flags.

• Hypoxaemia that does not improve within 1 hour of inhaled nitric oxide: consider alveolar capillary dysplasia, obstructed total anomalous pulmonary venous connection or a duct dependent cardiac lesion.
• Postductal saturation higher than preductal saturation.
• Pulmonary oedema pattern on chest X-ray with a normal heart size.

• Continuous preductal and postductal pulse oximetry, arterial blood gas and calculation of oxygenation index.
• Chest X-ray: shows the underlying lung disease, or clear and oligaemic lung fields when hypoxaemia is severe with little parenchymal disease.
• Echocardiography is the definitive test. Look for septal flattening or bowing to the left, right to left or bidirectional shunting at the duct and foramen ovale, a tricuspid regurgitant jet, right ventricular dilatation and function, and exclude critical congenital heart disease, especially obstructed pulmonary venous return.
• Hyperoxia test: a PaO2 under 150 mmHg in 100% oxygen suggests cyanotic heart disease or severe pulmonary hypertension. It does not replace echocardiography.
• Full blood count, CRP, blood culture, glucose, calcium, lactate and cranial ultrasound (before extracorporeal support).

Differential diagnosis. Cyanotic congenital heart disease (transposition, pulmonary atresia, total anomalous pulmonary venous connection, Ebstein anomaly), severe parenchymal lung disease, sepsis, pulmonary hypoplasia, methaemoglobinaemia, polycythaemia and alveolar capillary dysplasia.

Supportive measures.

• Minimal handling, normothermia, correction of acidosis, glucose over 2.6 mmol/L, normal calcium, haematocrit over 40%.
• Preductal saturation target 91 to 95%, PaO2 50 to 80 mmHg, PaCO2 40 to 50 mmHg. Avoid hyperoxia and alkalosis.
• Recruit the lung with adequate positive end expiratory pressure, avoiding over distension. Use high frequency oscillation when parenchymal disease is severe.
• Surfactant for parenchymal disease: poractant alfa 200 mg/kg (2.5 mL/kg) intratracheally, then 100 mg/kg (1.25 mL/kg) at 12-hour intervals for up to 2 further doses.
• Analgesia and sedation with fentanyl 1 to 3 micrograms/kg/h IV.

Circulatory support.

• Keep mean arterial pressure at or over 45 mmHg. Give 10 mL/kg of 0.9% sodium chloride only if hypovolaemic.
• Dopamine 5 to 10 micrograms/kg/min or noradrenaline 0.05 to 0.5 micrograms/kg/min IV. Hydrocortisone 1 mg/kg IV every 8 hours for catecholamine resistant hypotension.

Inhaled nitric oxide.

• Start in infants of 34 weeks or more when oxygenation index remains 15 to 25 or higher despite optimal lung recruitment. Dose 20 ppm. Do not exceed 20 ppm.
• Response is judged at 30 to 60 minutes by a rise in PaO2 of 20 mmHg or more or a fall in oxygenation index.
• Wean when FiO2 is 0.6 or less and oxygenation is stable: reduce by 5 ppm every 4 hours to 5 ppm, then by 1 ppm, and stop at 1 ppm. Abrupt withdrawal causes rebound. If rebound occurs, restart at 20 ppm.
• Measure methaemoglobin 4 to 8 hours after starting then daily. Reduce the dose if methaemoglobin is over 5% or nitrogen dioxide is over 3 ppm.
• Do not use in duct dependent systemic circulation or obstructed pulmonary venous return.

Adjunctive vasodilators.

• Sildenafil (off label): oral 0.5 to 2 mg/kg every 6 to 8 hours, or IV loading 0.4 mg/kg over 3 hours then 1.6 mg/kg/day by infusion. Watch for hypotension.
• Milrinone when ventricular dysfunction is present or inhaled nitric oxide fails: loading 50 micrograms/kg over 30 to 60 minutes (omit if hypotensive), then 0.33 to 0.75 micrograms/kg/min. Reduce the dose in renal impairment.
• Inhaled or IV prostacyclin analogues are specialist rescue treatment.

Extracorporeal support. Consider when oxygenation index is 40 or more on repeated gases despite optimal treatment, with gestation of 34 weeks or more, weight 2 kg or more, reversible disease and no major intracranial haemorrhage.

Monitoring. Continuous preductal and postductal saturations, arterial pressure, blood gases every 2 to 4 hours, lactate, glucose, methaemoglobin, platelets and daily echocardiography until stable.

Referral and escalation. Transfer early to a centre with inhaled nitric oxide and extracorporeal support when oxygenation index is 15 to 20 or higher and rising, rather than waiting for 40.

Special groups.

• Congenital diaphragmatic hernia: pulmonary vasodilators may worsen left ventricular filling pressures when the left heart is small. Direct use by echocardiography.
• Infants under 34 weeks: inhaled nitric oxide is not routine and is used selectively.