Persistent Pulmonary Hypertension of the Newborn

In normal fetal circulation, blood entering the right side of the heart has already been oxygenated via the placenta. Because the lungs are not ventilated, only a small amount of blood needs to go through the pulmonary artery. Most blood from the right side of the heart bypasses the lungs through the foramen ovale and ductus arteriosus. Normally, these two structures close shortly after birth. (See also Neonatal Cardiovascular Function.)

In PPHN (previously known as persistent fetal circulation), prenatal stress, postnatal stress, and anatomical differences may result in the persistence of elevated pulmonary vascular resistance after birth. Hypoxemia and acidosis cause the pulmonary arterioles to constrict and the ductus arteriosus to dilate, reversing the usual processes establishing newborn circulation at delivery and resulting in right-to-left shunting through the ductus arteriosus, foramen ovale, or both. This right-to-left shunting bypasses the lungs and causes nonoxygenated or poorly oxygenated blood to be delivered systemically.

The most common causes of persistent pulmonary hypertension of the newborn involve

• Perinatal asphyxia or hypoxia

A history of meconium staining of amniotic fluid or meconium in the trachea is common. Hypoxia triggers reversion to or persistence of elevated pulmonary vascular resistance, a normal state in the fetus.

Additional causes include

• Respiratory distress syndrome

• Premature ductus arteriosus or foramen ovale closure, which increases fetal pulmonary blood flow and may be triggered by maternal nonsteroidal anti-inflammatory drug (NSAID) use (1)

• Pulmonary hypoplasia with associated pulmonary vasculature hypoplasia leading to PPHN (2)

• Congenital diaphragmatic hernia, in which one lung is severely hypoplastic, also leading to pulmonary vasculature hypoplasia and PPHN

• Neonatal sepsis or neonatal pneumonia presumably because vasoconstrictive prostaglandins are produced by activation of the cyclooxygenase pathway by bacterial phospholipids, and acidosis due to systemic hypoperfusion caused by the infection also contributes to PPHN in this scenario

Whatever the cause, elevated resistance in the pulmonary arteries causes abnormal smooth muscle development and hypertrophy in the walls of the small pulmonary arteries and arterioles and right-to-left shunting via the ductus arteriosus or a foramen ovale, resulting in intractable systemic hypoxemia. Both pulmonary and systemic resistances are high, which leads to an increased load on the heart. This load increase may result in right heart dilation, tricuspid insufficiency, and right heart failure.

Symptoms and signs of persistent pulmonary hypertension of the newborn include tachypnea, retractions, and severe cyanosis or desaturation unresponsive to supplemental oxygen.

In infants with a right-to-left shunt via a patent ductus arteriosus, oxygenation is higher in the right brachial artery than in the descending aorta; thus, cyanosis may be differential (ie, oxygen saturation in the lower extremities is ≥ 5% lower than in the right upper extremity).

• Cyanosis unresponsive to oxygen therapy

• Echocardiogram

• X-ray to identify underlying disorders

Diagnosis of persistent pulmonary hypertension of the newborn should be suspected in any near-term infant with arterial hypoxemia, cyanosis, or both, especially one with a suggestive history whose oxygen saturation does not improve with administration of 100% oxygen.

Diagnosis is confirmed by echocardiogram, which can confirm the presence of elevated pressures in the pulmonary artery and simultaneously can exclude congenital heart disease.

Blood cultures should be done because prenatal infection is a possible cause of persistent pulmonary hypertension in the newborn.

On x-ray, lung fields may be normal or may show changes due to the underlying disorder (eg, meconium aspiration syndrome, neonatal pneumonia, congenital diaphragmatic hernia). X-ray abnormalities may be difficult to distinguish from bacterial pneumonia.

• Oxygen to dilate pulmonary vasculature and improve oxygenation

• Mechanical ventilation support

• Inhaled nitric oxide

• ECMO as needed

• Circulatory support

• Correction of metabolic and/or respiratory acidosis

The goal of treatment is to reverse the conditions that caused pulmonary vasoconstriction and treat the underlying conditions.

Treatment with oxygen, which is a potent pulmonary vasodilator, is begun immediately to prevent disease progression. Oxygen is delivered via bag-and-mask or mechanical ventilation; mechanical distention of alveoli aids vasodilation. FIO2 should initially be 1 but can be titrated downward to maintain PaO2 between 50 and 90 mm Hg to minimize lung injury once there is evidence of decreased pulmonary vascular resistance. Once PaO2 is stabilized, weaning can be attempted by reducing FIO2 in decrements of 2 to 3%, then reducing ventilator pressures; changes should be gradual, because a large drop in PaO2 can cause recurrent pulmonary artery vasoconstriction. High-frequency oscillatory ventilation expands and ventilates the lungs while minimizing barotrauma and should be considered for infants with underlying lung disease in whom atelectasis and ventilation/perfusion (V/Q) mismatch may exacerbate the hypoxemia of PPHN.

The oxygenation index (mean airway pressure [cm H2O] × fraction of inspired oxygen [FIO2] × 100/PaO2) is used to assess disease severity and determine timing of interventions (in particular for inhaled nitric oxide [oxygenation index 15 to 25] and extracorporeal membrane oxygenation [ECMO—oxygenation index > 35 to 40]).

Inhaled nitric oxide relaxes endothelial smooth muscle, dilating pulmonary arterioles, which increases pulmonary blood flow and rapidly improves oxygenation in as many as half of patients. Initial dose is 20 ppm, titrated downward by effect.

ECMO may be used in newborns with severe hypoxic respiratory failure defined by an oxygenation index > 35 to 40 despite maximum respiratory support.

Normal fluid, electrolyte, glucose, and calcium levels must be maintained. Infants should be kept in a neutral thermal environment and treated with antibiotics for possible sepsis until culture results are known. Inotropes and pressors may be required as part of circulatory support.

Overall mortality ranges from 10 to 60% and is related to the underlying disorder. About 25% of survivors exhibit developmental delay, hearing deficits, functional disabilities, or a combination. This rate of disability may be no different from that of other infants with severe illness.