Persistent Pulmonary Hypertension of the Newborn (PPHN)

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 (11% of total combined cardiac output) (1) needs to go through the pulmonary arteries. Most blood from the right side of the heart bypasses the lungs through the foramen ovale and ductus arteriosus. Normally, these 2 structures close shortly after birth. (See also Neonatal Cardiovascular Function.)

In PPHN (previously known as persistent fetal circulation), prenatal stress, postnatal stress (including meconium aspiration syndrome), 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 prevent closure of the ductus arteriosus, arresting or reversing the usual processes establishing newborn circulation at delivery. If the pulmonary artery pressure is higher than the systemic blood pressure (suprasystemic), right-to-left shunting occurs through the ductus arteriosus, foramen ovale, or both. This right-to-left shunting delivers deoxygenated blood to the systemic circulation rather than to the lungs. Even if the pulmonary artery pressure is not suprasystemic, decreased pulmonary blood flow causes hypoxemia. The increased right ventricular afterload can also cause right ventricular dilation and, in severe cases, dysfunction.

Common causes of PPHN include the following (2):

• Perinatal asphyxia or hypoxia: Hypoxia triggers reversion to or persistence of elevated pulmonary vascular resistance, the normal state in the fetus.

• Meconium aspiration syndrome

• Respiratory distress syndrome

• Premature ductus arteriosus or foramen ovale closure, which may be triggered by maternal nonsteroidal anti-inflammatory drug (NSAID) use (however, epidemiologically, NSAID use does not appear to increase the overall risk of PPHN) (3)

• Pulmonary hypoplasia with associated pulmonary vasculature hypoplasia (sometimes due to congenital diaphragmatic hernia), leading to PPHN (4)

• Neonatal sepsis or neonatal pneumonia due to inflammatory cytokines, hypoxia, and acidosis (5)

Whatever the ultimate cause, elevated pulmonary vascular resistance leads to reduced pulmonary blood flow and hypoxemia. Eventually, if pulmonary artery pressure becomes higher than systemic blood pressure (suprasystemic), right-to-left shunting via the ductus arteriosus or a foramen ovale can result in intractable systemic hypoxemia. Elevated pulmonary vascular resistance increases right ventricular afterload, which may result in right heart dilation, tricuspid insufficiency, and right ventricular dysfunction. Abnormal smooth muscle development and hypertrophy in the walls of the small pulmonary arteries and arterioles can also worsen the PPH itself.

Symptoms and signs of PPHN include tachypnea, retractions, and severe cyanosis or hypoxemia 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, and cyanosis is differential (ie, oxygen saturation in the lower [postductal] extremities is ≥ 5% lower than in the right upper [preductal] extremity or the ear).

• Hypoxemia unresponsive to oxygen therapy, sometimes with respiratory failure

• Differential cyanosis with pre- and postductal oximetry

• Echocardiogram

• Radiograph to identify underlying disorders

Diagnosis of PPHN should be suspected in any near-term infant with labile arterial hypoxemia, especially one with a suggestive history and differential cyanosis whose oxygen saturation does not improve with administration of 100% oxygen.

Diagnosis is confirmed by echocardiogram, which can show the presence of elevated pressures in the pulmonary artery, estimate the degree of pulmonary hypertension (subsystemic, systemic, or suprasystemic), evaluate for right heart failure, and exclude or identify congenital heart disease.

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

Blood cultures should be performed because prenatal infection is a possible cause of PPHN. Other laboratory tests to evaluate for sepsis may also be performed.

• Oxygen to dilate pulmonary vasculature and improve oxygenation

• Often inhaled nitric oxide or other pulmonary vasodilatorsOften inhaled nitric oxide or other pulmonary vasodilators

• Invasive ventilatory support as needed

• Correction of metabolic and/or respiratory acidosis

• Extracorporeal membrane oxygenation (ECMO) as needed

• Sometimes circulatory support

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

The infant is placed in a calm environment, and external stimulation is minimized. Treatment with oxygen, which is a potent pulmonary vasodilator, is begun immediately to prevent disease progression. Oxygen is delivered noninvasively or via mechanical ventilation; mechanical distention of alveoli aids vasodilation. Fraction of inspired oxygen (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 decreasing 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] × 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 ECMO [oxygenation index > 35 to 40]).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 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 (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 (1). Initial dose is 20 ppm, titrated downward by effect. Other pulmonary vasodilators, including sildenafil, bosentan, and prostacyclin analogues, may be used as adjuncts (). Initial dose is 20 ppm, titrated downward by effect. Other pulmonary vasodilators, including sildenafil, bosentan, and prostacyclin analogues, may be used as adjuncts (2).

Right ventricular failure may be managed with an inotrope such as milrinone, which also has pulmonary and systemic vasodilatory effects. Fluid resuscitation and or additional vasoactive agents may be required to maintain systemic blood pressure. Right ventricular failure may be managed with an inotrope such as milrinone, which also has pulmonary and systemic vasodilatory effects. Fluid resuscitation and or additional vasoactive agents may be required to maintain systemic blood pressure.

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

A quiet environment should be maintained; occasionally, sedation or muscle relaxants are necessary. Both respiratory and metabolic acidosis should be corrected. 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.

Mortality estimates range from 7 to 20%; risk is related to the underlying disorder (1, 2).

Long-term morbidities include developmental delay, hearing deficits, and chronic lung disease (3).