Update on PPHN: mechanisms and treatment

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory adaptation at birth, seen in about 2/1000 live born infants. While it is mostly seen in term and near-term infants, it can be recognized in some premature infants with respiratory distress or bronchopulmonary dysplasia. Most commonly, PPHN is secondary to delayed or impaired relaxation of the pulmonary vasculature associated with diverse neonatal pulmonary pathologies, such as meconium aspiration syndrome, congenital diaphragmatic hernia, and respiratory distress syndrome. Gentle ventilation strategies, lung recruitment, inhaled nitric oxide, and surfactant therapy have improved outcome and reduced the need for extracorporeal membrane oxygenation (ECMO) in PPHN. Newer modalities of treatment discussed in this article include systemic and inhaled vasodilators like sildenafil, prostaglandin E1, prostacyclin, and endothelin antagonists. With prompt recognition/treatment and early referral to ECMO centers, the mortality rate for PPHN has significantly decreased. However, the risk of potential neurodevelopmental impairment warrants close follow-up after discharge for infants with PPHN.

Keywords: Hypoxic respiratory failure; Nitric oxide; Persistent fetal circulation; Pulmonary vascular resistance; Systemic vasodilators.

Figure 1

Endothelium derived vasodilators – prostacyclin (PGI₂) and nitric oxide (NO) and vasoconstrictor (endothelin, ET-1). The enzymes, cyclooxygenase (COX) and prostacyclin synthase (PGIS) are involved in the production of prostacyclin. Prostacyclin acts on its receptor in the smooth muscle cell and stimulates adenylate cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Cyclic AMP is broken down by phosphodiesterase 3A (PDE 3A) in the smooth muscle cell. Milrinone inhibits PDE 3A and increases cAMP levels in pulmonary arterial smooth muscle cells and cardiac myocytes resulting in pulmonary (and systemic) vasodilation and inotropy. Endothelin is a powerful vasoconstrictor and acts on ET-A receptors in the smooth muscle cell and increases ionic calcium concentration. A second endothelin receptor (ET-B) on the endothelial cell stimulates nitric oxide release and vasodilation. Endothelial nitric oxide synthase (eNOS) produces NO which diffuses from the endothelium to the smooth muscle cell and stimulates soluble guanylate cyclase (sGC) enzyme to produce cyclic guanosine monophosphate (cGMP). Cyclic GMP is broken down by PDE 5 enzyme in the smooth muscle cell. Sildenafil inhibits PDE5 and increases cGMP levels in pulmonary arterial smooth muscle cells. Cyclic AMP and cGMP reduce cytosolic ionic calcium concentrations and induce smooth muscle cell relaxation and pulmonary vasodilation. Nitric oxide is a free radical and can avidly combine with superoxide anions to form a toxic vasoconstrictor, peroxynitrite. Hence, the bioavailability of NO in a tissue is determined by the local concentration of superoxide anions. Hyperoxic ventilation with 100% oxygen can increase the risk of formation of superoxide anions in the pulmonary arterial smooth muscle cells and limit the bioavailability of NO (copyright Satyan Lakshminrusimha).

Figure 2

Changes in pulmonary blood flow (secondary Y-axis on the right), mean systemic arterial pressure and mean pulmonary arterial pressure (primary Y-axis on the left) in normal term lambs ventilated with 21% oxygen over the first 30 min of life. The pulmonary arterial pressure is higher than the systemic arterial pressure during fetal period. Clamping the umbilical cord at birth increases systemic blood pressure and ventilation reduces pulmonary arterial pressure and increases pulmonary blood flow. Data derived from 8 lambs from the author’s laboratory.

Figure 3

Various etiological factors causing PPHN and hemodynamic changes in PPHN/HRF – PA – pulmonary artery; RV – right ventricle; LV – left ventricle; TR – tricuspid regurgitation; RA – right atrium; LA – left atrium; PDA – patent ductus arteriosus; PFO – patent foramen ovale. Surfactant deficiency (RDS) or inactivation (MAS or pneumonia) result in parenchymal lung disease and ventilation-perfusion (V/Q) mismatch. Increased pulmonary vascular resistance results in reduced pulmonary blood flow and right to left shunt through PDA and/or PFO. Pulmonary hypertension is often associated with systemic hypotension with septal deviation to the left. Cardiac dysfunction secondary to asphyxia, sepsis or congenital diaphragmatic hernia (CDH) may complicate HRF. Parenchymal lung disease secondary to RDS, pneumonia, transient tachypnea of newborn (TTN), pneumonia, and atelectasis can result in V/Q mismatch and hypoxemia and PPHN. Idiopathic or “black-lung” PPHN is not associated with parenchymal lung disease and results in reduced pulmonary blood flow with pulmonary vascular remodeling. Pulmonary hypoplasia secondary to CDH or due to oligohydramnios (prolonged leakage of fluid or reduced production due to renal compromise) causes alveolar and vascular hypoplasia and PPHN. The right subclavian artery (and blood flowing to the right upper extremity) is always preductal. The left subclavian artery may be preductal, juxtaductal or postductal. Hence, preductal oxygen saturations should be obtained from the right upper extremity (copyright Satyan Lakshminrusimha).

Figure 4

Pathophysiology of hemodynamic abnormalities in congenital diaphragmatic hernia. During fetal life, reduced pulmonary venous return contributes to left sided cardiac hypoplasia. In the immediate postnatal period, a short period of better oxygenation is referred to as “honeymoon” period. Subsequently, a period of left ventricular dysfunction results in pulmonary venous hypertension. Progressive volutrauma and oxygen toxicity leads to chronic lung disease and contributes to pulmonary hypertension. Maintenance of ductal patency with intravenous PGE1 and enhanced left ventricular function with milrinone may improve oxygenation in CDH (Copyright Satyan Lakshminrusimha)

Figure 5

Echocardiographic evaluation of neonatal hypoxemia based on ductal (black bar) and atrial (blue bar) shunts. Left to right shunt at the ductal and atrial level is considered normal but can also be seen in the presence of parenchymal lung disease resulting in hypoxemia in the absence of PPHN (lower left quadrant). The presence of right to left shunt at the atrial and ductal level is associated with PPHN (upper right quadrant). Right to left shunt at the ductal level but a left to right shunt at the atrial level is associated with left ventricular dysfunction, pulmonary venous hypertension and ductal-dependent systemic circulation (lower right quadrant) and is a contraindication for inhaled pulmonary vasodilators such as iNO. In patients with right sided obstruction (such as critical pulmonary stenosis – PS), right atrial blood flows to the left atrium through the PFO. Pulmonary circulation is dependent on a left to right shunt at the PDA (upper left quadrant). PA – pulmonary artery; RV – right ventricle; LV – left ventricle; TR – tricuspid regurgitation; RA – right atrium; LA – left atrium; PDA – patent ductus arteriosus; Ao – aorta; PGE1 (prostaglandin E1) (Copyright Satyan Lakshminrusimha)

Figure 6

Selective and micro-selective action of inhaled nitric oxide (NO); Inhaled NO is a selective dilator of the pulmonary circulation without any significant systemic vasodilation as it combines with hemoglobin to form methemoglobin. As it is an inhaled vasodilator, it selectively enters the well ventilated alveoli and improves blood flow to these alveoli and reduces V/Q mismatch (micro-selective effect) (Copyright Satyan Lakshminrusimha)

Figure 7

Management of PPHN by “gentle ventilation” – see text for details (Copyright Satyan Lakshminrusimha)