Persistent Pulmonary Hypertension in the Newborn

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of failed circulatory adaptation at birth due to delay or impairment in the normal fall in pulmonary vascular resistance (PVR) that occurs following birth. The fetus is in a state of physiological pulmonary hypertension. In utero, the fetus receives oxygenated blood from the placenta through the umbilical vein. At birth, following initiation of respiration, there is a sudden precipitous fall in the PVR and an increase of systemic vascular resistance (SVR) due to the removal of the placenta from circulation. There is dramatic increase in pulmonary blood flow with a decrease in, and later reversal of shunts at the foramen ovale and ductus arteriosus. The failure of this normal physiological pulmonary transition leads to the syndrome of PPHN. PPHN presents with varying degrees of hypoxemic respiratory failure. Survival of infants with PPHN has significantly improved with the use of gentle ventilation, surfactant and inhaled nitric oxide (iNO). PPHN is associated with significant mortality and morbidity among survivors. Newer agents that target different enzymatic pathways in the vascular smooth muscle are in different stages of development and testing. Further research using these agents is likely to further reduce morbidity and mortality associated with PPHN.

Keywords: hypoxemia; nitric oxide; oxygen; pulmonary blood flow.

Figure 1

Causes of persistent pulmonary Hypertension in the newborn. PROM—Premature rupture of membranes, CDH—Congenital diaphragmatic hernia, MAS—Meconium aspiration syndrome, PPHN—Persistent pulmonary hypertension of the newborn, LV—Left ventricle. Copyright Satyan Lakshminrusimha.

Figure 2

Echocardiographic findings in normal infants (left) and in PPHN (right). Soon after birth the pressures within the left-sided chambers of the heart are higher than in the right and the fetal shunts are reversed. The interatrial shunt and the shunt across the patent ductus arteriosus (PDA) is left to right. In infants with PPHN the pressures remain elevated in the right atrium and ventricle with right to left shunt at the atrial level and at the PDA causing desaturation (due to interatrial shunt) and differential cyanosis (due to PDA). There is right ventricular hypertrophy with bulging of the interventricular septum to the left and tricuspid regurgitation. SVR—Systemic vascular resistance, PVR—Pulmonary vascular resistance. Copyright Satyan Lakshminrusimha.

Figure 3

Pulmonary vasodilators—Endothelium-derived vasodilators: prostacyclin (PGI₂), nitric oxide (NO), and vasoconstrictor (endothelin, ET-1). The enzymes, cyclooxygenase (COX) and prostacyclin synthase (PGIS) are involved in the synthesis of prostacyclin. Prostacyclin through (PGI₂ receptor (IP) stimulates adenylate cyclase (AC) to produce cAMP. cAMP is broken down by phosphodiesterase 3A (PDE3A) in the smooth muscle cell. Milrinone inhibits PDE 3A and increases cAMP levels in pulmonary arterial smooth muscle cells and cardiac myocytes resulting in 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 NO release and vasodilation. Endothelial nitric oxide synthase (eNOS) catalyzes the production of NO which diffuses from the endothelium to the smooth muscle cell and stimulates soluble guanylate cyclase (sGC) enzyme to produce cyclic guanosine monophosphate (cGMP). cGMP is broken down by the PDE5 enzyme in the smooth muscle cell. Sildenafil inhibits PDE5 and increases cGMP levels in pulmonary arterial smooth muscle cells. cAMP and cGMP reduce cytosolic ionic calcium concentrations and induce smooth muscle relaxation and pulmonary vasodilation. NO is a free radical and avidly combines with superoxide anions to form a toxic vasoconstrictor, peroxynitrite. The bioavailability of NO in a tissue is determined by the local concentration of superoxide anions. Hyperoxic ventilation 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 4

Guidelines for initiation and weaning iNO in PPHN/hypoxic respiratory failure (HRF) in Neonatal Intensive Care Unit (NICU) (adapted from the protocol at Women & Children’s Hospital of Buffalo). The recommended starting dose of iNO is 20 parts per million (ppm). Improvement in PaO₂ ≥ 20 mm Hg or hemoglobin saturation by pulse oximetry ≥ 5% is considered complete response. In patients who fail to respond iNO, measures needed to optimize of lung recruitment and hemodynamics need to be undertaken. iNO should be discontinued if there no response. In responders wean FiO₂ initially while maintaining PaO₂ between 60 and 80 mm Hg. Once PaO₂ is stable and FiO₂ is below 0.6, start weaning iNO by 5 ppm every 4 h till 5 ppm. Below 5 ppm wean iNO by 1 ppm every 4 h. During weaning >5% drop in pulse oximetry or sustained increase in FiO₂ > 0.15 to maintain PaO₂ > 60 mm Hg is considered weaning failure, and previous dose of iNO should be resumed. Weaning should be resumed once stable. Monitor methemoglobin levels at baseline, 2 and 8 h following initiation and every 48 h thereafter [37]. PEEP—Positive End Expiratory Pressure, MAP—Mean Airway Pressure, ECMO—Extracorporeal Membrane Oxygenation. Copyright Satyan Lakshminrusimha.