Persistent pulmonary hypertension of the newborn

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance resulting in right-to-left shunting of blood and hypoxemia. PPHN is often secondary to parenchymal lung disease (such as meconium aspiration syndrome, pneumonia or respiratory distress syndrome) or lung hypoplasia (with congenital diaphragmatic hernia or oligohydramnios) but can also be idiopathic. The diagnosis of PPHN is based on clinical evidence of labile hypoxemia often associated with differential cyanosis. The diagnosis is confirmed by the echocardiographic demonstration of - (a) right-to-left or bidirectional shunt at the ductus or foramen ovale and/or, (b) flattening or leftward deviation of the interventricular septum and/or, (c) tricuspid regurgitation, and finally (d) absence of structural heart disease. Management strategies include optimal oxygenation, avoiding respiratory and metabolic acidosis, blood pressure stabilization, sedation and pulmonary vasodilator therapy. Failure of these measures would lead to consideration of extracorporeal membrane oxygenation (ECMO); however decreased need for this rescue therapy has been documented with advances in medical management. While trends also note improved survival, long-term neurodevelopmental disabilities such as deafness and learning disabilities remain a concern in many infants with severe PPHN. Funded by: 1R01HD072929-0 (SL).

Keywords: Fetal circulation; Meconium aspiration; Milrinone; Natriuretic peptide; Nitric Oxide; Prostaglandin E1; Pulmonary vascular remodeling; Sildenafil; Surfactant.

Figure 1

Fetal and postnatal (adult) circulation: in fetuses, placenta is the organ of gas exchange. The umbilical vein carries oxygenated blood from the placenta has the highest fetal oxygen saturation of approximately 80%. Oxygen saturation in various blood vessels is shown in crimson circles. Oxygenated blood is streamed through the ductus venosus and along the left margin of the inferior vena cava. In the heart, oxygenated blood gets shunted across the foramen ovale (FO) to the left heart to supply the cerebral and coronary circulation. Poorly oxygenated blood from the upper half of the body goes to the right side of the heart, the main pulmonary artery and gets shunted through the ductus arteriosus (DA) to the descending aorta. Blood in the descending aorta has a saturation of around 55 %, and this blood flows back to placenta for oxygenation through umbilical arteries. In spite of relative hypoxia, adequate oxygen delivery to the fetal tissues is maintained by (a) high cardiac output, (b) high hemoglobin level in the term fetus and (c) the presence of fetal hemoglobin (HbF) with high oxygen affinity. The saturation gradient across the placenta (85 – 55 = 30%) is similar to the saturation gradient across the lungs in adults (98 – 70% = 28%) but is achieved at a much lower partial pressure of oxygen (PO₂ ~ 32 mmHg in the umbilical vein) in the fetus compared to the adult (PaO₂ ~ 95 mmHg) limiting the fetal risk for oxygen toxicity. (copyright Satyan Lakshminrusimha).

Figure 2

Endothelium derived vasodilators – prostacyclin (PGI₂) and nitric oxide (NO) and vasoconstrictor (endothelin, ET-1). Cyclooxygenase (COX) and prostacyclin synthase (PGIS) are involved in the production of prostacyclin. Prostacyclin acts on its receptor (IP) 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, the enzyme most prevalent in vasculature) in the smooth muscle cell. Milrinone inhibits PDE 3A and increases cAMP levels in arterial smooth muscle cells and cardiac myocytes resulting in pulmonary (and systemic) vasodilation and inotropy. Nitric oxide (NO) stimulates PDE 3A [151,152]. 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) 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 PDE5 enzyme in the smooth muscle cell. Sildenafil inhibits PDE5 and increases cGMP levels in pulmonary arterial smooth muscle cells. Natriuretic peptides stimulate particulate guanylate cyclase (pGC) to produce cGMP. 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 and stimulate PDE5 activity [81]. Medications used in PPHN are shown in black boxes (copyright Satyan Lakshminrusimha).

Figure 3

Pathophysiology of PPHN. Parenchymal lung disease and ventilation-perfusion (V/Q) mismatch result in hypoxemia. Increased pulmonary vascular resistance results in reduced pulmona ry blood flow and right to left shunt through PDA and/or PFO. Pulmonary hypertension is often associated with systemic hypotension with deviation of the interventricular septum to the left. 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 and compared with lower extremity to assess differential cyanosis. 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. (copyright Satyan Lakshminrusimha).

Figure 4

Inhaled Nitric Oxide therapy in neonates with PPHN: The diagnosis of PPHN is based on clinical (labile hypoxemia and differential cyanosis) or echocardiographic findings. Optimal oxygenation and lung recruitment with optimal lung inflation and surfactant in the presence of parenchymal lung disease is the initial step in the management of PPHN. An OI of 20 is a reasonable threshold to initiate iNO. The presence of hemodynamic instability and severe hypoxemia (OI ~ 40 range) is an indication for ECMO. See text for details. (copyright Satyan Lakshminrusimha).

Figure 5

Flow chart showing the author’s suggested guidelines for management of iNO resistant PPHN. (copyright Satyan Lakshminrusimha).

Figure 6

Causes of hypotension in infants with PPHN: Sepsis and hypoxia causes intravascular oligemia due to capillary leak or due to systemic vasodilation. Neonates with PPHN often require high mean airway pressure that impedes venous return to the right side of heart. Increased pulmonary vascular resistance results in less blood flow through pulmonary circulation reducing left ventricular preload. The deviation of the interventricular septum towards left ventricle further impedes left ventricular filling. Neonates with PPHN secondary to sepsis, hypoxia and CDH can also experience systemic hypotension secondary to left ventricular dysfunction. (copyright Satyan Lakshminrusimha).

Figure 7

Asphyxia and PPHN: Fetal hypoxia (secondary to in-utero asphyxia and meconium aspiration) causes pulmonary vascular remodeling, which down regulates iNO signaling pathways and causes PPHN. In infants with perinatal hypoxia, the combination of hypoxia and acidosis increases the risk of PPHN. Preexisting PPHN may be exacerbated by therapeutic hypothermia. Errors in PaCO₂ measurement secondary to body temperature changes may result in fluctuations in PCO₂ leading to changes in cerebral and pulmonary vascular resistance (see text for details). (copyright Satyan Lakshminrusimha).