Persistent Pulmonary Hypertension of the Newborn

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is often secondary to parenchymal lung disease (such as meconium aspiration syndrome) or lung hypoplasia (with congenital diaphragmatic hernia) but can also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance, resulting in right-to-left shunting of blood and hypoxemia. The diagnosis of PPHN is based on clinical evidence of labile hypoxemia often associated with differential cyanosis and confirmed by echocardiography. Lung volume recruitment with optimal use of positive end-expiratory pressure or mean airway pressure and/or surfactant is very important in secondary PPHN due to parenchymal lung disease. Other management strategies include optimal oxygenation, avoiding respiratory and metabolic acidosis, blood pressure stabilization, sedation, and pulmonary vasodilator therapy. Failure of these measures leads to consideration of extracorporeal membrane oxygenation, although this rescue therapy is needed less frequently with advances in medical management. Randomized clinical trials with long-term follow-up are required to evaluate various therapeutic strategies in PPHN.

Figure 1

Endothelium-derived mediators: the vasodilators prostacyclin (PGI₂) and nitric oxide (NO) and the 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). cAMP is broken down by phosphodiesterase 3A (PDE3A). Milrinone inhibits PDE3A and increases cAMP levels in arterial smooth muscle cells and cardiac myocytes. Endothelin acts on ET-A receptors causing vasoconstriction. A second endothelin receptor (ET-B) on the endothelial cell stimulates NO release and vasodilation. Endothelial nitric oxide synthase (eNOS) produces NO, which stimulates soluble guanylate cyclase (sGC) enzyme to produce cyclic guanosine monophosphate (cGMP). cGMP is broken down by PDE5 enzyme. 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 cell relaxation and pulmonary vasodilation. NO is a free radical and can avidly combine with superoxide anions to form the toxic vasoconstrictor peroxynitrite. Medications used in PPHN are shown in black boxes. Modified from Sharma et al. (6) Copyright Satyan Lakshminrusimha.

Figure 2

Etiology and pathophysiology of persistent pulmonary hypertension of the newborn (PPHN). Secondary PPHN can be due to various lung diseases, such as retained lung fluid or transient tachypnea of newborn (TTN), pneumonia, aspiration syndromes, respiratory distress syndrome (RDS), and congenital diaphragmatic hernia with lung hypoplasia. Use of high concentrations of inspired oxygen (approximately 100%) without positive pressure (oxygen hood) can lead to absorption atelectasis and worsening of ventilation-perfusion mismatch. Lung disease and V/Q mismatch result in hypoxemia. Increased pulmonary vascular resistance results in reduced pulmonary blood flow and right-to-left shunt through patent ductus arteriosus (PDA) and/or patent foramen ovale (PFO). Pulmonary hypertension is often associated with systemic hypotension with deviation of the interventricular septum to the left. The right subclavian artery (SCA) (and blood flowing to the right upper extremity) is always preductal. The left SCA 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. LA = left atrium; LV = left ventricle; PA = pulmonary artery; RA = right atrium RV = right ventricle; TR = tricuspid regurgitation. Copyright Satyan Lakshminrusimha.

Figure 3

Echocardiographic features of persistent pulmonary hypertension of the newborn (PPHN): high right ventricular pressure results in tricuspid regurgitation (TR) and deviation of the interventricular septum to the left. Assessment of tricuspid regurgitation velocity by continuous wave Doppler is used to calculate systolic pulmonary arterial pressure. The presence of right-to-left shunt at patent foramen ovale (PFO) and patent ductus arteriosus (PDA) is commonly observed in infants with severe PPHN. Impaired right and left ventricular function is associated with poor outcome in PPHN. Copyright Satyan Lakshminrusimha.

Figure 4

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 persistent pulmonary hypertension of the newborn (PPHN) (lower left quadrant). The presence of right-to-left shunt at the atrial and ductal levels 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 inhaled nitric oxide. 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 patent ductus arteriosus (PDA) (upper left quadrant). Ao = aorta; LA = left atrium; LV = left ventricle; PA = pulmonary artery; PGE1 = prostaglandin E1; RA = right atrium; RV = right ventricle; Rx = treatment; TR = tricuspid regurgitation. Modified from Nair and Lakshminrusimha. (15) Copyright Satyan Lakshminrusimha.

Figure 5

Management of acute persistent pulmonary hypertension of the newborn (PPHN) (suggested guidelines as recommended by the authors are shown in this figure): (1) minimal stimulation with the use of eye covers and ear muffs; (2) sedation and analgesia with a narcotic agent and a benzodiazepine (avoid muscle paralysis if possible); (3) maintain preductal oxygen saturation in the low to mid-90s and postductal saturations above 70% as long as metabolic acidosis, lactic acidosis, and/or oliguria are not present; (4) lung recruitment with adequate positive end-expiratory pressure (PEEP) or mean airway pressure and/or surfactant to maintain 8- to 9-rib expansion during inspiration; and (5) maintain adequate blood pressure and avoid supraphysiological systemic pressure. See text for details. HFOV = high frequency oscillatory ventilation; MAS = meconium aspiration syndrome; OI = oxygenation index; PIP = peak inspiratory pressure. Modified from Nair and Lakshminrusimha. (15) Copyright Satyan Lakshminrusimha.

Figure 6

Algorithm showing practical approach to persistent pulmonary hypertension of the newborn (PPHN) based on oxygenation, systemic blood pressure, and cardiac function. See text for details. ECMO = extracorporeal membrane oxygenation; IV = intravenous; LR = lactated ringers solution; NO = nitric oxide; OI=oxygenation index; P_aw = mean airway pressure; PEEP = positive end-expiratory pressure; PGE₁ = prostaglandin E₁; PGI₂ = prostaglandin I₂; PO-OG = per oral or orogastric. Copyright Satyan Lakshminrusimha.