Persistent pulmonary hypertension of the newborn (PPHN)

It is defined as the failure of the normal circulatory transition that occurs after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left extrapulmonary shunting of blood Clinically, PPHN is most often recognized in term or near-term neonates, but it can occur, albeit infrequently, in premature neonates

Fetal pulmonary hypertension

Pulmonary hypertension is a normal and necessary state for the fetus. Because the placenta, not the lungs, serves as the organ of gas exchange, most of the right ventricular output crosses the ductus arteriosus to the aorta, and only 5-10% of the combined ventricular output is directed to the pulmonary vascular bed. Multiple pathways appear to be involved in maintaining high pulmonary vascular tone prior to birth. Pulmonary vasoconstrictors in the normal fetus include low oxygen tension, endothelin-1, leukotrienes, and Rho kinase. Vasoconstriction is also promoted by low basal production of vasodilators, such as prostacyclin and nitric oxide (NO).

Normal cardiopulmonary transition

A dramatic cardiopulmonary transition occurs at birth, characterized by a rapid fall in pulmonary vascular resistance (PVR) and pulmonary artery pressure and a 10-fold rise in pulmonary blood flow. The most critical signals for these transitional changes are mechanical distension of the lung, a decrease in carbon dioxide tension, and an increase in oxygen tension in the lungs. The fetus prepares for this transition late in gestation by increasing pulmonary expression of nitric oxide synthases and soluble guanylate cyclase.

Types of PPHN
Persistent PPHN can be generally characterized as one of 3 following types: PPHN characterized by abnormally constricted pulmonary vasculature due to lung parenchymal diseases (eg, meconium aspiration syndrome, respiratory distress syndrome, pneumonia) PPHN characterized by hypoplastic vasculature, as seen in congenital diaphragmatic hernia PPHN in which the lung has normal parenchyma and remodeled pulmonary vasculature (also known as idiopathic PPNH) Persistent pulmonary hypertension of the newborn is most commonly associated with 1 of 3 underlying etiologies, as follows:

A) Acute pulmonary vasoconstriction

The first and most commonly encountered scenario in PPHN is acute pulmonary vasoconstriction due to acute perinatal events, such as the following: Alveolar hypoxia secondary to parenchymal lung disease, such as meconium aspiration syndrome, respiratory distress syndrome, or pneumonia Hypoventilation resulting from asphyxia or other neurologic conditions Hypothermia Hypoglycemia

B) Hypoplasia of the pulmonary vascular bed

Congenital diaphragmatic hernia is an abnormality of diaphragmatic development that allows the abdominal viscera to enter the chest and compress the lung.

The oligohydramnios sequence may produce pulmonary hypoplasia and associated persistent pulmonary hypertension of the newborn. A congenital cystic adenomatoid malformation may lead to lung hypoplasia, although persistent pulmonary hypertension of the newborn is rarely associated with this malformation, even if the defect is large.

C)

Idiopathic pulmonary hypertension

One cause of idiopathic PPHN is constriction of the fetal ductus arteriosus in utero, which can occur after exposure to nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or naproxen, during the third trimester. Data also suggest that exposure to SSRIs during late gestation is associated with a 6-fold increase in the prevalence of PPHN, although how many infants have severe disease is unclear.[1] Severe cases of idiopathic PPNH are almost certainly affected by parenchymal and vascular disease. An abnormally remodeled vasculature may develop in utero in response to prolonged fetal stress, hypoxia, and/or pulmonary hypertension. Excessive and peripheral muscularization of pulmonary arterioles can be seen in these cases. Indeed, evaluation of infants at autopsy shows clinically significant remodeling of their pulmonary vasculature, with vascular wall thickening and smooth muscle hyperplasia. Furthermore, the smooth muscle extends to the level of the intra-acinar arteries, which does not normally occur until late in the postnatal period

Clinical Manifestations:
Infants with PPHN become ill in the delivery room or within the 1st 12 hr of life. PPHN related to polycythemia, idiopathic causes, hypoglycemia, or asphyxia may result in severe cyanosis with tachypnea, although initial signs of respiratory distress may be minimal. Infants who have PPHN associated with meconium aspiration, group B streptococcal pneumonia, diaphragmatic hernia, or pulmonary hypoplasia usually exhibit cyanosis, grunting, flaring, retractions, tachycardia, and shock. Multiorgan involvement may be present. Myocardial ischemia, papillary muscle dysfunction with mitral and tricuspid regurgitation, and biventricular dysfunction produce cardiogenic shock with decreases in pulmonary blood flow, tissue perfusion, and oxygen delivery. The hypoxemia is often labile and out of proportion to the findings on chest roentgenograms.

Diagnosis
PPHN should be suspected in all term infants who have cyanosis with or without a history of fetal distress, intrauterine growth restriction, meconium-stained amniotic fluid, hypoglycemia, polycythemia, diaphragmatic hernia, pleural effusions, and birth asphyxia. Hypoxemia is universal and is unresponsive to 100% oxygen given by oxygen hood, but it may respond transiently to hyperoxic hyperventilation administered after endotracheal intubation or to the application of a bag and mask. A Pao2 gradient between a preductal (right radial artery) and a postductal (umbilical artery) site of blood sampling >20 mm Hg suggests right-to-left shunting through the ductus arteriosus, as does an oxygenation saturation gradient >5% between preductal and postductal sites on pulse oximetry. Physical examination the primary finding is cyanosis, which is usually associated with tachypnea and respiratory distress. (Respiratory distress and cyanosis typically occur within 6-12 hours of birth. Cardiac examination may reveal a loud, single S2 sound or a harsh systolic murmur secondary to tricuspid regurgitation.

The patient may have evidence of poor cardiac function and perfusion. ABG. CBC (Check for polycythemia, Hct, TLC) (Platelet count is frequently depressed in newborns with MA$ or asphyxia Serum electrolytes (especially bl. Sugar and calcium level) CXR For underlying parenchymal lung disease and underlying disorders In Idiopathic PPHTN; the lung fields appear clear with decreased vascular markings. Echocardiography To exclude Congenital cyanotic heart disease Ultrasonography To exclude IVHge or Infarcts. Laboratory studies

Differential Diagnosis
Congenital Diaphragmatic Hernia Meconium Aspiration Syndrome Partial Anomalous Pulmonary Venous Connection (and other causes of cyanotic heart disease) Pneumonia Pneumothorax Pulmonary Atresia With Intact Ventricular Septum Pulmonary Hypoplasia Pulmonary Sequestration Respiratory Distress Syndrome Sepsis Other problems to be considered include the following: Alveolar capillary dysplasia Surfactant protein B deficiency Total anomalous pulmonary venous connection Transposition of the great arteries Tricuspid atresia

Treatment:
1) Continuous monitoring of oxygenation, blood pressure, and perfusion is critical. 2) When one cares for newborns, use a minimal stimulation protocol to minimize the need to handle the patient and to perform invasive procedures, such as suctioning 3) Management of fluid and electrolyte levels, particularly calcium, is important. An adequate circulating blood volume is necessary to maintain right ventricular filling and cardiac output; however, repeated bolus administration of crystalloid and colloid solutions does not provide additional benefit. 4) Inotropes: (1) Support with dopamine, dobutamine, and/or milrinone is frequently helpful in maintaining adequate cardiac output and systemic blood pressure while avoiding excessive volume administration. Although dopamine is frequently used as a first-line agent, other agents, such as dobutamine and milrinone, are helpful when myocardial contractility is poor. (2) Place a central venous catheter into the umbilical or other vein to allow for the administration of inotropic agents or hypertonic solutions (eg, calcium gluconate solution). (3) Avoid catheter placement into the jugular vessels; save these vessels for extracorporeal support, if needed 5) Surfactant administration: In a large, multicenter study, the administration of surfactant reduced the need for extracorporeal support and appeared to be most effective early in the course of disease. The reduced need for ECMO was most apparent in newborns with primary diagnoses of meconium aspiration syndrome or sepsis.

6) Mechanical Ventilation: Endotracheal intubation and mechanical ventilation are almost always necessary for the newborn with persistent pulmonary hypertension of the newborn (PPHN). The goal of mechanical ventilation should be to maintain normal functional residual capacity (FRC) by recruiting areas of atelectasis, as well as to avoid overexpansion. (N.B: In skilled hands, gentle ventilation with normocarbia or permissive hypercarbia results in excellent outcomes and a low incidence of chronic lung disease.) Because of their lability and ability to fight the ventilator, newborns with persistent pulmonary hypertension of the newborn nearly always require sedation. The author's practice is to use fentanyl (often in combination with a benzodiazepine) because it tends to decrease the sympathetic response to pain and noxious stimuli. 7) High Frequency Ventilation: It is used when optimal support fails to maintain acceptable oxygenation and perfusion. 8) NO Gas: is an endothelium-derived signaling molecule that relaxes vascular smooth muscle and can be delivered to the lung by inhalation. Use of iNO reduces the need for ECMO support by approximately 40%. 9) ECMO: Is used to treat carefully selected, severely ill infants with hypoxemic respiratory failure caused by RDS, meconium aspiration pneumonia, congenital diaphragmatic hernia, PPHN, or sepsis. Is a form of cardiopulmonary bypass that augments systemic perfusion and provides gas exchange.

(References: Medscape Medicine and Nelson Textbook of Pediatrics 19ed)