Background

During fetal life, pulmonary blood flow is low, with less than 10% of the combined cardiac output directed to the lungs. In fetal life, numerous factors, including hypoxia, maintain high pulmonary vascular resistance (PVR). After birth, PVR decreases, and pulmonary blood flow increases dramatically as the lungs assume the function of gas exchange. The combination of rhythmic ventilation of the lung and increased alveolar oxygen tension stimulate these changes. Each stimulus, by itself, decreases PVR and increases pulmonary blood flow, but effects are greatest when the 2 events occur simultaneously. In some newborns, the normal decrease in pulmonary vascular tone does not occur, and the result is persistent pulmonary hypertension of the newborn (PPHN). This syndrome causes substantial morbidity and mortality in otherwise healthy, term newborns.

Pathophysiology

PPHN is 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. With inadequate pulmonary perfusion, neonates develop refractory hypoxemia, respiratory distress, and acidosis.

Respiratory failure and hypoxemia in the term newborn results from a heterogeneous group of disorders, and the therapeutic approach and response often depend on the underlying disease. PPHN often results when structurally normal pulmonary vessels constrict in response to alveolar hypoxia due to hypoventilation or parenchymal disorders, such as hyaline membrane disease or meconium aspiration syndrome (MAS). However, PPHN can also occur idiopathically in the absence of underlying parenchymal disease. In these cases, the syndrome is believed to be the result of an abnormally remodeled vasculature that develops 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.

Finally, PPHN is commonly associated with lung hypoplasia, as seen in congenital diaphragmatic hernia. These underlying causes of PPHN are structurally different, and functional differences in response to vasodilators, such as inhaled nitric oxide (iNO), are commonly observed. Knowledge of biologic alterations seen with PPHN is instrumental in expanding available therapeutic options.

Frequency

United States

Neonatal respiratory failure affects nearly 80,000 newborns per year, and it is responsible for as many as one half of all neonatal deaths. Nearly one third of all infants with respiratory failure were born at term or near-term, and they are at risk for PPHN.

Recent data suggest that the PPHN syndrome may occur as often as 2-6 cases per 1000 live births. PPHN is a frequent complicating factor in the term or near-term newborn with parenchymal lung disease, such as MAS or pneumonia. An increased incidence of PPHN is reported for mothers who use selective serotonin reuptake inhibitors (SSRIs) during the last half of their pregnancies.

Mortality/Morbidity

• As recently as 15 years ago, the mortality rate reached 40%, and the prevalence of major neurologic disability was 15-60%.

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• The introduction of extracorporeal membrane oxygenation (ECMO) and other new therapies has had a major effect on reducing the mortality rate associated with PPHN. In the United Kingdom, the effect of ECMO technology was studied in a randomized trial, the only one to use death as an endpoint (UK Collaborative ECMO Trail Group, 1996). The mortality rate decreased from approximately 60% in the group randomly assigned to receive conventional therapy to 30% for the group randomly assigned to receive ECMO.

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• If all available therapies are used, the mortality rate appears to be less than 10%. However, the prevalence of major neurologic disabilities among surviving newborns remains approximately 15-20%.

Age

• By definition, PPHN a disorder of the newborn.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Newborns with PPHN typically present with cyanosis and tachypnea. Marked lability in oxygenation is frequently part of their history.

• The most common cause of PPHN is MAS, which affects 25,000-30,000 infants, with 1000 deaths occurring each year in the United States.
• • Approximately 13% of all live births are complicated by meconium-stained fluid, but only 5% of infants who had this complication subsequently develop MAS.

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  • Although the traditional belief is that aspiration occurs with the first breath after birth, relatively recent data suggest that, in severely affected infants, aspiration most likely occurs in utero. Therefore, perinatal distress or meconium staining of the amniotic fluid may be part of the patient's antenatal history.

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• Idiopathic PPHN, or black-lung PPHN, is the second most common etiology of PPHN and the most common in newborns born at term and near-term (>34 wks of gestation).
• • 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.

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  • One cause of idiopathic PPHN is constriction of the fetal ductus arteriosus in utero because of exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) during the third trimester. Therefore, a history of NSAID should be sought from the mother.

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  • Another recently reported association with idiopathic PPHN is maternal use of SSRIs, particularly during the second trimester.

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Physical

PPHN most typically affects infants who are phenotypically normal, though the syndrome may occur most frequently in newborns with Down syndrome. On initial examination, the primary finding is cyanosis, which is usually associated with tachypnea and respiratory distress. Cardiac examination may reveal a loud, single S2 or a harsh systolic murmur secondary to tricuspid regurgitation. The patient may have evidence of poor cardiac function and perfusion.

Causes

PPHN is most commonly associated with 1 of 3 underlying etiologies.

• The first and most commonly encountered scenario is acute pulmonary vasoconstriction due to acute perinatal events, such as the following:
• • Alveolar hypoxia secondary to parenchymal lung disease, such as respiratory distress syndrome (RDS) or pneumonia

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  • Hypoventilation resulting from asphyxia or other neurologic conditions

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  • Hypothermia

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  • Hypoglycemia

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• The second cause, idiopathic PPHN is associated with a normal chest radiograph and no parenchymal lung disease. Newborns with idiopathic PPHN present with pure vascular disease. Some clinicians refer to this syndrome as black-lung PPHN or clear-lung PPHN.
• • This syndrome typically results from an abnormally remodeled pulmonary arterial bed, which perhaps secondary to chronic stress in utero.

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  • Other potential associations include maternal use of NSAIDs, such as ibuprofen or naproxen, or SSRIs in the last half of pregnancy

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• Hypoplasia of the pulmonary vascular bed is a third cause of PPHN.
• • Congenital diaphragmatic hernia is an abnormality of diaphragmatic development that allows the abdominal viscera to enter the chest and compress the lung.

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  • Patient may have an oligohydramnios sequence.

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  • Another finding is congenital cystic adenomatoid malformation, though PPHN is rarely associated with this malformation, even if the defect is large.

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