Persistent pulmonary hypertension of the newborn

OVERVIEW: What every practitioner needs to know

Are you sure your patient has PPHN? What are the typical findings for this disease?

Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome typically associated with lung diseases including congenital diaphragmatic hernia (CDH) and other causes of pulmonary hypoplasia, meconium aspiration syndrome (MAS), and sepsis/pneumonia. Idiopathic PPHN is a relatively uncommon form of this disorder that is not associated with parenchymal lung disease nor cardiac performance issues.

PPHN is characterized by hypoxemia due to suprasystemic pulmonary hypertension, causing right-to-left shunting across the arterial duct (patent ductus arteriosus, PDA) and/or the oval foramen (patent foramen ovale, PFO) despite high inspired oxygen concentrations. Clinically, right-to-left shunting across the PDA causes decreased pulse oximetry saturation in the lower extremities compared with the right arm; however, the diagnosis requires more detailed information provided by echocardiography.

What other disease/condition shares some of these symptoms?

A number of conditions can cause suprasystemic pulmonary hypertension with right-to-left shunting across the PDA. These include ductal-dependent systemic blood flow lesions (hypoplastic left heart syndrome, aortic stenosis, coarctation of the aorta, and interrupted arch). Other anatomic lesions can increase pulmonary vascular resistance and cause right-to-left shunting across the PDA, including alveolar-capillary dysplasia and congenital pulmonary vein stenosis, but these conditions are rare.

Left ventricular diastolic dysfunction can cause increased pulmonary vascular resistance with right-to-left shunting at the PDA, but left-to-right shunting at the FO. This problem frequently complicates the course of infants with perinatal asphyxia and CDH.

What caused this disease to develop at this time?

The classic description of PPHN (initially called persistent fetal circulation, PFC) was of severe pulmonary hypertension causing extrapulmonary right-to-left shunting at the PFO and/or FO, leading to critical hypoxemia despite high inspired oxygen concentrations in newborns without radiographic evidence of lung disease. The pulmonary hypertension was due to failure of the pulmonary circulation to relax and dilate upon delivery, and was associated with structural and functional changes in the pulmonary circulation. One association was with maternal ingestion of aspirin, causing fetal constriction of the ductus arteriosus and markedly increased pressure on the pulmonary circulation.

More commonly, PPHN is associated with diseases that are also marked by severe parenchymal lung disease (meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), sepsis/pneumonia) or pulmonary hypoplasia (prolonged oligohydramnios, CDH). In these conditions, pulmonary hypertension can be exacerbated by lung underinflation (pulmonary vascular resistance increases as lung volumes decrease below functional residual capacity), cytokine mediated vasoconstriction, decreased endogenous vasodilator production, and a decreased cross-sectional area for pulmonary blood flow (hypoplasia).

Some genetic disorders are associated with an increased risk of PPHN, including trisomy 21 and 18.

Maternal ingestion of non-steroidal anti-inflammatory drugs (NSAIDs), and more recently, anti-depressant drugs of the class selective serotonin reuptake inhibitors (SSRIs) have been associated with PPHN.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

See clinical decision algorithm below

Would imaging studies be helpful? If so, which ones?

See clinical decision algorithm below

Confirming the diagnosis

Described below is an initial evaluation of the infant with hypoxemia. This approach is designed, upon the initial clinical encounter, to begin to distinguish among the many causes of hypoxemia in the immediate newborn period. In general, severe hypoxemia can be caused by congenital heart disease (intracardiac veno-arterial admixture), parenchymal lung disease with intrapulmonary veno-arterial shunting, and pulmonary hypertension causing extrapulmonary shunting across the PDA and/or FO.

This approach will help you understand if the infant has heart disease, lung disease, or pulmonary vasular disease. However, it is important to remember that infants with PPHN commonly have severe pulmonary vasoconstriction complicated by both parenchymal lung disease and compromised cardiac performance.
History: Clues to the cause of hypoxemia and respiratory failure can be gleaned from the prenatal history. Any results of prenatal ultrasound studies should be reviewed carefully for evidence of anomalies, oligohydramnios (severity and duration related to pulmonary hypoplasia), fetal brady/tachy arrhythmia, fetal distress and umbilical vessel Doppler studies. The presence of meconium-stained amniotic fluid suggests fetal distress and the potential for perturbations in the transitional circulation. Risk factors for infection should be reviewed, including the nature of membrane rupture (preterm – before 37 weeks gestation; premature – before the onset of labor; prolonged – >18 hours)
Physical exam: The key question on first evaluating the newborn with hypoxemia is the presence or absence of respiratory distress (grunting, nasal flaring, retractions). Although respiratory distress has many causes (e.g., upper airway obstruction, severe metabolic acidemia, etc.), most commonly it suggests decreased lung compliance and the presence of parenchymal lung disease. Often patients with severe PH have a murmur associated with tricuspid regurgitation. This murmur sounds similar to that caused by a ventricular septal defect (VSD) in an older infant after pulmonary vascular resistance has decreased.
Response to high inspired oxygen: When called to evaluate an infant with hypoxemia who has been treated with supplemental oxygen (mask, hood oxygen), it is important to ask about the pulse oximetry change that occurred when oxygen was provided. Newborns with cyanotic (structural) heart disease are unlikely to show a marked increase in saturation (>90%) with supplemental oxygen. The most common cyanotic heart disease presenting with marked hypoxemia in the first day of life is transposition of the great vessels (TGV). Infants with TGV have pulse oximetry saturations <75% despite high inspired oxygen. A marked increase in saturation after providing supplemental oxygen is consistent with parenchymal lung disease or PPHN.
Pulse oximetry measurements: Pulse oximetry measurements are essential in the initial evaluation of an infant with hypoxemia/respiratory distress. Two oximeters should be used to compare the saturation from the right arm with a lower extremity. The results of these measurements are that the readings are equal (1), the right hand (preductal) measurement is higher than the lower extremity (postductal) (2), or the lower extremity measurement is higher than the right hand (3).

If the readings are equivalent and saturations are low (<80%), there are 3 possible explanations: the cause of hypoxemia is intrapulmonary shunting (lung disease); the cause is cyanotic heart disease with ductal dependent pulmonary blood (i.e., obligate left-to-right blood flow with lesions such as pulmonary stenosis, tricuspid atresia, Ebstein’s anomaly), or severe PH with a closed ductus (extremely uncommon).
If the right hand (preductal) measurement is higher than the lower extremity (postductal), this suggests right-to-left shunting (R-L) across the PDA. R-L PDA shunting occurs in PPHN, but so does a ductal-dependent systemic blood flow lesion (hypoplastic left heart syndrome, aortic stenosis, coarctation, and interrupted arch).
If the lower extremity measurement is higher than the right hand, this is usually caused simply by measurement error. However, if saturations are extremely low (e.g., 65% at the lower extremity and 55% at the right hand), this is diagnostic of TGV with either pulmonary hypertension or coarctation.

Chest radiograph: The most important question to ask when reviewing the CXR is: “Is the oxygen requirement out of proportion to the radiographic changes?” In other words, an infant treated with high inspired oxygen and low saturations who has a clear (black) CXR does not have parenchymal lung disease, and the next step should be echocardiography.
Echocardiography: After the initial assessments described above have been performed, echocardiography is essential in understanding the structural and functional characteristics of the heart in the newborn with suspected PPHN. The first goal of echocardiography is to rule out congenital heart disease conditions that could explain the hypoxemia or pre-post ductal saturation differences (described above). In an infant with a structurally normal heart, the key windows on the pulmonary circulation include the direction (right-to-left, bidirectional, left-to-right) of shunting across the PFO and PDA, and the estimate of RV systolic pressure using Doppler measurements of the peak velocity of the tricuspid regurgitation jet. In an anatomically normal heart, the Doppler estimate of RV systolic pressure should reflect pulmonary artery systolic pressure. If there is no bidirectional or right-to-left shunting across the PFO or PDA, then pulmonary hypertension is not the immediate cause of severe hypoxemia. (PPHN is a labile condition, and these measurements can acutely change during the course.)

In other words, in an infant with severe hypoxemia despite high inspired oxygen who has a structurally normal heart without evidence of suprasystemic pulmonary artery pressure causing right-to-left venoarterial admixture, the likely cause of hypoxemia is severe lung disease and intrapulmonary shunting.

Finally, pulmonary vasodilator drugs should be used with caution in an infant with pulmonary hypertension, right-to-left PDA shunting but left-to-right PFO shunting, and evidence of LV systolic/diastolic dysfunction with mitral insufficiency. In this setting, high left atrial pressure can contribute to pulmonary venous hypertension, and efforts should focus on improving cardiac performance before pulmonary vasodilation.

If you are able to confirm that the patient has PPHN, what treatment should be initiated?

For an infant with PPHN, the emphasis is often on specific therapy for pulmonary hypertension – inhaled nitric oxide. However, it is important to remember that most cases of PPHN also show evidence of parenchymal lung disease and hemodynamic perturbations. Thus, the first goal should be to optimize lung recruitment (remember that pulmonary vascular resistance increases above and below functional residual capacity (FRC)). That is, both overinflation (excessive mechanical ventilator support) and underinflation (decreased lung volume) can contribute to PH.

While optimizing lung recruitment, it is also important to assess cardiac performance and the need for volume resuscitation and catecholamine drug support. The most commonly used medications to improve systolic performance and blood pressure are dopamine, dobutamine, epinephrine, and milrinone. The specific role of each of these agents depends upon the goal of inotropy, increasing systemic vascular tone, or afterload reduction, and should be guided by careful assessments of end organ perfusion and the results of echocardiography.

Treatment with inhaled nitric oxide (iNO): After optimizing lung volume and hemodynamic support, and evaluating the severity of PH by echocardiography as discussed above, current recommendations for initiating inhaled nitric oxide include an oxygenation index >25. The oxygenation index is calculated by multiplying the FiO2*mean airway pressure*100 / PaO2. Treatment for PPHN in near-term and term newborns (>34 weeks) should be initiated with inhaled nitric oxide at 20 ppm.

There is no compelling evidence that treatment of PPHN at oxygenation index (OI) levels <25 improves outcomes.

In addition to iNO, numerous drugs have been used to treat PPHN. However, currently there are insufficient data to support the routine use of these agents in newborns with PPHN.

What are the adverse effects associated with each treatment option?

Methemoglobinemia can occur with prolonged exposure to high doses of inhaled NO (80 ppm).

There is a potential for adverse effects on platelet adhesion after exposure to high doses of iNO; however, there were no differences in bleeding complications in term infants treated with iNO compared with controls in randomized, controlled trials.

Inhaled nitric oxide should not be used in infants with ductal-dependent systemic blood flow lesions (e.g., hypoplastic left heart syndrome).

If nitric oxide is used in a non-extracorporeal membrane oxygenation (ECMO) center, arrangments should be in place to continue NO during transport.

What are the possible outcomes of PPHN?

Although PPHN is a potentially life-threatening disease, the pulmonary vascular component typically improves in several days. Clear exceptions to this rule include infants with pulmonary hypoplasia/CDH. ECMO remains an important therapy for infants failing treatment with iNO, and treatment centers should have plans in place for initiating ECMO or transfer to an ECMO center when indicated.

In the infant with “PPHN”, lack of response to inhaled NO should prompt further investigation into other anatomic causes of PH. However, the most common cause of decreased NO responsiveness acutely is underinflation associated with severe lung disease.

Infants with PPHN are at increased risk of neurodevelopmental impairment, in some cases likely related to an unfavorable in utero environment that contributed to the initial pulmonary vascular, parenchymal ,and cardiac perturbations.

What causes this disease and how frequent is it?

Idiopathic PPHN is a relatively uncommon form of this disorder that is not associated with parenchymal lung disease nor cardiac performance issues.

Pulmonary hypertension can be exacerbated by lung underinflation (pulmonary vascular resistance increases as lung volumes decrease below functional residual capacity), cytokine mediated vasoconstriction, decreased endogenous vasodilator production, and a decreased cross-sectional area for pulmonary blood flow (hypoplasia).

The incidence of PPHN has been estimated at 1.9/1000 live births.

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

What is the evidence?

Clark, RH, Kueser, TJ, Walker, MW. “Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Reseach group”. N Engl J Med. vol. 342. 2000. pp. 469-74.

“Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group”. N Engl J Med. vol. 336. 1997. pp. 597-604. (These 2 articles provided the pivotal evidence for FDA approval of inhaled nitric oxide in the treatment of PPHN.)

Kinsella, JP, Abman, SH. “Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia”. J Pediatr. vol. 136. 2000. pp. 717-26. (This article provides a review of treatment strategies for PPHN.)

Kinsella, JP, Truog, WE, Walsh, WF. “Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn”. J Pediatr. vol. 131. 1997. pp. 55-62. (This study demonstrated the important interaction of lung disease and pulmonary hypertension in responses to HFOV and iNO in PPHN.)

Kinsella, JP, Abman, SH. “Inhaled nitric oxide in the premature newborn”. J Pediatr. vol. 151. 2007. pp. 10-5.

Cole, FS, Alleyne, C, Barks, JD. “NIH Consensus Development Conference: Inhaled nitric oxide therapy for premature infants”. NIH Consens State Sci Statements. vol. 27. 2010. (A summary of the current status of clinical evidence for iNO in premature newborns.)

Ongoing controversies regarding etiology, diagnosis, treatment

The role of inhaled nitric oxide in the prevention of bronchial pulmonary dysplasia (BPD) in premature infants remains controversial. Several studies are ongoing and will likely help clarify the potential risks/benefits of iNO in this population.

For premature infants with PPHN (an uncommon but life-threatening condition, particularly in infants with pulmonary hypoplasia), low-dose iNO (5 ppm) is likely the safest and most effective treatment strategy (in contrast to other drugs or treatments targeting a reduction in pulmonary vascular resistance.

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