Persistent Newborn Pulmonary Hypertension
- Author: Salaam Sallaam, MD; Chief Editor: Howard S Weber, MD, FSCAI more...
Persistent pulmonary hypertension of the newborn (PPHN) 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 secondary to right-to-left shunting of blood.
Signs and symptoms
PPHN is often associated with the following signs and symptoms of perinatal distress:
Tachypnea, respiratory distress
Loud, single second heart sound (S2) or a harsh systolic murmur (secondary to tricuspid regurgitation)
Low Apgar scores
Cyanosis; poor cardiac function and perfusion
Symptoms of shock
Idiopathic persistent pulmonary hypertension of the newborn can present without signs of acute perinatal distress. Marked lability in oxygenation is frequently part of the clinical history.
Suspect PPHN whenever the level of hypoxemia is out of proportion to the level of pulmonary disease. Clinically, PPHN is most often recognized in term or near-term neonates, but it can occur in premature neonates, albeit infrequently.
In contrast to adult primary pulmonary hypertension, the newborn syndrome is not defined by a specific pressure of the pulmonary circulation. The diagnosis is confirmed regardless of the pulmonary arterial pressure, as long as it is accompanied by right-to-left shunt and absence of congenital heart disease.
Echocardiography is considered the most reliable noninvasive test to establish the diagnosis, assess cardiac function, and exclude associated structural heart disease.
Arterial blood gas levels (through indwelling line): To assess the pH, partial pressure of carbon dioxide in arterial gas (PaCO 2), and the partial pressure of oxygen (PaO 2)
Complete blood count with differential: To evaluate for high hematocrit level (polycythemia and hyperviscosity syndrome may lead to or exacerbate PPHN); to determine whether an underlying sepsis or pneumonia is present
Coagulation studies (eg, platelet count, prothrombin time, partial thromboplastin time, international normalized ratio): To assess for coagulopathy (increased disease severity)
Serum electrolytes (eg, calcium) and glucose levels
Preductal and postductal oxygen saturation measurements via pulse oximetry to assess for differential cyanosis
Chest radiography: To assess for presence of underlying parenchymal lung disease (eg, meconium aspiration syndrome, pneumonia, surfactant deficiency) and/or to exclude underlying disorders (eg, congenital diaphragmatic hernia); see the image below
Echocardiography: To screen and assist in making the diagnosis of PPHN and to rule out total anomalous pulmonary venous return before considering administration of extracorporeal membrane oxygenation therapy (ECMO)
Echocardiography with Doppler flow: To assess presence/direction of the intracardiac shunt at the ductus arteriosus and foramen ovale, as well as estimate the pulmonary arterial systolic/diastolic pressures
Cranial ultrasonography: To assess for intraventricular bleeding and for peripheral areas of hemorrhage or infarct if ECMO is necessary
Cranial ultrasonography with Doppler flow: To assess whether a nonhemorrhagic infarct is present
Brain computed tomography scanning or magnetic resonance imaging: To evaluate for central nervous system injury
Cardiac catheterization: Rarely utilized to exclude congenital heart disease (eg, obstructed anomalous pulmonary venous return, pulmonary vein stenosis) because echocardiographic findings are typically diagnostic
The treatment strategy for PPHN is aimed at maintaining adequate systemic blood pressure, decreasing pulmonary vascular resistance, ensuring oxygen release to tissues, and minimizing lesions induced by high levels of inspired oxygen and ventilator high pressure settings.
General management principles include the following:
Continuous monitoring of oxygenation, blood pressure, and perfusion
Maintaining a normal body temperature
Correction of electrolytes/glucose abnormalities and metabolic acidosis
Minimal stimulation/handling of the newborn
Minimal use of invasive procedures (eg, suctioning)
PPHN treatment may consist of the following:
Inotropic support (eg, dopamine [first line], dobutamine, milrinone)
Surfactant administration: For premature and full-tem newborns with parenchymal lung disease
Endotracheal intubation and mechanical ventilation: To maintain normal functional residual capacity by recruiting areas of atelectasis; to avoid overexpansion
High-frequency ventilation: Used in newborns with underlying parenchymal lung disease and low lung volumes; therapy is best in centers with clinicians experienced in achieving/maintaining optimal lung distention
Correction of acidosis and alkalosis
Induced paralysis: Controversial; paralytic agents are typically reserved for newborns who cannot be treated with sedatives alone (Note: paralysis, especially with pancuronium, may promote atelectasis of dependent lung regions and promote ventilation-perfusion mismatch.)
ECMO: Used when optimal ventilatory support fails to maintain acceptable oxygenation and perfusion [2, 3]
Pulmonary vasodilators (eg, inhaled nitric oxide) and inhaled supplemental oxygen
Vasodilators are potentially beneficial for chronic PPHN after the newborn period (eg, prostacyclin, phosphodiesterase inhibitors, endothelin receptor antagonists)
Persistent pulmonary hypertension of the newborn (PPHN) 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 secondary to right-to-left shunting of blood.
Because most newborns have a patent foramen ovale and a patent ductus arteriosus early in life, elevated pulmonary vascular resistance leads to right-to-left shunting of blood and severe hypoxemia. With inadequate pulmonary perfusion, neonates are at risk for developing refractory hypoxemia, hypercarbia, and acidosis.
Clinically, PPHN is most often recognized in term or near-term neonates, but it can occur, albeit infrequently, in premature neonates.
Contrary to primary pulmonary hypertension in adults, the newborn syndrome is not defined by a specific pressure of the pulmonary circulation, although it is typically equal to the systemic blood pressure in the presence of a nonrestrictive patent ductus arteriosus. The diagnosis is confirmed regardless of the pulmonary arterial pressure, as long as it is accompanied by right-to-left shunting and absence of congenital heart disease.
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.
Mechanisms that maintain high pulmonary vascular resistance (PVR) in utero include low fetal oxygen content, the lack of a gas-liquid interface, and the presence of vasoconstrictor mediators. Pulmonary vasoconstrictors in the normal fetus include 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, as pulmonary blood flow increases 8- to 10-fold and pulmonary arterial pressure decreases by 50% within 24 hours. This is due to a marked increase in oxygen tension, the establishment of an air-liquid interface, and rhythmic distention of the lungs.[4, 5] The most critical signals for these transitional changes are mechanical distentsion of the lungs, a decrease in carbon dioxide tension, and an increase in oxygen tension in the lungs. The fetus adapts late in gestation by increasing pulmonary expression of NO synthases and soluble guanylate cyclase, which are important for subsequent pulmonary vasodilation.
Failure of circulatory transition
In some newborns, this normal decrease in pulmonary vascular tone does not occur, resulting in PPHN. This results in shunting of blood away from the lungs and severe central hypoxemia.
Severe PPHN can be associated with poor cardiac output and shock, signs of which include tachycardia, ashen or gray color, capillary refill time more than 3 seconds, oliguria, hypotension, and lactic acidosis. This is commonly seen when the ductus arteriosus is restrictive and right-to-left shunting is compromised at this level.
Although most surviving newborns with persistent pulmonary hypertension of the newborn have normal neurodevelopmental outcomes, as many as 25% have significant neurodevelopmental sequelae with a high prevalence of both expressive and receptive linguistic deficits.
The factors that produce antenatal vascular remodeling are not completely understood.
Several vasoactive substances are known to modulate the vasomotor tone of the pulmonary arteries, including endothelin-1 (ET-1), nitric oxide (NO), and prostacyclin (PGI2). Endothelial nitric oxide synthase (eNOS) (or nitric oxide synthase type 3) is the most extensively studied enzyme in persistent pulmonary hypertension of the newborn (PPHN). When activated by shear stress or adenosine triphosphate (ATP), it converts L-arginine into NO and L-citrullin.
NO stimulates the soluble guanylate cyclase enzyme in the pulmonary vascular smooth muscle cells, leading to the conversion of guanosine triphosphate nucleotide into cyclic guanosine monophosphate (cGMP). The increase in intracellular cGMP leads to a decrease in calcium influx and relaxation of smooth muscle cells by stimulating protein kinase G.[7, 8] cGMP is down-regulated by phosphodiesterase 5 activity. Phosphodiesterase 5, which is abundantly expressed in lung tissue, particularly during fetal life, is a key regulator of perinatal pulmonary circulation.
Experimental studies of chronic pulmonary hypertension in newborn animals have demonstrated impaired endothelial release of NO and increased production of vasoconstrictors (eg, endothelin-1). Endothelin-1, a 21–amino acid polypeptide elaborated by the endothelium, is a vasoconstrictor to the pulmonary arteries and enhances oxygen formation that depletes NO bioavailability and promotes the growth of the pulmonary artery muscular layer.
Vascular endothelial growth factor (VEGF) is another potent endothelial cell mitogen and regulator of angiogenesis. In vivo, inhibition of VEGF receptors in normal fetal sheep results in impaired vascular growth and leads to pulmonary hypertension.
Genetic factors may increase susceptibility to pulmonary hypertension. Strong links between PPHN and polymorphisms of the carbamoyl phosphate synthase gene have been reported. However, the importance of this finding is uncertain, and further work is needed in this area.
Epidemiologic studies demonstrate that black and Asian maternal race is associated with a significant higher risk for PPHN. Male sex is also associated with a higher incidence of PPHN.
Selective serotonin reuptake inhibitors (SSRIs), commonly prescribed antidepressants, have been reported to be associated with PPHN, especially during the third trimester of pregnancy. The prevalence of PPHN in newborns exposed to SSRIs in the second half of pregnancy is increased 6-fold. However, one recent study involving 1104 infants born to mothers who received antidepressants in the third trimester and an equal number of controls failed to demonstrate this association.
Therefore, the US Food and Drug Administration (FDA) has stated that it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN. They are advising healthcare professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program.
PPHN is most commonly associated with 1 of 3 underlying etiologies :
Acute pulmonary vasoconstriction
Hypoplasia of the pulmonary vascular bed (commonly seen with congenital diaphragmatic hernia)
Idiopathic pulmonary hypertension
Acute pulmonary vasoconstriction
The most commonly encountered scenario in PPHN is acute pulmonary vasoconstriction due to acute perinatal events, such as:
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
Hypoplasia of the pulmonary vascular bed
Hypoplasia of the pulmonary vascular bed is another cause of persistent pulmonary hypertension of the newborn.
Congenital diaphragmatic hernia is an abnormality of diaphragmatic development that allows the abdominal viscera to enter the chest and compress the lung, impairing growth.
Oligohydramnios may also produce pulmonary hypoplasia and associated persistent pulmonary hypertension of the newborn.
A congenital cystic adenomatoid malformation may lead to lung hypoplasia, but PPHN is not a common finding in this condition.
Idiopathic pulmonary hypertension
One cause of idiopathic PPHN is constriction, or premature closure of the ductus arteriosus in utero, which can occur after exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen, naproxen) during the third trimester. Evaluation of infants at autopsy shows 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. As a result, infants do not vasodilate their pulmonary vessels adequately in response to birth-related stimuli, and they present with hypoxemia and hyperlucent lung fields on radiography, which is termed black lung PPHN.
Incidence in the United States
Data suggest that 1-2 cases of persistent pulmonary hypertension of the newborn (PPHN) occur per 1000 live births. By definition, PPHN is a disorder of newborn infants. It affects mainly term or post-term newborns, although PPHN may also occur in late preterm infants.
Morbidity and mortality
As recently as the late 20th century, the mortality rate for PPHN was nearly 40%, and the prevalence of major neurologic disability was 15-60%. The introduction of inhaled nitric oxide and extracorporeal membrane oxygenation (ECMO) has had a major effect on reducing the mortality rate associated with PPHN (see Treatment, below).[2, 3, 20]
Although persistent pulmonary hypertension of the newborn (PPHN) is often associated with perinatal distress, such as asphyxia, low Apgar scores, meconium staining, and other factors, idiopathic persistent pulmonary hypertension of the newborn can present without signs of acute perinatal distress. Marked lability in oxygenation is noted immediately after birth.
Meconium aspiration syndrome
The most common cause of persistent pulmonary hypertension of the newborn is meconium aspiration syndrome. See the image below.
In the United States, meconium-stained amniotic fluid occurs in as many as 10-15% of live births. The reported incidence of meconium aspiration syndrome varies widely, but is of the order of 1-2 cases per 1000 live births.
Aspiration usually occurs in utero as a consequence of hypoxia-induced gasping. Most infants who have meconium aspiration syndrome (60%) are born by cesarean delivery, indicating that they aspirate meconium before birth. Some aspiration may occur during the second stage of labor. It remains debatable if there is a significant amount of meconium present in the oropharynx to cause meconium aspiration syndrome.
Idiopathic persistent pulmonary hypertension
Idiopathic persistent pulmonary hypertension of the newborn is the second most common etiology.
Newborns with idiopathic PPNH present with pure vascular disease.
One cause of idiopathic persistent pulmonary hypertension of the newborn 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 use should be sought from the mother.
Persistent pulmonary hypertension of the newborn (PPHN) most typically affects infants who are phenotypically normal, although PPHN occurs with higher frequency in newborns with Down syndrome and structurally normal hearts.
Upon initial examination, the primary finding is cyanosis, which is usually associated with tachypnea and respiratory distress.
Cardiac examination may reveal a loud, single second heart sound (S2) or a harsh systolic murmur secondary to tricuspid regurgitation.
The patient may also present with systemic hypotension and symptoms of shock with echocardiographic evidence of poor cardiac function.
The differential diagnosis for persistent pulmonary hypertension of the newborn (PPHN) includes the following:
Congenital heart disease, including transposition of the great arteries,  total anomalous pulmonary venous connection, tricuspid atresia, and pulmonary atresia with intact ventricular septum
Primary parenchymal lung disease such as bronchopulmonary dysplasia (BPD),  neonatal pneumonia, respiratory distress syndrome, pulmonary sequestration, and pulmonary hypoplasia resulting in hypercarbia and respiratory acidosis
Alveolar capillary dysplasia
Surfactant protein B deficiency
Metabolic acidosis of any etiology
The studies discussed below are indicated in persistent pulmonary hypertension of the newborn (PPHN).
Arterial blood gas
Check arterial blood gases (ABGs) initially and frequently, ideally through an indwelling line. Assess the pH, the partial pressure of carbon dioxide in arterial gas (PaCO2), and the partial pressure of oxygen (PaO2). Using the fraction of inspired oxygen (FiO2 ), the alveolar-arterial (A-a) difference in the PaO2 can be calculated.
Be aware that the choice of sampling site can affect the ABG results. Newborns with PPHN frequently have right-to-left shunting across the patent ductus arteriosus. Therefore, their PaO2 values may be elevated when a preductal sampling site is used compared with postductal sites.
Oxygenation is often assessed by using the oxygenation index (OI). The OI is calculated as the mean airway pressure multiplied by the FiO2, and this product is divided by the postductal PaO2. An OI of 40 typically prompts consideration of extracorporeal membrane oxygenation (ECMO) support.
In sick infants, the placement of an indwelling catheter into the umbilical artery or a peripheral artery (eg, radial or posterior tibial artery) allows for frequent monitoring of ABGs.
Complete blood count
Evaluate the complete blood count (CBC) for a high hematocrit level, because polycythemia and hyperviscosity syndrome may produce or aggravate PPHN.
The white blood cell (WBC) count and differential may help in determining whether an underlying sepsis or pneumonia is present.
Laboratory tests to assess for coagulopathy includes a platelet count, prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). If present, such coagulopathy may indicate more severe disease.
Monitor serum electrolyte and glucose levels initially and frequently.
In particular, maintaining glucose and ionized calcium levels within the reference ranges is important, because hypoglycemia and hypocalcemia tend to worsen PPHN. Calcium is a critical cofactor for NO synthase activity.
Chest radiography maybe useful in determining whether underlying parenchymal lung disease (eg, meconium aspiration syndrome, pneumonia, surfactant deficiency) is present. Chest radiography also assists in excluding underlying disorders, such as congenital diaphragmatic hernia.
In newborns with idiopathic persistent pulmonary hypertension of the newborn (PPHN), the lung fields appear clear, with decreased vascular markings.
The heart size is typically normal in infants with PPHN.
The diagnosis of persistent pulmonary hypertension of the newborn (PPHN) should be suspected whenever the level of hypoxemia is out of proportion to the level of pulmonary disease. Echocardiography plays a major role in screening and assisting in making the diagnosis of PPHN. It is considered the most reliable, convenient, and noninvasive test to establish the diagnosis of PPHN, assess the function of the heart, and to rule out an associated structural heart disease.
Echocardiography with Doppler flow allows the physician to assess the presence and direction of the shunt at the ductus arteriosus and foramen ovale. It can estimate the pulmonary arterial systolic and diastolic pressures especially when the ductus arteriosus is restrictive. The right ventricle systolic pressure (RVSP) is estimated from the regurgitant tricuspid flow velocity (v) and the estimated right atrial pressure (RAP) in the modified Bernoulli equation: RVSP= 4v2 + RAP. In newborns, a reasonable estimate of RAP is 5 mm Hg. Pulmonary diastolic pressure (PDP) can be estimated when pulmonary insufficiency is present as: PDP= 4V2 + RAP, where V is the insufficiency peak velocity.
Echocardiographic factors that appear to be predictive of poor outcomes (progression to death/ECMO) in infants with PPHN include diminished tricuspid annular plane systolic excursion (TAPSE), right ventricular global longitudinal peak strain (GLPS), and a predominant right-to-left shunt across the patent ductus arteriosus.
Echocardiography is also used to define the anatomy of the pulmonary veins and to rule out total anomalous pulmonary venous return, which presents in a similar clinical scenario, prior to initiating extracorporeal membrane oxygenation (ECMO).
Although rarely utilized, additional morphologic and functional information can be acquired by magnetic resonance imaging (MRI) and computed tomography (CT) of the chest tomography, if lung pathology is suspected.
Perform cranial ultrasonography if extracorporeal membrane oxygenation (ECMO) is considered in a newborn, to evaluate for intraventricular bleeding and for peripheral areas of hemorrhage or infarct as systemic heparinization is necessary.
Doppler flow studies can be a helpful adjunct in determining whether a nonhemorrhagic infarct is present.
Continuous pulse oximetry screening is valuable in the ongoing treatment of the newborn with persistent pulmonary hypertension (PPHN), allowing the caregiver to assess the patient's oxygen saturation over time and as a guide to the adequacy of oxygen delivery at the tissue level.
Oximeter probes can be placed on preductal (right hand) and postductal (feet) sites to assess for right-to-left shunting at the level of the ductus arteriosus. A difference greater than 10% between preductal and postductal oxygen saturations correlates to right-to-left ductal shunting. Sites on the left hand should be avoided, because it may be preductal or postductal. Significant right-to-left shunting at the level of the foramen ovale may result in lower-than-expected preductal oxygen saturations, although a significant differential should still be evident when compared to postductal oxygen saturations.
Cardiac catheterization is rarely utilized to confirm the diagnosis of PPHN because echocardiography is diagnostic in excluding complex congenital heart disease and in evaluating the severity of pulmonary artery hypertension. The risk/benefit ratio is also increased in this patient population when considering transportation of a sick newborn with PPHN to the catheterization laboratory and the possibility of precipitating a pulmonary hypertensive crisis during catheter manipulation.
Treatment & Management
General management principles for the newborn with persistent pulmonary hypertension (PPHN) includes maintaining a normal body temperature and correction of electrolytes or glucose abnormalities and metabolic acidosis.
The treatment strategy is aimed at maintaining adequate systemic blood pressure, decreasing pulmonary vascular resistance, ensuring oxygen release to tissues, and minimizing lesions induced by high levels of inspired oxygen and ventilator high pressure settings.
The care of newborns with PPHN requires meticulous attention to detail. Continuous monitoring of oxygenation, blood pressure, and perfusion is critical.
It is important for all those caring for sick newborns to use minimal stimulation to reduce the need to handle the patient and to minimize the use of invasive procedures, such as suctioning.
2015 American Heart Association and American Thoracic Society guidelines on pediatric pulmonary hypertension
In November 2015, the American Heart Association and American Thoracic Society released updated guidelines on the diagnosis, evaluation, and management of pediatric pulmonary hypertension. Among their recommendations are the following :
Inhaled nitric oxide should be used to reduce the need for ECMO in term and near-term infants with PPHN or hypoxemic respiratory failure who have an oxygenation index that exceeds 25.
Cardiac catheterization should include acute vasoreactivity testing unless there is a specific contraindication.
Genetic testing with counseling can be useful for children with idiopathic pulmonary artery hypertension (PAH) or in families with heritable PAH to define the pathogenesis, to determine family members at risk, and for family planning.
Longitudinal care in an interdisciplinary pediatric pulmonary hypertension program is recommended for infants with congenital diaphragmatic hernia who have pulmonary hypertension or are at risk of developing late pulmonary hypertension. Extracorporeal membrane oxygenation (ECMO) is recommended for patients with congenital diaphragmatic hernia with severe pulmonary hypertension who do not respond to medical therapy.
Screening for pulmonary hypertension by echocardiogram is recommended in infants with bronchopulmonary dysplasia. Evaluation and treatment of lung disease, including assessments for hypoxemia, aspiration, structural airway disease, and the need for changes in respiratory support, are recommended in infants with bronchopulmonary dysplasia and pulmonary hypertension before initiation of PAH-targeted therapy.
Anticoagulation should not be used in young children with PAH because of concerns about harm from hemorrhagic complications.
Optimal circulatory support is important to maintain adequate perfusion and maximize tissue oxygenation. Rapid infusion of colloid or crystalloid solutions, unless there is evidence of intravascular depletion, should be avoided as it results in further increase in right atrial pressure and subsequently worsening of the right-to-left shunting at the foramen ovale.
Inotropic 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.
Placement of a central venous catheter into the umbilical or other vein will allow for the administration of inotropic agents or hypertonic solutions (eg, calcium gluconate solution).
Avoid catheter placement into the neck vessels, which should be saved for extracorporeal support, if needed.
Surfactant therapy does not appear to be effective when PPHN is the primary diagnosis ; however, it should be considered in patients with parenchymal lung disease, which is often associated with surfactant deficiency, inactivation, or both.
Single-center trials have shown that surfactant improves oxygenation, reduces air leak, and reduces the need for extracorporeal membrane oxygenation (ECMO) in infants with meconium aspiration. A multicenter trial showed benefit in infants with parenchymal lung disease, such as meconium aspiration syndrome and sepsis, but this trial failed to show reduction in ECMO use in newborns with idiopathic PPHN.
High-frequency ventilation (HFV) is another important modality if a newborn has underlying parenchymal lung disease with low lung volumes. This modality is best used in a center with physicians who are experienced in achieving and maintaining optimal lung distention.
The response to HFV can be rapid, and care must be taken to prevent hypocarbia and lung overdistention.
Extracorporeal membrane oxygenation
ECMO, an adaptation of cardiopulmonary bypass, is used when aggressive ventilatory support fails to maintain acceptable oxygenation and perfusion.[2, 3]
The most common indications for ECMO use among neonates in the United States are meconium aspiration and congenital diaphragmatic hernia. An analysis of the Extracorporeal Life Support Organization (ELSO) registry from 1999-2004 reported that neonates with PPHN represented more than 20% of those requiring ECMO support.
Several studies demonstrated a reduction in ECMO use from 1990-2000 because of the advancement in the medical management of PPHN, specifically the use of high-frequency ventilation, inhaled nitric oxide (NO), and surfactant administration.[31, 32] However, since 2000, the number of PPHN cases reported to the ELSO registry has remained relatively stable, ranging from 115 to 157 cases per year, which may demonstrate a plateau in the benefit for medical therapy for PPHN.
One criterion for the institution of ECMO is an elevated oxygenation index (OI) that is consistently 40 or higher.
Veno-veno ECMO support can now be provided using a double-lumen catheter in the internal jugular vein; thus, veno-aterial ECMO and ligation of the right common carotid artery can be avoided.
Although inhaled NO (iNO) is an effective selective pulmonary vasodilator, ECMO remains the only therapy that has been proven to be life-saving for PPHN. Therefore, timely transfer to an ECMO center is vital for newborns with severe PPHN.
It is often difficult to determine the proper timing of a referral to an ECMO center. Referral and transfer should occur before refractory hypoxemia develops. Early consultation and discussion with clinicians at the ECMO center is strongly recommended.
Identifying and maintaining communication with clinicians at an ECMO center is especially important given the widespread availability of iNO therapy. Continuous delivery of NO is required during transport. The referring center is responsible for determining what transport capabilities are available in order to administer a successful therapeutic iNO program.
Current ECMO entry criteria are suitable for situations in which newborns with PPHN respond well or not at all to iNO and/or high-frequency oscillatory treatment. In newborns with partial response to iNO and/or high-frequency oscillatory treatment, because ECMO criteria are never met, these patients may develop lung damage and even die waiting.
Guidelines for transfer to an ECMO center for consultation are published on the ELSO Web site. Individual centers may have modified guidelines. Therefore, an ongoing relationship with the closest ECMO center is needed to provide optimal care.
Baseline criteria for consideration for ECMO include an evaluation of risk factors, because of the invasive nature of the therapy and a need for heparinization.
Baseline criteria for newborns considered for ECMO are generally as follows:
Gestation of more than 34 weeks
Weight more than 2000 g
No major intracranial hemorrhage on cranial sonograms (ie, larger than a grade II hemorrhage)
Reversible lung disease
No evidence of lethal congenital anomalies or congenital heart disease that is presenting as PPHN
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.
Adjust ventilator settings to maintain normal lung expansion (ie, of approximately 9 ribs) on chest radiography. Monitoring of tidal volume and of pulmonary mechanics is frequently helpful in preventing overexpansion, which can elevate PVR, aggravate right-to-left shunting, and increase the risk for pneumothorax.
In newborns with severe airspace disease who require high peak inspiratory pressures (ie, >30 cm water) or mean airway pressures (>15 cm water), consider HFV to reduce barotraumas and associated air leak syndrome. When HFV is used, the goal should still be to optimize lung expansion and FRC and to avoid overdistention.
A frequent concern is determining the target arterial PaO2 level. Although hyperoxic ventilation continues to be a mainstay in the treatment of PPHN, surprisingly little is known about what oxygen concentrations maximize benefits and minimize risks. PaO2 levels of 50 mm Hg or more typically provide for adequate tissue oxygen delivery. Aiming for higher PaO2 concentrations may lead to increased ventilator support and barotrauma. Further, the use of extreme hyperoxia in PPHN management may be toxic to the developing lung, owing to the formation of reactive oxygen radicals.
Newborns with PPHN nearly always require sedation to minimize agitation, which increases pulmonary vascular resistance (PVR), and such sedation is provided by fentanyl (often in combination with a benzodiazepine).
Acidosis and alkalosis correction
Acidosis can act as a pulmonary vasoconstrictor and should be avoided. The use of sodium bicarbonate was common prior to the approval of inhaled nitric oxide. Previous studies have shown that the pulmonary vascular response to alkalosis is transient, and prolonged alkalosis may paradoxically worsen pulmonary vascular tone, reactivity, and permeability edema. Further, alkalosis causes cerebral constriction and reduces cerebral blood flow and oxygen delivery to the brain and thus might be associated with worse neurodevelopmental outcomes.
Currently, there is no evidence suggesting that using sodium bicarbonate infusions to induce alkalosis provides any short- or long-term benefit.
Some still advocate using sodium bicarbonate infusions to maintain an alkaline pH. Serum sodium concentration should be carefully monitored if bicarbonate infusions are used, and ventilation must be adequate to allow for carbon dioxide clearance.
Walsh-Sukys et al reported that the use of alkaline infusion is associated with an increased need for ECMO when the newborn is aged 28 days. Therefore, use this approach with caution.
Many clinicians have good success without using alkalinization. In a series of 15 patients, Wung et al applied a strategy designed to maintain PaO2 at 50-70 mm Hg and PaCO2 at less than 60 mm Hg (ie, gentle ventilation). This approach resulted in excellent outcomes and a low incidence of chronic lung disease.
The use of paralytic agents is highly controversial and is typically reserved for newborns who cannot be treated with sedatives alone. Be aware that paralysis, in particular with pancuronium, may promote atelectasis of dependent lung regions and promote ventilation-perfusion mismatch.
A review of 385 newborns with persistent pulmonary hypertension of the newborn by Walsh-Sukys et al suggested that paralysis may be associated with an increased risk of death.
Sedation and analgesia with opioids are often necessary to achieve adequate mechanical ventilation in patients with persistent pulmonary hypertension of the newborn (PPHN).
The administration of surfactant may be helpful if parenchymal disease is present.
Cardiac output is maintained with the use of inotropic agents and with judicious volume replacement.
Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that may decrease the need for invasive therapy, such as extracorporeal membrane oxygenation (ECMO).
Inhaled nitric oxide
NO is a rapid and potent vasodilator that can be delivered through a ventilator because of its low molecular weight. Once in the bloodstream, it binds to hemoglobin, limiting its systemic vascular activity and increasing its selectivity for the pulmonary circulation.
Treatment with iNO is indicated for newborns with an oxygen index (OI) of 25 or more. NO is an endothelially derived signalling molecule that relaxes vascular smooth muscle and that can be delivered to the lung by means of an inhalation device (INOvent; Ikaria, Clinton NJ).[36, 37]
In 2 large randomized trials, NO reduced the need for ECMO support by approximately 40%. Although these trials led to the US Food and Drug Administration (FDA) approving iNO as a therapy for PPHN, iNO did not reduce mortality, the length of hospitalization, or the risk of neurodevelopmental impairment.
A randomized study showed that beginning iNO at an earlier point in the disease course (for an OI of 15-25) did not decrease the incidence of ECMO and/or death or improve other patient outcomes, including the incidence of neurodevelopmental impairment.
The use of iNO has not been demonstrated to reduce the need for ECMO in newborns with congenital diaphragmatic hernia. In these newborns, iNO should be used in non-ECMO centers to allow for acute stabilization, followed by immediate transfer to a center that can provide ECMO.
Contraindications to iNO include congenital heart disease characterized by ductal dependent systemic blood flow (eg, interrupted aortic arch, critical aortic stenosis, hypoplastic left heart syndrome) and severe left ventricular dysfunction.
Currently, the initial recommended concentration of iNO is 20 ppm. Higher concentrations are not more effective and are associated with a higher incidence of methemoglobinemia and formation of nitrogen dioxide.
In infants who respond, an improvement in oxygenation is evident within few minutes. Some studies have shown that concentrations of up to 5 ppm are effective in improving oxygenation.[39, 40] Lower concentrations (2 ppm) are not effective. Once initiated, iNO should be gradually weaned to prevent rebound vasoconstriction.
During iNO treatment, continuous monitoring of nitrogen dioxide and daily serum levels of methemoglobin should be obtained (methemoglobin levels should be kept at < 5%).
Appropriate lung recruitment and expansion are essential to achieve the best response. If a newborn has severe parenchymal lung disease and PPHN, strategies such as high-frequency ventilation (HFV) may be required.
In centers that do not have immediate availability of ECMO support, use of iNO must be approached with caution. Since iNO cannot be abruptly discontinued, transport with iNO is usually needed if a subsequent referral for ECMO is necessary. This capability should be determined in collaboration with the ECMO center before treatment is started. The use of iNO with HFV creates particular problems for transport, and this should be considered before these therapies are combined in a non-ECMO center.
Vasodilators potentially beneficial for persistent pulmonary hypertension beyond the newborn period
Prostacyclin is a vascular endothelium–derived product of arachidonic acid metabolism with potent vasodilatory activity. It also has inhibitory effects on platelet aggregation, inflammation, and vascular smooth muscle proliferation. It has been used successfully in older patients with pulmonary hypertension but not commonly for PPHN. Treatment with epoprostenol in a randomized control trial has shown improvements over placebo in exercise capacity as assessed by the distance walked in 6 minutes, quality of life, pulmonary hemodynamics, and survival in idiopathic pulmonary hypertension.
Its use requires permanent vascular access as it has very short half life (~5 min), and any abrupt interruption in its delivery due to catheter dislodgment, blockage, or leak may result in potentially fatal rebound pulmonary hypertension. Its effect can wean overtime owing to the phenomenon of tachyphylaxis. Common observed adverse effects are due to systemic vasodilation and include headache, dizziness, facial flushing, jaw pain, leg cramps, and gastrointestinal upset.
Among the 11 isoforms of phosphodiesterases (PDEs), the most important are the PDE3 and PDE5, which degrade cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), respectively.
Sildenafil, a PDE5 inhibitor was shown to selectively reduce pulmonary vascular resistance in both animal models and adult humans. It also has been reported to be successful in the treatment of infants with PPHN.
In a Cochrane meta-analysis with 37 newborns from centers that did not have access to NO and HFV, significant improvement in oxygenation was observed in the group receiving sildenafil. This study noted that sildenafil may be a treatment option for PPHN.
Additional studies are needed to assess the safety and efficacy of sildenafil compared with treatment with the more costly inhaled NO.
Abmen et al reported on the FDA's recent warning against using sildenafil for pediatric pulmonary hypotension in patients aged 1-17 years because of an apparent increase in mortality if used in high doses for long-term therapy. This warning, which is based on extremely limited data, indicates the need for further assessment of the efficacy and safety of sildenafil, especially with long-term treatment.
A more recent systematic review (2015) of off-label use of sildenafil in premature infants at risk for bronchopulmonary dysplasia (BPD) or BPD-associated pulmonary hypertension as well as term or near-term infants with pulmonary hypertension reported little evidence to support the use of sildenafil in term or near-term infants with PPHN in areas where NO is available. The investigators also noted the need for more data sildenafil dosing, safety, and efficacy in premature, term, and near-term infants with pullmonary hypertension.
Endothelin receptor antagonists
The endothelins (ETs) comprise a family of three 21-amino acid peptides, ET-1, ET-2, and ET-3. Of these, only ET-1 plays an important role in the regulation of vascular tone. ET-1 is a very potent vasoconstrictor and smooth muscle mutagen produced primarily by vascular endothelial cells.[50, 51]
The development of the endothelin receptor antagonists represents an important milestone in the therapeutic approach for pulmonary hypertension.
Bosentan is the first orally active treatment to show efficacy in a randomized trial of pulmonary arterial hypertension. Randomized controlled trials and systematic reviews in adults have shown that bosentan improves the outcomes of patients with pulmonary hypertension.[52, 53] There are 2 main concerns: the potential for serious hepatic injury and teratogenic effects. Monthly monitoring of liver function tests for the duration of treatment is mandatory, as approximately 10% of patients receiving bosentan show an increase in liver transaminase levels of 3-fold or greater. To avoid the risk of major birth defects in women exposed to endothelin antagonists, effective contraception must be practiced and monthly pregnancy testing is required.
Other drugs under investigation
Studies have shown that Rho A/Rho kinase activation causes pulmonary vasoconstriction and promotes pathogenic vascular remodeling. Previous investigators have demonstrated that inhibition of the activity of Rho A/Rho kinases using the Rho kinase inhibitor fasudil has beneficial effects on the pulmonary vasculature on different animal models of pulmonary hypertension.
Magnesium sulfate promotes vasodilatation by antagonizing the entry of calcium ions into the smooth muscle cells. However, its pulmonary vasodilator properties have not been studied in the adult or pediatric population.
Combination therapy offers a greater option to enhance pulmonary vasodilatation compared with monotherapy. For example, NO can work synergistically with PDE-5 inhibitors to increase cGMP levels; prostacyclin (PGI2) (which enhances c-AMP) can work synergistically with NO (which enhances c-GMP); endothelin receptors antagonists can work synergistically with NO.
Additional Inpatient Care
After recovery, consider evaluation for central nervous system (CNS) injury by performing brain computed tomography (CT) scanning or magnetic resonance imaging (MRI).
Advise a complete examination for the patient by a neurologist or a developmental pediatrician after discharge, as the incidence of significant neurodevelopmental impairment is 25%.
Since the prevalence of hearing loss is high, order an automated hearing test before discharging the patient.
Newborns recovering from persistent pulmonary hypertension of the newborn often feed poorly for several days or weeks.
Nasogastric (NG) feeding is frequently required to support the newborn until oral feeding is established.
Speech therapy may be helpful in reestablishing normal patterns of feeding.
Owing to the high risk of neurodevelopmental impairment and sensorineural hearing loss, infants should be monitored closely for the first 2 years of life, preferably in a specialty follow-up clinic for developmental follow-up care.
The pulmonary hypertension clinic also offers comprehensive evaluation and an individual treatment plan for patients with persistence of any level of pulmonary hypertension.
Recommend complete screening before pediatric patients enter school, to determine if they have any subtle deficits that may predispose them to learning disabilities.
Reassess the infant's hearing when he or she is aged 6 months and again as the results indicate. Late sensorineural hearing loss has been reported in a high percentage of patients.
Cabral JE, Belik J. Persistent pulmonary hypertension of the newborn: recent advances in pathophysiology and treatment. J Pediatr (Rio J). 2013 May-Jun. 89(3):226-42. [Medline].
Bahrami KR, Van Meurs KP. ECMO for neonatal respiratory failure. Semin Perinatol. 2005 Feb. 29(1):15-23. [Medline].
Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO: focus on PPHN. Semin Perinatol. 2005 Feb. 29(1):8-14. [Medline].
Cassin S, Dawes GS, Mott JC, Ross BB, Strang LB. The vascular resistance of the foetal and newly ventilated lung of the lamb. J Physiol. 1964 May. 171:61-79. [Medline]. [Full Text].
Dawes GS, Mott JC, Widdicombe JG, Wyatt DG. Changes in the lungs of the new-born lamb. J Physiol. 1953 Jul. 121(1):141-62. [Medline].
Berti A, Janes A, Furlan R, Macagno F. High prevalence of minor neurologic deficits in a long-term neurodevelopmental follow-up of children with severe persistent pulmonary hypertension of the newborn: a cohort study. Ital J Pediatr. 2010 Jun 13. 36:45. [Medline]. [Full Text].
Schmidt HH, Schmidt PM, Stasch JP. NO- and haem-independent soluble guanylate cyclase activators. Handb Exp Pharmacol. 2009. 191:309-39. [Medline].
Stasch JP, Hobbs AJ. NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol. 2009. (191):277-308. [Medline].
Jaillard S, Larrue B, Deruelle P, et al. Effects of phosphodiesterase 5 inhibitor on pulmonary vascular reactivity in the fetal lamb. Ann Thorac Surg. 2006 Mar. 81(3):935-42. [Medline].
Villamor E, Le Cras TD, Horan MP, Halbower AC, Tuder RM, Abman SH. Chronic intrauterine pulmonary hypertension impairs endothelial nitric oxide synthase in the ovine fetus. Am J Physiol. 1997 May. 272(5 Pt 1):L1013-20. [Medline].
Hanson KA, Ziegler JW, Rybalkin SD, Miller JW, Abman SH, Clarke WR. Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity. Am J Physiol. 1998 Nov. 275(5 Pt 1):L931-41. [Medline].
Pearson DL, Dawling S, Walsh WF, et al. Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med. 2001 Jun 14. 344(24):1832-8. [Medline].
Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Mitchell AA. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics. 2007 Aug. 120(2):e272-82. [Medline].
Jain L, Eaton DC. Physiology of fetal lung fluid clearance and the effect of labor. Semin Perinatol. 2006 Feb. 30(1):34-43. [Medline].
US food and drug administration. FDA Drug Safety Communication: Selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and reports of a rare heart and lung condition in newborn babies. Available at http://www.fda.gov/drugs/drugsafety/ucm283375.htm. Accessed: December 14, 2011.
Teng RJ, Wu TJ. Persistent pulmonary hypertension of the newborn. J Formos Med Assoc. 2013 Apr. 112(4):177-84. [Medline].
Atkinson JB, Ford EG, Kitagawa H, Lally KP, Humphries B. Persistent pulmonary hypertension complicating cystic adenomatoid malformation in neonates. J Pediatr Surg. 1992 Jan. 27(1):54-6. [Medline].
Robin H Steinhorn, MD and Kathryn N Farrow, MD, PhD. Pulmonary hypertension in the neonate. NeoReviews. January 1, 2007. 8:e14 -e21. [Full Text].
Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000 Jan. 105(1 Pt 1):14-20. [Medline].
Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr. 2009 Dec. 155(6):841-847.e1. [Medline].
Yoder BA, Kirsch EA, Barth WH, Gordon MC. Changing obstetric practices associated with decreasing incidence of meconium aspiration syndrome. Obstet Gynecol. 2002 May. 99(5 Pt 1):731-9. [Medline].
Yeh TF. Core concepts: Meconium aspiration syndrome: Pathogenesis and current management. NeoReviews. 2010 Sep. 11(9):e503-12. [Full Text].
Weijerman ME, van Furth AM, van der Mooren MD, et al. Prevalence of congenital heart defects and persistent pulmonary hypertension of the neonate with Down syndrome. Eur J Pediatr. 2010 Oct. 169(10):1195-9. [Medline].
Sallaam S, Natarajan G, Aggarwal S. Persistent pulmonary hypertension of the newborn with D-transposition of the great arteries: management and prognosis. Congenit Heart Dis. 2015 Nov 11. [Medline].
Silva DM, Nardiello C, Pozarska A, Morty RE. Recent advances in the mechanisms of lung alveolarization and the pathogenesis of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol. 2015 Dec 1. 309 (11):L1239-72. [Medline].
Malowitz JR, Forsha DE, Smith PB, Cotten CM, Barker PC, Tatum GH. Right ventricular echocardiographic indices predict poor outcomes in infants with persistent pulmonary hypertension of the newborn. Eur Heart J Cardiovasc Imaging. 2015 Nov. 16 (11):1224-31. [Medline].
Abman SH, Hansmann G, Archer SL, et al. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015 Nov 24. 132 (21):2037-99. [Medline].
Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. Survanta in Term Infants Study Group. J Pediatr. 1998 Jan. 132(1):40-7. [Medline].
Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics. 1996 Jan. 97(1):48-52. [Medline].
Brown KL, Sriram S, Ridout D, et al. Extracorporeal membrane oxygenation and term neonatal respiratory failure deaths in the United Kingdom compared with the United States: 1999 to 2005. Pediatr Crit Care Med. 2010 Jan. 11(1):60-5. [Medline].
Hintz SR, Suttner DM, Sheehan AM, Rhine WD, Van Meurs KP. Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): how new treatment modalities have affected ECMO utilization. Pediatrics. 2000 Dec. 106(6):1339-43. [Medline].
Christou H, Van Marter LJ, Wessel DL, et al. Inhaled nitric oxide reduces the need for extracorporeal membrane oxygenation in infants with persistent pulmonary hypertension of the newborn. Crit Care Med. 2000 Nov. 28(11):3722-7. [Medline].
Lazar DA, Cass DL, Olutoye OO, et al. The use of ECMO for persistent pulmonary hypertension of the newborn: a decade of experience. J Surg Res. 2012 Oct. 177(2):263-7. [Medline].
Laffey JG, Engelberts D, Kavanagh BP. Injurious effects of hypocapnic alkalosis in the isolated lung. Am J Respir Crit Care Med. 2000 Aug. 162(2 Pt 1):399-405. [Medline].
Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics. 1985 Oct. 76(4):488-94. [Medline].
Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus standard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics. 2004 Mar. 113(3 Pt 1):559-64. [Medline].
Steinhorn RH. Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol. 2008 Dec. 28 Suppl 3:S67-71. [Medline].
American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics. 2000 Aug. 106(2 Pt 1):344-5. [Medline].
Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial. Lancet. 1999 Sep 25. 354(9184):1061-5. [Medline].
Davidson D, Barefield ES, Kattwinkel J, et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study Group. Pediatrics. 1998 Mar. 101(3 Pt 1):325-34. [Medline].
Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. N Engl J Med. 2000 Feb 17. 342(7):469-74. [Medline].
Pawlik TD, Porta NF, Steinhorn RH, Ogata E, deRegnier RA. Medical and financial impact of a neonatal extracorporeal membrane oxygenation referral center in the nitric oxide era. Pediatrics. 2009 Jan. 123(1):e17-24. [Medline].
Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996 Feb 1. 334(5):296-301. [Medline].
Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994 Sep 15. 121(6):409-15. [Medline].
Ahsman MJ, Witjes BC, Wildschut ED, et al. Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube. Arch Dis Child Fetal Neonatal Ed. 2010 Mar. 95(2):F109-14. [Medline].
Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2007 Jul 18. CD005494. [Medline].
Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2011 Aug 10. CD005494. [Medline].
Abman SH, Kinsella JP, Rosenzweig EB, et al. Implications of the U.S. Food and Drug Administration warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension. Am J Respir Crit Care Med. 2013 Mar 15. 187(6):572-5. [Medline].
Perez KM, Laughon M. Sildenafil in term and premature infants: a systematic review. Clin Ther. 2015 Nov 1. 37 (11):2598-2607.e1. [Medline].
Dakshinamurti S. Pathophysiologic mechanisms of persistent pulmonary hypertension of the newborn. Pediatr Pulmonol. 2005 Jun. 39(6):492-503. [Medline].
Abman SH. Role of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Annu Rev Med. 2009. 60:13-23. [Medline].
Galie N, Rubin Lj, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008 Jun 21. 371(9630):2093-100. [Medline].
Liu C, Chen J, Gao Y, Deng B, Liu K. Endothelin receptor antagonists for pulmonary arterial hypertension. Cochrane Database Syst Rev. 2009 Jul 8. CD004434. [Medline].
Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J. 2007 Aug. 30(2):338-44. [Medline].
Oka M, Fagan KA, Jones PL, McMurtry IF. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br J Pharmacol. 2008 Oct. 155(4):444-54. [Medline]. [Full Text].
Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J. 1984 Jul. 108(1):188-93. [Medline].
Brauser D. Moms' SSRI use linked to pulmonary hypertension in newborns. Medscape Medical News. January 16, 2014. Available at http://www.medscape.com/viewarticle/819326. Accessed: January 27, 2014.
Grigoriadis S, Vonderporten EH, Mamisashvili L, et al. Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis. BMJ. 2014 Jan 14. 348:f6932. [Medline].