eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Pulmonary Hypertension, Persistent-Newborn

Robin H Steinhorn, MD, Raymond and Hazel Speck Berry Professor of Pediatrics, Division Head of Neonatology, Associate Chair of Pediatrics, Northwestern University School of Medicine

Updated: Sep 22, 2009

Introduction

Background

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).

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.

In some newborns, the normal decrease in pulmonary vascular tone does not occur, and the result is persistent pulmonary hypertension of the newborn (PPHN). Severe persistent pulmonary hypertension of the newborn has been estimated to occur in 2 per 1000 of live-born term infants, and some degree of pulmonary hypertension complicates the course of more than 10% of all neonates with respiratory failure.

Pathophysiology

Persistent pulmonary hypertension of the newborn 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. Because a patent foramen ovale and patent ductus arteriosus are normally present early in life, elevated pulmonary vascular resistance in the newborn produces extrapulmonary shunting of blood, leading to severe and potentially unresponsive hypoxemia. With inadequate pulmonary perfusion, neonates are at risk for developing 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. Persistent pulmonary hypertension of the newborn can be generally characterized as one of 3 types: (1) the abnormally constricted pulmonary vasculature due to lung parenchymal diseases (eg, meconium aspiration syndrome, respiratory distress syndrome, pneumonia); (2) the lung with normal parenchyma and remodeled pulmonary vasculature, also known as idiopathic persistent pulmonary hypertension of the newborn; or (3) the hypoplastic vasculature as seen in congenital diaphragmatic hernia. 

Although idiopathic pulmonary hypertension is responsible for only 10-20% of all infants with persistent pulmonary hypertension of the newborn, severe cases are almost certainly affected by both 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.

Frequency

United States

Neonatal respiratory failure affects 2% of all life births, or nearly 80,000 newborns per year, and is responsible for nearly half of all neonatal deaths. Nearly one third of all infants with respiratory failure were born at term or near-term and are at especially high risk for persistent pulmonary hypertension of the newborn.

Recent data suggest that persistent pulmonary hypertension of the newborn occurs as often as 2-6 cases per 1000 live births. Persistent pulmonary hypertension of the newborn is a frequent complicating factor in the term or near-term newborn with parenchymal lung disease (eg, meconium aspiration syndrome, pneumonia).

Mortality/Morbidity

As recently as 15 years ago, the mortality rate for persistent pulmonary hypertension of the newborn was nearly 40%, and the prevalence of major neurologic disability was 15-60%.

The introduction of extracorporeal membrane oxygenation (ECMO) and other new therapies has had a major effect on reducing the mortality rate associated with persistent pulmonary hypertension of the newborn. In the United Kingdom, the effect of ECMO technology was studied in a randomized trial, the only one to use death as an endpoint.¹ 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.

If all available therapies are used, the mortality rate is less than 10%. However, the prevalence of major neurologic disabilities among surviving newborns remains approximately 20% or higher, even for infants with moderate pulmonary hypertension of the newborn.

Age

By definition, persistent pulmonary hypertension of the newborn a disorder of the newborn. However, pulmonary hypertension may complicate the course of older infants with chronic respiratory insufficiency due to bronchopulmonary dysplasia.

Clinical

History

Clinically, persistent pulmonary hypertension of the newborn (PPHN) is most often recognized in term or near term neonates but may infrequently occur in premature neonates. Persistent pulmonary hypertension of the newborn typically presents as respiratory distress and cyanosis within 6-12 hours of birth. Although persistent pulmonary hypertension of the newborn 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 frequently part of the clinical history.

• The most common cause of persistent pulmonary hypertension of the newborn is meconium aspiration syndrome, which affects 25,000-30,000 infants, with 1000 deaths each year in the United States.
  
  

  

  Meconium aspiration. Serial radiographs in a newborn with uncomplicated meconium aspiration. Radiograph obtained shortly after birth shows ill-defined, predominantly perihilar opacities in the lungs; these are more severe on the right than on the left. The lungs are hyperexpanded. The neonate's heart size is within normal limits. The abnormalities on the initial chest radiograph, aside from the presence of an endotracheal tube and an umbilical artery catheter, are identical to those seen in severe cases of transient tachypnea of the newborn.

  
  
  • Approximately 13% of all live births are complicated by meconium-stained fluid, but only 5% of infants who had this complication subsequently develop meconium aspiration syndrome.
  • Although the traditional belief is that aspiration occurs with the first breath after birth, 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.
• Idiopathic persistent pulmonary hypertension of the newborn, or “black-lung” persistent pulmonary hypertension of the newborn, is the second most common etiology of persistent pulmonary hypertension of the newborn.
  • 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.
  • 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. Even if this history is negative, NSAIDs are frequently recovered from the meconium of infants with persistent pulmonary hypertension of the newborn.
  • Another recently reported association with idiopathic persistent pulmonary hypertension of the newborn is maternal use of selective serotonin reuptake inhibitors (SSRIs), particularly during the second trimester. However, the association between SSRI use and severe persistent pulmonary hypertension of the newborn is unclear.

Physical

• Persistent pulmonary hypertension of the newborn most typically affects infants who are phenotypically normal, although the syndrome occurs with higher frequency in newborns with Down syndrome.
• Upon initial examination, the primary finding is cyanosis, which is usually associated with tachypnea and respiratory distress. 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.

Causes

• The factors that produce antenatal vascular remodeling are less well understood. Genetic factors may increase susceptibility for pulmonary hypertension. Strong links between persistent pulmonary hypertension of the newborn 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.
• One cause of idiopathic persistent pulmonary hypertension of the newborn is constriction of the fetal ductus arteriosus in utero, which can occur after exposure to NSAIDs during the third trimester. New data suggest that exposure to selective serotonin reuptake inhibitors (SSRI’s) during late gestation is associated with a 6-fold increase in the prevalence of persistent pulmonary hypertension of the newborn, although how many infants have severe disease is unclear.
• Newborn rats exposed in utero to fluoxetine develop pulmonary vascular remodeling, abnormal oxygenation, and higher mortality when compared with vehicle-treated controls. Because SSRIs have been reported to reduce pulmonary vascular remodeling in adult models of pulmonary hypertension, these findings highlight the unique nature of fetal pulmonary vascular development.
• Persistent pulmonary hypertension of the newborn 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 meconium aspiration syndrome, respiratory distress syndrome, or pneumonia
  • Hypoventilation resulting from asphyxia or other neurologic conditions
  • Hypothermia
  • Hypoglycemia
• The second cause, idiopathic persistent pulmonary hypertension of the newborn, is associated with normal chest radiography findings and no parenchymal lung disease. Newborns with idiopathic persistent pulmonary hypertension of the newborn present with pure vascular disease. Some clinicians refer to this syndrome as "black lung" persistent pulmonary hypertension of the newborn or "clear lung" persistent pulmonary hypertension of the newborn. This syndrome typically results from an abnormally remodeled pulmonary arterial bed, which perhaps secondary to chronic stress in utero. Other potential associations include maternal use of NSAIDs, such as ibuprofen or naproxen, or SSRIs in the last half of pregnancy
• Hypoplasia of the pulmonary vascular bed is a third 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.
  • 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.

Differential Diagnoses

Other Problems to Be Considered

Alveolar capillary dysplasia
Surfactant protein B deficiency

Workup

Laboratory Studies

The following studies are indicated in persistent pulmonary hypertension of the newborn (PPHN):

• ABG
  • Check ABGs initially and frequently, ideally through an indwelling line. Assess the pH, partial pressure of carbon dioxide in arterial gas (PaCO₂), and the (PaO₂). Using the FiO₂, alveolar-arterial (A-a) difference in the partial pressure of oxygen (PaO₂) can be calculated.
  • Be aware that the choice of sampling site can affect the ABG results. Newborns with persistent pulmonary hypertension of the newborn frequently have extrapulmonary right-to-left shunting across the patent ductus arteriosus. Therefore, their PaO₂ values may be elevated when a preductal sampling site is used.
  • Oxygenation is often assessed by using the oxygenation index (OI), which accounts for the postductal PaO₂ and the ventilator settings. The OI is calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (FiO₂) and the 100, and the product is divided by the postductal PaO₂. An OI of 40 typically prompts consideration of ECMO support.
• CBC count
  • Evaluate the CBC count for a high hematocrit level because polycythemia and hyperviscosity syndrome may produce or aggravate persistent pulmonary hypertension of the newborn.
  • The WBC count and differential may help in determining whether an underlying sepsis syndrome or pneumonia is present.
  • The platelet count is frequently depressed, particularly in newborns with meconium aspiration syndrome or asphyxia.
• Serum electrolytes
  • 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 persistent pulmonary hypertension of the newborn. Calcium is a critical cofactor for nitric oxide synthase activity.

Imaging Studies

• Chest radiography
  • Chest radiography is 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, the lung fields appear clear, with decreased vascular markings.
  • Heart size is typically normal or slightly enlarged.
• Cardiac ultrasonography (echocardiography)
  • Ultrasonography of the heart (echocardiography) is necessary to exclude cyanotic congenital heart disease. Defining the anatomy of the pulmonary veins can be extremely difficult if extrapulmonary right-to-left shunting of blood is present. Cardiac catheterization is seldom required for diagnosis of persistent pulmonary hypertension of the newborn.
  • Cardiac ultrasonography can also be used to determine if right-to-left shunting of blood across the ductus arteriosus, foramen ovale, or both is present. A skilled ultrasonographer can use the peak velocity of the regurgitant flow across the tricuspid valve to calculate right ventricular systolic pressures and, thus, estimate right-sided vascular pressures.
  • Cardiac ultrasonography is needed before therapy with inhaled nitric oxide (iNO) is begun. The image allows the clinician to rule out left-sided obstructive lesions, such as an interrupted aortic arch, a hypoplastic left ventricle, and critical aortic stenosis. These lesions require right-to-left shunting through the ductus to maintain systemic perfusion and, therefore, are contraindications to iNO treatment.
  • Although right-to-left shunting at the patent ductus arteriosus and patent foramen ovale is typical for persistent pulmonary hypertension of the newborn, predominant right-to-left shunting at the patent ductus arteriosus but left-to-right shunt at the patent foramen ovale may help to identify the important role of left ventricular dysfunction to the underlying pathophysiology. This must be corrected before considering the use of pulmonary vasodilators.
• Cranial ultrasonography
  • 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.
  • Doppler flow studies can be a helpful adjunct for determining whether a nonhemorrhagic infarct is present.

Other Tests

• Pulse oximetry
  • Continuous pulse oximetry is extremely valuable in the ongoing treatment of the newborn with persistent pulmonary hypertension of the newborn, allowing the caregiver to assess the patient's oxygen saturation over time and to determine whether oxygen delivery at the tissue level is adequate.
  • Oximeter probes can be placed on preductal (right hand) and postductal (right or left foot) sites to assess for right-to-left shunt at the level of the ductus arteriosus. Remember that sites on the left hand should be avoided because it may be preductal or postductal.
  • Although it is a useful indicator of persistent pulmonary hypertension of the newborn when present, a ductus-level shunt is frequently absent.
• Cardiac catheterization: In rare cases, cardiac ultrasonographic findings are not definitive, and cardiac catheterization may be necessary to exclude congenital heart disease, particularly anomalous pulmonary venous return.

Procedures

• Mechanical ventilation
  • Endotracheal intubation and mechanical ventilation are almost always necessary for the newborn with persistent pulmonary hypertension of the newborn. The goal of mechanical ventilation should be to maintain normal functional residual capacity (FRC) by recruiting areas of atelectasis but also to avoid overexpansion.
  • Adjust ventilator settings to maintain normal expansion (ie, of approximately 9 ribs) on chest radiography. Monitoring of tidal volume and pulmonary mechanics monitoring is frequently helpful in preventing overexpansion, which can elevate PVR and aggravate right-to-left shunting.
  • In newborns with severe airspace disease who require high peak inspiratory pressures (ie, >30 cm H₂ O) or mean airway pressures (>15 cm H₂ O), consider high-frequency ventilation (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 overdistension.
• Central venous catheter placement
  • 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).
  • Avoid catheter placement into the jugular vessels; save these vessels for extracorporeal support, if needed.
• Arterial catheter placement: Place an indwelling catheter into the umbilical artery or a peripheral artery (eg, radial or posterior tibial artery) to allow for frequent monitoring of ABGs.
• Surfactant administration
  • Parenchymal lung disease of the term or near-term newborn is often associated with surfactant deficiency, inactivation, or both.
  • Data from small studies suggest that a benefit occurs after surfactant is administered to the newborn with meconium aspiration syndrome.
  • 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.
• HFV
  • 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 experienced in achieving and maintaining optimal lung distension.
  • The response to HFV can be rapid, and care must be taken to prevent hypocarbia and lung overdistension.
• ECMO
  • ECMO is used when optimal support fails to maintain acceptable oxygenation and perfusion. This therapy, which is an adaptation of cardiopulmonary bypass, is provided at less than 100 centers in the United States.
  • Recent developments allow ECMO support to be provided by using a double-lumen catheter in the internal jugular vein; thus, ligation of the right common carotid artery can be avoided.

Treatment

Medical Care

• General considerations
• The care of newborns with persistent pulmonary hypertension of the newborn (PPHN) requires meticulous attention to detail. Continuous monitoring of oxygenation, blood pressure, and perfusion is critical.
• 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.
• 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.
• Inotropic support with dopamine, dobutamine, and/or milrinone alone or in combination, 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.
• Mechanical ventilation
• Mechanical ventilation is usually needed to maintain adequate oxygenation. Determine the exact strategy on the basis of the underlying lung disease. For instance, newborns with clinically significant airspace disease due to pneumonia or respiratory distress syndrome likely require airway pressures higher than those needed for patients with idiopathic "black lung" persistent pulmonary hypertension of the newborn. Likewise, newborns with clinically significant airspace disease are most likely to respond to other lung recruitment strategies, such as surfactant administration and/or high-frequency oscillatory ventilation.
• A frequent concern is determining the target arterial PaO₂ level. Although hyperoxic ventilation continues to be a mainstay in the treatment of persistent pulmonary hypertension of the newborn, surprisingly little is known about what oxygen concentrations maximize benefits and minimize risks.Levels of 50 mm Hg or more typically provide for adequate oxygen delivery. Aiming for high PaO₂ concentrations may lead to increased ventilator support and barotrauma. Further, the use of extreme hyperoxia in persistent pulmonary hypertension of the newborn management may be toxic to the developing lung by the formation of reactive oxygen species.
• 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.
• Acidosis and alkalosis
• Metabolic acidosis and respiratory acidosis require correction. Sodium bicarbonate is typically used to correct metabolic acidosis. However, if carbon dioxide clearance is a problem, administering bicarbonate may produce a respiratory acidosis. In these situations, tromethamine (THAM) 1-2 mmol/kg may be a useful alternative, although THAM should never be administered to patients with anuria or uremia.
• Forced alkalosis by using sodium bicarbonate and hyperventilation were popular therapies in the past because of their ability to produce acute pulmonary vasodilation and increase PaO₂. These therapies have little evidence base. Further, hypocarbia is associated with constriction of the cerebral vasculature, reduction of cerebral blood flow, and systemic hypotension. Extreme alkalosis and hypocarbia are strongly associated with late neurodevelopmental deficits, including a high rate of sensorineural hearing loss.
• Some advocate using sodium bicarbonate infusions to maintain an alkaline pH. Serum sodium concentration should carefully be monitored if bicarbonate infusions are used, and ventilation must be adequate to allow for carbon dioxide clearance. Walsh-Sukys and colleagues reported that the use of alkaline infusions is associated with increased use of extracorporeal membrane oxygenation (ECMO) and oxygen when the newborn is aged 28 days.² 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).³ This approach resulted in excellent outcomes and a low incidence of chronic lung disease.
• Induced paralysis
• The use of paralytic agents is highly controversial and 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 and colleagues suggests that paralysis may be associated with an increased risk of death.²
• Another report indicates that prolonged administration of pancuronium during the neonatal period is associated with sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia.
• Treatment with inhaled nitric oxide (iNO)
• Treatment with iNO is indicated for newborns with an oxygen index (OI) of less than 25. Nitric oxide (NO) is an endothelial-derived gas signaling molecule that relaxes vascular smooth muscle and that can be delivered to the lung by means of an inhalation device (INOVent; Ikaria, Clinton NJ).
• 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 persistent pulmonary hypertension of the newborn, iNO did not reduce mortality, length of hospitalization, or reduce the risk of neurodevelopmental impairment.
• A randomized study has confirmed that beginning iNO at a milder or earlier point in the disease course (for an oxygenation index of 15-25) did not decrease the incidence of ECMO and/or death or improve other patient outcomes, including the incidence of neurodevelopmental impairment.
• Contraindications to iNO include congenital heart disease characterized by left ventricular outflow tract obstruction (eg, interrupted aortic arch, critical aortic stenosis, hypoplastic left heart syndrome) and severe left ventricular dysfunction.
• The appropriate starting dose is 20 ppm. Doses higher than this have not been shown to be more effective and have been associated with adverse effects, including methemoglobinemia and increased levels of nitrogen dioxide (NO₂).
• 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 HFV may be required.
• Most newborns require iNO for less than 5 days. In general, the dose can be weaned to 5 ppm after 6-24 hours of therapy. The dose is then slowly weaned and discontinued when the FiO₂ is less than 0.4-0.6 and the iNO dose is 1 ppm. Abrupt discontinuation at higher doses should be avoided become it may cause abrupt rebound pulmonary hypertension.
• In centers that do not have immediate availability of ECMO support, use of iNO must be approached with caution. Because 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 high-frequency ventilation (HFV) creates particular problems for transport, and this should be considered before these therapies are combined in a non-ECMO center.
• The use of iNO has not been demonstrated to reduce 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.

Medication

Sedation and analgesia with opioids is often necessary to achieve adequate mechanical ventilation in patients with persistent pulmonary hypertension of the newborn (PPHN). Muscle paralysis may be used for the same purpose; however, this method is controversial because adverse circulatory effects and alveolar collapse in dependent regions of the lung may develop. The administration of a surfactant may be helpful if parenchymal disease is present.

Cardiac output is maintained with the use of inotropic agents and with judicious volume replacement.

Opioid analgesics

These drugs are used for deep sedation and analgesia to enable adequate mechanical ventilation. Use of agents such as fentanyl may also decrease sympathetic tone during stressful interventions and maintain a relaxed pulmonary vascular bed.

Fentanyl (Sublimaze)

Synthetic opioid 75-200 times more potent than morphine. Highly lipophilic and protein bound. Prolonged exposure leads to accumulation in fat and delays weaning. By itself, causes little cardiovascular compromise, though addition of benzodiazepines or other sedatives may decrease cardiac output and blood pressure.

Dosing

Adult

Pediatric

Intermittent: 1-5 mcg/kg slow IV bolus q2h
Continuous infusion: 1-2 mcg/kg IV initially, followed by 0.5-1 mcg/kg/h; may slowly uptitrate

Interactions

Phenothiazines may antagonize analgesic effects of opiate agonists; tricyclic antidepressants (TCAs) may potentiate adverse effects of fentanyl when used concurrently

Contraindications

Documented hypersensitivity; hypotension or potentially compromised airway when establishing rapid airway control may be difficult

Precautions

Pregnancy

Precautions

Acute muscle rigidity or chest-wall syndrome may occur after rapid infusion; tolerance develops rapidly; notable withdrawal symptoms may develop if infusions used for >5 d; prescribing clinicians must be skilled in airway management

Neuromuscular-blocking agents

Paralysis is sometimes required in newborns whose condition remains unstable despite adequate sedation.

Pancuronium (Pavulon)

Relatively long-acting nondepolarizing muscle relaxant. Onset of action 1-2 min. Duration of action typically 45-90 min; may be prolonged in renal or hepatic failure. Excretion 80% renal and 20% hepatic.

Dosing

Adult

Pediatric

0.05-0.15 mg/kg/dose IV bolus q1-2h prn movement; alternatively, 0.01-0.1 mg/kg/h IV continuous infusion

Interactions

Increased toxicity with magnesium sulfate and furosemide (dose dependently); can increase or decrease neuromuscular blockade

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

Precautions

Blocks cardiac muscarinic receptors and commonly produces tachycardia; hypotension frequent; infants often require expansion of intravascular blood volume to maintain blood pressure; assess (and may need to frequently adjust) ventilation and gas exchange after administration because of spontaneous ventilation loss; consider airway protection

Vecuronium (Norcuron)

Intermediate-acting nondepolarizing muscle relaxant. Onset of action 1-2 min; duration of action typically 45-90 min. Primary route of excretion is hepatic.

Dosing

Adult

Pediatric

0.05-0.15 mg/kg/dose IV q1-2h prn; alternatively, may be administered as continuous infusion

Interactions

Enhances neuromuscular blockage when used concurrently with inhalational anesthetics; renal or hepatic failure and concomitant administration of steroids may prolong blockade despite withdrawal

Contraindications

Documented hypersensitivity; myasthenia gravis or related syndromes

Precautions

Pregnancy

Precautions

Few or no adverse hemodynamic adverse effects; may be preferred to pancuronium as muscle relaxant in infants with PPHN; 4 times more expensive than pancuronium; as with pancuronium, assess (and may need to frequently adjust) ventilation and gas exchange after administration because of spontaneous ventilation loss

Vasopressors

Targeted use of vasoactive agents may increase cardiac output without affecting systemic or pulmonary vascular resistance (PVR).

Dopamine is unique compared to other catecholamines. Unlike norepinephrine, epinephrine, and isoproterenol, low doses of dopamine increase renal blood flow without increasing heart rate or systemic arterial pressure. It is an effective vasopressor for treating shock and hypotension in cases unresponsive to plasma volume expansion (eg, with crystalloids or colloids). Dopamine also dilates the mesenteric and renal blood vessels to improve renal blood flow and increase the glomerular filtration rate, sodium excretion, and urine output. However, dosages of more than 20 mcg/kg/min may decrease renal blood flow secondary to reversal of the dopaminergic vasodilation.

Dobutamine produces selective positive inotropic effects and therefore produces a mild chronotropic effect. Its structure is similar to those of isoproterenol and epinephrine. Dobutamine is characterized as a selective beta1-agonist as a result of its primary effect of increasing myocardial contractility by means of beta1 stimulation. Milrinone is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase inhibitor that also produces positive inotropic and lusitropic effects. Recent evidence suggests it may enhance the pulmonary vasodilatory effects of iNO.

Dopamine (Intropin)

Believed to increase blood pressure primarily by stimulating alpha-adrenergic receptors. Mechanism of action in newborn infants remains controversial. Because of developmental differences in endogenous norepinephrine stores and expression and function of alpha-adrenergic receptors. Therefore, individualize dose for each patient.

Dosing

Adult

Pediatric

Continuous infusion: 2-20 mcg/kg/min IV

Interactions

Incompatible when IV mixed with acyclovir, amphotericin B, indomethacin, insulin, or sodium bicarbonate; phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and monoamine oxidase inhibitors (MAOIs) increase and prolong effects.

Contraindications

Outflow tract obstructions (eg, subaortic stenosis)

Precautions

Pregnancy

Precautions

Dosages >10 mcg/kg/min may cause pulmonary vasoconstriction; severe local tissue ischemia and sloughing may occur with IV infiltration (therefore best administered by means of central access); if administration by using peripheral IV unavoidable, promptly treat extravasation with phentolamine (Regitine) SC

Dobutamine (Dobutrex)

Increases blood pressure primarily by stimulating beta1-adrenergic receptors. Appears to have more prominent effect on cardiac output than on blood pressure.

Dosing

Adult

Pediatric

Continuous infusion: 2-25 mcg/kg/min IV

Interactions

Beta-adrenergic blockers antagonize effects; general anesthetics may increase toxicity

Contraindications

Outflow-tract obstruction (eg, subaortic stenosis)

Precautions

Pregnancy

Precautions

Extreme caution after myocardial infarction; correct hypovolemic state before use

Milrinone (Primacor)

Bipyridine inotropic/vasodilator agent with phosphodiesterase inhibitor activity. Increases blood pressure primarily by increasing cardiac cAMP. Appears to have more prominent effect on cardiac output than on blood pressure.

Dosing

Adult

Pediatric

Continuous infusion: 0.2-0.5 mcg/kg/min IV

Interactions

Incompatible with furosemide when administered within same IV (forms precipitates)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

Precautions

Monitor fluids, electrolyte changes and renal function during therapy (decrease dose with insufficient renal function); excessive diuresis may increase potassium loss and predispose digitalized patients to arrhythmias; important to correct hypokalemia with potassium supplementation prior to treatment; patients showing excessive decreases in blood pressure should have infusion rates slowed or stopped; previous vigorous diuretic therapy has caused significant decreases in cardiac filling pressure, cautiously administer milrinone and monitor blood pressure, heart rate, and clinical symptomatology

Surfactants

Exogenous surfactant can help in the treatment of airspace disease (eg, RDS). Surfactant may also be helpful in other conditions, such as MAS, though it is not yet approved for such use. After inhaled administration, surface tension is reduced and alveoli are stabilized to decrease the work of breathing and increase lung compliance.

Beractant (Survanta)

Semisynthetic bovine-lung extract containing phospholipids, fatty acids, and surfactant-associated proteins B (7 mcg/mL) and C (203 mcg/mL).

Dosing

Adult

Pediatric

Intratracheal: 100 mg (ie, 4 mL)/kg divided in 4 aliquots administered at least 6 h apart

Interactions

None reported

Contraindications

None known

Precautions

Pregnancy

Precautions

Must be warmed to room temperature; administer only under carefully supervised conditions because of risk of acute airway obstruction

Calfactant (Infasurf)

Natural calf-lung extract containing phospholipids, fatty acids, and surfactant-associated proteins B (260 mcg/mL) and C (390 mcg/mL).

Dosing

Adult

Pediatric

Intratracheal: 3 mL/kg; may repeat q6-12h, not to exceed 3-4 doses

Interactions

None reported

Contraindications

None known

Precautions

Pregnancy

Precautions

Administer only under carefully supervised conditions because of risk of acute airway obstruction

Alkalinizing agents

These drugs are used to correct metabolic acidosis. In addition, maintaining a normal or slightly alkaline pH with sodium bicarbonate may decrease PVR.

Sodium bicarbonate

Buffer that breaks down to water and carbon dioxide after picking up free hydrogen ions. Acts as buffer against acidosis by raising blood pH.

Dosing

Adult

Pediatric

Slow bolus infusion: 2-3 mEq/kg IV

Interactions

Precipitates if administered with calcium or phosphate; inactivates catecholamines, calcium salts, and atropine when mixed; urinary alkalinization induced by increased concentrations may decrease levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine

Contraindications

Alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain

Precautions

Pregnancy

Precautions

Use neonatal dilution of 4.2% or 0.5 mEq/mL because of hypertonicity of concentrated solutions; administer only when ventilation is adequate (otherwise PCO₂ rises); avoid extravasation

Pulmonary vasodilating agents

NO is the most specific therapeutic modality for newborns with persistent pulmonary hypertension of the newborn, and it is an important mediator of vascular tone. NO is delivered to the lung as inhaled gas. Three multicenter studies demonstrated that NO decreases the need for extracorporeal support by more than 35%. NO is produces by a wide range of cell types under normal physiologic conditions. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP), which leads to vasodilation. When inhaled, NO produces pulmonary vasodilation.

The efficacy of sildenafil has been clearly demonstrated in adults with pulmonary hypertension, leading the FDA to approve it in 2005 for use in pulmonary arterial hypertension in adults under a different brand name (Revatio). Baquero et al conducted a small randomized and blinded study testing the effect of enteral sildenafil in persistent pulmonary hypertension of the newborn, treating 13 patients with severe persistent pulmonary hypertension of the newborn with either sildenafil or placebo in a NICU in Colombia, a country with no access to iNO or ECMO. They reported improved oxygenation and lower mortality with oral sildenafil.⁴

Steinhorn et al recently reported the results of an open-label pharmacokinetic trial of intravenous sildenafil in 36 infants with persistent pulmonary hypertension of the newborn.⁵ Sildenafil was effective in improving oxygenation in patients with persistent pulmonary hypertension of the newborn with and without prior exposure to iNO. Systemic hypotension was the most common adverse effect. These data suggest a beneficial effect for oral as well as intravenous sildenafil in persistent pulmonary hypertension of the newborn, although sildenafil is not yet FDA approved for use in pediatric patients.

Nitric oxide, inhaled (INOmax)

Exogenous or inhaled NO is used to decrease PVR and improve lung blood flow. Administer only under controlled conditions in which NO and NO₂ can be monitored accurately. Monitor methemoglobin levels at start of therapy because some infants may have relative deficiency of methemoglobin reductase. Wean gradually because abrupt discontinuation may be associated with severe rebound pulmonary hypertension. Relaxes vascular smooth muscle by binding heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cGMP, leading to vasodilation.

Dosing

Adult

Pediatric

20 ppm inhaled via respirator initially; ongoing dose ranges between 5-20 ppm by means of inhalation-controlled device; taper dose to 1 ppm before discontinuing
Administered by system that measures NO concentrations in breathing gas with a constant concentration throughout respiratory cycle and that does not cause generation of excessive inhaled nitrogen dioxide (NO₂)

Interactions

None known; theoretically, other NO-donor compounds (eg, nitroprusside, nitroglycerin) may add to risk of methemoglobinemia

Contraindications

Left ventricular outflow tract obstruction and/or known dependency on right-to-left shunting of blood; congenital or acquired methemoglobin reductase deficiency

Precautions

Pregnancy

Precautions

Monitor for excess PaO2, methemoglobin, and NO2; abrupt discontinuation may lead to worsening oxygenation and increasing pulmonary arterial pressure (PAP); caution in thrombocytopenia, anemia, leukopenia, or bleeding disorders

Sildenafil citrate (Revatio)

Promotes selective smooth muscle relaxation in lung vasculature possibly by inhibiting phosphodiesterase type 5 (PDE5). This results in subsequent reduction of blood pressure in pulmonary arteries and increase in cardiac output.

Dosing

Adult

Pediatric

Not established; limited data suggest 1 mg/kg q6h

Interactions

Potentiates vasodilatory effect of NO or other organic nitrates, resulting in potentially sudden drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil; coadministration with bosentan increases bosentan levels by 50% and reduces sildenafil levels by 63%

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

Precautions

Currently only available for enteral use; may cause headache, flushing, upset stomach, and nasal congestion

Follow-up

Further Inpatient Care

• Neurologic evaluation of persistent pulmonary hypertension of the newborn (PPHN)
  • After recovery, consider evaluation for CNS injury by performing brain CT or MRI.
  • Advise complete examination by a neurologist or a developmental pediatrician after discharge, as the incidence of significant neurodevelopmental impairment is 25%.
  • Because the prevalence of hearing loss is high, order an automated hearing test before discharging the patient.
• Feeding
  • 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 therapists may be helpful in reestablishing normal patterns of feeding.

Further Outpatient Care

• Because of 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.
• 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.

Transfer

• Guidelines for transfer to an extracorporeal membrane oxygenation (ECMO) center for consultation are published on the Extracorporeal Life Support Organization (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 for 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 or mechanical ventilation for 7-14 days
  • No evidence of lethal congenital anomalies or inoperable cardiac disease
• The timing of a referral to an ECMO center is often a difficult decision. However, referral and transfer should occur before refractory hypoxemia develops. Early consultation and discussion with clinicians at the ECMO center is strongly recommended.

Prognosis

• Pulmonary recovery
  • Overall, the survival rate for newborns with persistent pulmonary hypertension of the newborn is greater than 90% when all resources, including ECMO, are provided.
  • Pulmonary recovery is typically complete, and survivors do not have residual pulmonary disease.
• Neurologic sequelae
  • Although most surviving newborns with persistent pulmonary hypertension of the newborn have normal neurodevelopmental outcomes, as many as 25% have significant neurodevelopmental sequelae.
  • Prolonged hyperventilation is associated with an increased prevalence of neurodevelopmental sequelae, especially sensorineural hearing loss.

Miscellaneous

Medicolegal Pitfalls

• The main pitfall in the treatment of persistent pulmonary hypertension of the newborn is in recognizing its existence and severity. Although inhaled nitric oxide (iNO) is an effective pulmonary vasodilator, extracorporeal membrane oxygenation (ECMO) remains the only therapy that has been proven to be life-saving for persistent pulmonary hypertension of the newborn. Timely transfer to an ECMO center is life saving for newborns with severe persistent pulmonary hypertension of the newborn.
• 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.

Multimedia

Media file 1: Meconium aspiration. Serial radiographs in a newborn with uncomplicated meconium aspiration. Radiograph obtained shortly after birth shows ill-defined, predominantly perihilar opacities in the lungs; these are more severe on the right than on the left. The lungs are hyperexpanded. The neonate's heart size is within normal limits. The abnormalities on the initial chest radiograph, aside from the presence of an endotracheal tube and an umbilical artery catheter, are identical to those seen in severe cases of transient tachypnea of the newborn.

References

1. UK Collaborative ECMO Trial Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet. Jul 13 1996;348(9020):75-82. [Medline].

2. 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. Jan 2000;105(1 Pt 1):14-20. [Medline].

3. Wung JT, James LS, Kilchevsky E, James E. Management of infants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics. Oct 1985;76(4):488-94. [Medline].

4. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics. Apr 2006;117(4):1077-83. [Medline].

5. Steinhorn RH, Kinsella JP, Pierce C, Butrous G, Dilleen M, Oakes M, et al. Intravenous Sildenafil in the Treatment of Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN). J Pediatr. 2009; in press.

6. Abman SH. Neonatal pulmonary hypertension: a physiologic approach to treatment. Pediatr Pulmonol Suppl. 2004;26:127-8. [Medline].

7. Abman SH. New developments in the pathogenesis and treatment of neonatal pulmonary hypertension. Pediatr Pulmonol Suppl. 1999;18:201-4. [Medline].

8. Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn. Pediatrics. Mar 2001;107(3):519-23. [Medline].

9. Auten RL, Notter RH, Kendig JW, Davis JM, Shapiro DL. Surfactant treatment of full-term newborns with respiratory failure. Pediatrics. Jan 1991;87(1):101-7. [Medline].

10. Bahrami KR, Van Meurs KP. ECMO for neonatal respiratory failure. Semin Perinatol. Feb 2005;29(1):15-23. [Medline].

11. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. Feb 9 2006;354(6):579-87. [Medline].

12. Cheung PY, Tyebkhan JM, Peliowski A, Ainsworth W, Robertson CM. Prolonged use of pancuronium bromide and sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia. J Pediatr. Aug 1999;135(2 Pt 1):233-9. [Medline].

13. Clark RH, Gerstmann DR. Controversies in high-frequency ventilation. Clin Perinatol. Mar 1998;25(1):113-22. [Medline].

14. 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. Feb 17 2000;342(7):469-74. [Medline].

15. 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. Mar 1998;101(3 Pt 1):325-34. [Medline].

16. Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO: focus on PPHN. Semin Perinatol. Feb 2005;29(1):8-14. [Medline].

17. Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics. Jan 1996;97(1):48-52. [Medline].

18. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2001;CD000399. [Medline].

19. 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. Dec 2000;106(6):1339-43. [Medline].

20. 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. Feb 27 1997;336(9):597-604. [Medline].

21. Kanto WP Jr, Bunyapen C. Extracorporeal membrane oxygenation. Controversies in selection of patients and management. Clin Perinatol. Mar 1998;25(1):123-35. [Medline].

22. Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr. Dec 2002;141(6):830-2. [Medline].

23. Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in the newborn with hypoxemia. J Pediatr. Jun 2000;136(6):717-26. [Medline].

24. Kinsella JP, Griebel J, Schmidt JM, Abman SH. Use of inhaled nitric oxide during interhospital transport of newborns with hypoxemic respiratory failure. Pediatrics. Jan 2002;109(1):158-61. [Medline].

25. Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol. Apr 2005;29(2):123-8. [Medline].

26. 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. Mar 2004;113(3 Pt 1):559-64. [Medline].

27. Lakshminrusimha S, Russell JA, Steinhorn RH, et al. Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen. Pediatr Res. Sep 2007;62(3):313-8. [Medline].

28. 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. Jan 1998;132(1):40-7. [Medline].

29. Paranka MS, Clark RH, Yoder BA, Null DM Jr. Predictors of failure of high-frequency oscillatory ventilation in term infants with severe respiratory failure. Pediatrics. Mar 1995;95(3):400-4. [Medline].

30. 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. Jan 2009;123(1):e17-24. [Medline].

31. Steinhorn RH. Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol. Dec 2008;28 Suppl 3:S67-71. [Medline].

32. Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet. Jan 13 2001;357(9250):118-20. [Medline].

33. Ziegler JW, Ivy DD, Kinsella JP, Abman SH. The role of nitric oxide, endothelin, and prostaglandins in the transition of the pulmonary circulation. Clin Perinatol. Jun 1995;22(2):387-403. [Medline].

Keywords

persistent fetal circulation, PFC, persistent pulmonary hypertension in the newborn, persistent pulmonary hypertension of the newborn, PPHN, pulmonary vascular resistance, PVR, pulmonary perfusion, black lung PPHN, clear lung PPHN, pulmonary vasodilation, persistent newborn pulmonary hypertension, patent foramen ovale, patent ductus arteriosus, meconium aspiration syndrome, respiratory distress syndrome, pneumonia, congenital diaphragmatic hernia, bronchopulmonary dysplasia, hypothermia, hypoglycemia, cystic adenomatoid malformations, treatment, diagnosis

Contributor Information and Disclosures

Author

Robin H Steinhorn, MD, Raymond and Hazel Speck Berry Professor of Pediatrics, Division Head of Neonatology, Associate Chair of Pediatrics, Northwestern University School of Medicine
Robin H Steinhorn, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Heart Association, American Pediatric Society, American Thoracic Society, and Society for Pediatric Research
Disclosure: Ikaria (INO Therapeutics) Consulting fee Consulting

Medical Editor

Steven M Donn, MD, Professor of Pediatrics, University of Michigan Medical School; Director, Division of Neonatal-Perinatal Medicine, Department of Pediatrics, CS Mott Children's Hospital, University of Michigan Health System
Steven M Donn, MD is a member of the following medical societies: American Pediatric Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Arun K Pramanik, MD, MBBS, Professor of Pediatrics, Director of Neonatal Fellowship, Louisiana State University Health Sciences Center
Arun K Pramanik, MD, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, National Perinatal Association, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Gilbert Z Herzberg, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Cardiology, New York Medical College; Consulting Staff, Department of Pediatrics, Sound Shore Medical Center
Gilbert Z Herzberg, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Chief Editor

Stuart Berger, MD, Professor of Pediatrics, Division of Cardiology, Medical College of Wisconsin; Chief of Pediatric Cardiology, Medical Director of Pediatric Heart Transplant Program, Medical Director of The Heart Center, Children's Hospital of Wisconsin
Stuart Berger, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American College of Chest Physicians, American Heart Association, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)