Persistent Newborn Pulmonary Hypertension

Author: Robin H Steinhorn, MD; Chief Editor: Stuart Berger, MD

Overview
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 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. Clinically, PPHN is most often recognized in term or near-term neonates, but it can occur, albeit infrequently, in premature neonates.

Fetal pulmonary hypertension

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

Normal cardiopulmonary transition

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

Failure of circulatory transition

In some newborns, the normal decrease in pulmonary vascular tone does not occur, resulting in PPHN. Severe PPHN has been estimated to occur in 2 out of 1000 live-born term infants, and some degree of pulmonary hypertension complicates the course of more than 10% of all neonates with respiratory failure. 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. Idiopathic pulmonary hypertension is responsible for 10-20% of all infants with PPHN.

Types of PPHN
Persistent PPHN can be generally characterized as one of 3 following types: PPHN characterized by abnormally constricted pulmonary vasculature due to lung parenchymal diseases (eg, meconium aspiration syndrome, respiratory distress syndrome, pneumonia; see the image of meconium aspiration below) PPHN characterized by hypoplastic vasculature, as seen in congenital diaphragmatic hernia

PPHN in which the lung has normal parenchyma and remodeled pulmonary vasculature (also known as idiopathic PPNH)

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. Some clinicians refer to idiopathic PPNH as "black lung" PPNH or "clear lung" PPNH.

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.

Etiology
The factors that produce antenatal vascular remodeling are not completely understood. Genetic factors may increase susceptibility to pulmonary hypertension. Strong links between persistent pulmonary hypertension of the newborn (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. Newborn rats exposed in utero to fluoxetine develop pulmonary vascular remodeling, abnormal oxygenation, and higher mortality when compared with vehicle-treated controls. Because selective serotonin reuptake inhibitors (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.[1] Persistent pulmonary hypertension of the newborn is most commonly associated with 1 of 3 underlying etiologies, as follows: Acute pulmonary vasoconstriction Hypoplasia of the pulmonary vascular bed Idiopathic pulmonary hypertension

Acute pulmonary vasoconstriction

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

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. 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.

Idiopathic pulmonary hypertension

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

Epidemiology
Incidence in the United States
Data suggest that 2-6 cases of PPHN occur per 1000 live births.

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 extracorporeal membrane oxygenation (ECMO) and other new therapies has had a major effect on reducing the mortality rate associated with PPHN (see Treatment, below).[2, 3, 4] In a randomized trial on the effects of ECMO in newborns with severe respiratory failure, the investigators found that the morality rate in newborns who received ECMO therapy was 32%, while the mortality rate in newborns who received conventional therapy was almost 60%.[5]

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

Patient History
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.

Meconium aspiration syndrome

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 have 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

Idiopathic persistent pulmonary hypertension of the newborn is the second most common etiology of persistent pulmonary hypertension of the newborn. 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. Even if this history is negative, NSAIDs are frequently recovered from the meconium of infants with persistent pulmonary hypertension of the newborn. Another reported association with idiopathic PPHN is maternal use of SSRIs, particularly during the second trimester. However, the association between SSRI use and severe persistent pulmonary hypertension of the newborn is unclear.

Physical Examination
Persistent pulmonary hypertension of the newborn (PPHN) 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. (Respiratory distress and cyanosis typically occur within 6-12 hours of birth.) Cardiac examination may reveal a loud, single S2 sound or a harsh systolic murmur secondary to tricuspid regurgitation. The patient may have evidence of poor cardiac function and perfusion.

Differential Diagnosis
The differential diagnosis for persistent pulmonary hypertension of the newborn (PPHN) includes the following: Congenital Diaphragmatic Hernia Meconium Aspiration Syndrome Partial Anomalous Pulmonary Venous Connection Pneumonia Pneumothorax Pulmonary Atresia With Intact Ventricular Septum Pulmonary Hypoplasia

Pulmonary Sequestration Respiratory Distress Syndrome Sepsis Other problems to be considered include the following: Alveolar capillary dysplasia Surfactant protein B deficiency Total anomalous pulmonary venous connection Transposition of the great arteries Tricuspid atresia

Laboratory Studies
The following studies 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), 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 extrapulmonary right-toleft shunting across the patent ductus arteriosus. Therefore, their PaO 2 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 PaO 2 and the ventilator settings. The OI is calculated as the mean airway pressure multiplied by the FiO 2 and the 100, and the product is divided by the postductal PaO2. An OI of 40 typically prompts consideration of ECMO support. 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.

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 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 PPHN. Calcium is a critical cofactor for NO synthase activity.

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 (PPHN), the lung fields appear clear, with decreased vascular markings. Heart size is typically normal or slightly enlarged in infants with PPHN.

Echocardiography
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. Echocardiography can be used to determine if right-to-left shunting of blood across the ductus arteriosus and/or foramen ovale 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. Echocardiology 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 played by left ventricular dysfunction in the underlying pathophysiology. This must be corrected before considering the use of pulmonary vasodilators.

Ultrasonography
Perform cranial ultrasonography if 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 in 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 (PPHN), 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 PPHN when present, a ductus-level shunt is frequently absent.

Cardiac catheterization
In rare cases, echocardiographic findings are not definitive, and cardiac catheterization may be necessary to exclude congenital heart disease, particularly anomalous pulmonary venous return.

Treatment & Management

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 drugs

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. 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.

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.

High-frequency ventilation
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 distension. The response to HFV can be rapid, and care must be taken to prevent hypocarbia and lung overdistension.

Extracorporeal membrane oxygenation

ECMO, an adaptation of cardiopulmonary bypass, is used when optimal support fails to maintain acceptable oxygenation and perfusion.[3, 4] The introduction of ECMO and other new therapies has had a major effect on reducing the mortality rate associated with persistent pulmonary hypertension of the newborn (PPHN). However, ECMO is provided at relatively few centers in the United States. In a randomized trial on the effects of ECMO in newborns with severe respiratory failure, investigators found that the morality rate in newborns who received ECMO therapy was 32%, while the mortality rate in newborns who received conventional therapy was almost 60%.[5] ECMO support can now be provided using a double-lumen catheter in the internal jugular vein; thus, ligation of the right common carotid artery can be avoided. Although iNO is an effective 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. However, 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. Guidelines for transfer to an 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 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 or mechanical ventilation for 7-14 days

No evidence of lethal congenital anomalies or inoperable cardiac disease

Mechanical ventilation
Endotracheal intubation and mechanical ventilation are almost always necessary for the newborn with persistent pulmonary hypertension of the newborn (PPHN). The goal of mechanical ventilation should be to maintain normal functional residual capacity (FRC) by recruiting areas of atelectasis, as well as to avoid overexpansion. Adjust ventilator settings to maintain normal 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 and aggravate right-to-left shunting. 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 overdistension. Determine the exact mechanical ventilation 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" PPHN. 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 PaO 2 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. Levels of 50 mm Hg or more typically provide for adequate oxygen delivery. Aiming for high PaO 2 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 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 correction

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 PaO 2. 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 ECMO and oxygen when the newborn is aged 28 days.[6] 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).[7] 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 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 ventilationperfusion 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. [6] 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

Treatment with iNO is indicated for newborns with an oxygen index (OI) of less than 25. Nitric oxide (NO) is an endothelially 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).[8, 9] 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 (PPHN), iNO did not reduce mortality, the length of hospitalization, or the risk of neurodevelopmental impairment. A randomized study confirmed that beginning iNO at a milder or earlier point in the disease course (for an oxygenation index of 1525) 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 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 because 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 HFV creates particular problems for transport, and this should be considered before these therapies are combined in a non-ECMO center.[10] The referring center is responsible for determining what transport capabilities are available in order to administer a successful therapeutic iNO program.

Medications
Sedation and analgesia with opioids are 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; as previously mentioned, 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. Maintaining a normal or alkaline pH level with infusions of sodium bicarbonate may decrease pulmonary-artery pressure and improve oxygenation. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator that reduces the need for invasive therapies, such as ECMO.

Additional Inpatient Care

Neurologic evaluation
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%. 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.

Follow-Up 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.