ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn
Authors:
Ann R Stark, MD
Eric C Eichenwald, MD
Section Editor:
Joseph A Garcia-Prats, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Apr 2022. | This topic last updated: Jan 29, 2021.

INTRODUCTION — Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) remains abnormally elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways. This in turn leads to severe hypoxemia that may not respond to conventional respiratory support. The prevalence of PPHN has been estimated at 1.9 per 1000 live births [1].

The pathophysiology, clinical manifestations, diagnosis, and management of PPHN are discussed here.

PHYSIOLOGY

Fetal and postnatal circulation — In the fetus, the pulmonary and systemic circuits operate in parallel. Both the right and left ventricles (RV/LV) eject blood into the aorta with subsequent perfusion of the placenta, the fetal organ of respiration (figure 1). The RV is dominant, and blood is shunted right-to-left through the foramen ovale and ductus arteriosus, mostly bypassing the lung, which is not participating in gas exchange.

In contrast, the mature postnatal circulation operates in series. All venous return passes through the right side of the heart and into the lung, where gas exchange occurs. The oxygenated blood returns to the left side of the heart and is pumped into the systemic circulation for oxygen delivery to the tissues. No mixing occurs between the two sides of the circulation.

Transitional circulation — Major circulatory adjustments occur at birth as the organ of gas exchange changes from the placenta to the lung. Under normal circumstances, a progressive fall in pulmonary vascular resistance (PVR) accompanies the immediate rise in systemic vascular resistance (SVR) that occurs after birth. For a short period, a transitional circulatory pattern exists that combines features of both the fetal and adult circulatory patterns. The decline in the PVR/SVR ratio results in a steady increase in pulmonary blood flow and oxygen uptake in the lung.

The process of transition depends upon several factors. Factors that contribute to the postnatal increase in SVR include removal of the placenta, the catecholamine surge associated with birth, and the relatively cold extrauterine environment. Factors that promote the postnatal decrease in PVR include expansion of the lung to normal resting volume, establishment of adequate alveolar ventilation and oxygen tension, and successful clearance of fetal lung fluid.

Conditions that interfere with the normal postnatal decline in the PVR/SVR ratio cause the transitional circulation to persist and result in PPHN.

PATHOGENESIS — PPHN occurs primarily in term or late preterm infants ≥34 weeks gestation. Three types of abnormalities of the pulmonary vasculature underlie the disorder: underdevelopment, maldevelopment, and maladaptation [2-6]. Experimental and clinical evidence suggests that injury to the developing pulmonary circulation may disrupt vascular endothelial growth factor (VEGF) signaling and contribute to these abnormalities [7].

Underdevelopment — In abnormalities of underdevelopment, the cross sectional area of the pulmonary vasculature is reduced, resulting in a relatively fixed elevation of pulmonary vascular resistance (PVR). Underdevelopment occurs with pulmonary hypoplasia associated with a variety of conditions. These include congenital diaphragmatic hernia (CDH), congenital pulmonary (cystic adenomatoid) malformation, renal agenesis, oligohydramnios accompanying obstructive uropathy, and fetal growth restriction. Although some degree of postnatal pulmonary vasodilatation can occur, this adaptive mechanism is limited. As a result, mortality risk is greatest in this category of patients. (See "Congenital diaphragmatic hernia in the neonate" and "Congenital pulmonary airway malformation" and "Renal agenesis: Prenatal diagnosis" and "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)" and "Renal hypodysplasia" and "Infants with fetal (intrauterine) growth restriction".)

Maldevelopment — Maldevelopment is a perturbation that occurs in lungs that are normally developed, including branching and alveolar differentiation, and have a normal number of pulmonary vessels. The characteristics include abnormal thickening of the muscle layer of the pulmonary arterioles, and extension of this layer into small vessels that normally have thin walls and no muscle cells [5]. The extracellular matrix that surrounds the pulmonary vessels also is excessive. In this disorder, remodeling of the pulmonary vascular bed is thought to occur during the first 7 to 14 days after birth, with an accompanying fall in PVR.

The mechanisms that stimulate maldevelopment of the pulmonary vasculature are uncertain, but vascular mediators appear to play a role. In one report, for example, infants with severe PPHN had, compared with healthy controls, higher plasma concentrations of the vasoconstrictor endothelin-1 and lower concentrations of cyclic guanosine monophosphate (representing stimulation of guanylate cyclase by nitric oxide [NO], a vasodilator that cannot be readily measured) [8].

Genetic predisposition may influence the availability of precursors for NO synthesis and affect cardiopulmonary adaptation at birth. This was illustrated in a report in which infants with pulmonary hypertension (PH) had lower plasma concentrations of arginine, a precursor of NO and a urea cycle intermediate, and NO metabolites than control infants with respiratory distress [9]. A functional polymorphism of the gene encoding carbamoyl-phosphate synthetase, which controls the rate-limiting step in the urea cycle, occurred more frequently in all of the infants with respiratory distress, with or without PH, than in the general population.

Conditions associated with PPHN caused by vascular maldevelopment include postterm delivery, meconium staining, and meconium aspiration syndrome (MAS). In these disorders, the pulmonary vasculature responds poorly to stimuli that normally result in a decrease in PVR, such as increased alveolar oxygen tension and the establishment of effective ventilation. (See "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis".)

Disorders producing excessive perfusion of the fetal lung also may predispose to vascular maldevelopment. They include premature closure of the ductus arteriosus (eg, caused by nonsteroidal anti-inflammatory drugs [NSAIDs]) or foramen ovale, high placental vascular resistance, and total anomalous pulmonary venous drainage. It has been proposed that the use of NSAIDs in pregnancy is associated with PPHN due to ductal constriction in the fetus [10]. However, subsequent data are conflicting on whether there is a true association between maternal use of NSAIDs and PPHN [11,12].

Maladaptation — In maladaptation, the pulmonary vascular bed is normally developed. However, adverse perinatal conditions cause active vasoconstriction and interfere with the normal postnatal fall in PVR. These conditions include perinatal depression, pulmonary parenchymal diseases, and bacterial infections, especially those caused by group B streptococcus (GBS). The mechanism of increased PVR with GBS infection is activation of vasoactive mediators by bacterial phospholipid components. In a study in newborn lambs, PH was induced by infusion of cardiolipin and phosphatidylglycerol, phospholipids located primarily in the cell wall of GBS [13]. (See "Group B streptococcal infection in neonates and young infants", section on 'Pneumonia'.)

EPIDEMIOLOGY — The incidence of PPHN is approximately 0.2 percent as illustrated by a population-based study of infants born at ≥34 weeks gestation without congenital heart disease from California [14]. In this report based on a state-wide database that links maternal and infant hospital discharges, multiple regression analysis identified the following risk factors for PPHN: gestational age 34 to <37 weeks (ie, late preterm infants), Black maternal race, infants who were either large or small for gestational age, and mothers with preexisting and gestational diabetes, obesity, and advanced age. Factors associated with a lower risk of PPHN included female sex, Hispanic ethnicity, and multiple gestation. Associated disorders included infection, meconium aspiration, respiratory distress syndrome, congenital diaphragmatic hernia, and other anomalies of the respiratory tract.

CLINICAL MANIFESTATIONS — PPHN usually occurs in term infants, although it may also present in late preterm or postterm infants [1]. Although the diagnosis has been thought to be rare in very low birth weight (VLBW) infants (BW <1500 g) [15], data from a retrospective multicenter study suggest that the prevalence of PPHN has increased in extremely preterm infants (gestational age [GA] <28 weeks) and the risk increases with decreasing GA [16].

PPHN is characterized by both prenatal and neonatal features, as illustrated in a study of 385 infants with PPHN (mean GA 39 weeks) cared for in participating centers in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network [1].

Prenatal factors — Prenatal findings associated with PPHN are thought to be signs of intrauterine and perinatal asphyxia. These include fetal heart rate abnormalities (ie, bradycardia and tachycardia) and meconium-stained amniotic fluid [1]. In utero exposure of selective serotonin reuptake inhibitors (SSRIs) during the second half of pregnancy has also been associated with a sixfold increased risk of PPHN compared with nonexposed infants. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Neonatal outcomes", section on 'Persistent pulmonary hypertension of the newborn'.)

Although PPHN is rare in VLBW preterm infants, prolonged premature rupture of the membranes (PPROM) appears to be a common feature. In a prospective study of 765 preterm infants (GA ≤32 weeks), PPROM was seen in all 17 patients with echocardiographic evidence of pulmonary hypertension (PH) [15].

Neonatal findings — Most neonates with PPHN present within the first 24 hours of life with signs of respiratory distress (eg, tachypnea, retractions, and grunting) and cyanosis. In the NICHD study, more than half of the infants had low apgar scores and almost all of the patients received delivery room interventions including oxygen therapy, bag and mask ventilation, and endotracheal intubation [1].

As noted above, the physical examination is characterized by cyanosis and signs of respiratory distress. In addition, there may be meconium staining of skin and nails, which may be indicative of intrauterine stress. The cardiac examination of infants with PPHN may be notable for a prominent precordial impulse, and a narrowly split and accentuated second heart sound. A harsh systolic murmur consistent with tricuspid insufficiency sometimes is heard at the lower left sternal border.

The majority of infants also have other respiratory diagnoses associated with PPHN. In the previously mentioned NICHD cohort, the following primary respiratory disorders and their relative frequencies were noted [1]:

Meconium aspiration syndrome (MAS, 41 percent) (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis")

Pneumonia (14 percent) (see "Neonatal pneumonia")

Respiratory distress syndrome (RDS, 13 percent) (see "Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn")

Pneumonia and/or RDS, when they could not be distinguished (14 percent)

Congenital diaphragmatic hernia (CDH, 10 percent) (see "Congenital diaphragmatic hernia in the neonate")

Pulmonary hypoplasia (4 percent)

Idiopathic (no other respiratory condition observed, 17 percent)

In the previously mentioned population-based study from California, infection was the most common cause of PPHN [14].

Initial laboratory tests — The majority of patients will undergo initial testing that includes pulse oximetry screening, arterial blood gas sampling, and chest radiography. However, the diagnosis is generally made by echocardiography. (See 'Diagnosis' below.)

Pulse oximetry assessment — Pulse oximetry assessment generally demonstrates a difference of greater than 10 percent between the pre- and postductal (right thumb and either great toe) oxygen saturation. This differential is due to right-to-left shunting through the patent ductus arteriosus (PDA). However, it is important to recognize that the absence of a pre- and postductal gradient in oxygenation does not exclude the diagnosis of PPHN, since right-to-left shunting can occur predominantly through the foramen ovale rather than the PDA.

Arterial blood gas — An arterial blood gas sample typically will show low arterial partial pressure of oxygen (PaO2 below 100 mmHg in patients receiving 100 percent inspired oxygen concentration), particularly samples that are postductal. However, in contrast to infants with cyanotic lesions, many infants with PPHN have at least one measurement of PaO2 >100 mmHg early in the course of their illness. The arterial partial pressure of carbon dioxide (PaCO2) is normal in infants without accompanying lung disease. The right-to-left shunting of blood through the PDA can also be documented in differences in PaO2 between samples obtained from the right radial artery (preductal sample) and the umbilical artery (postductal sample). (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Measurement of oxygenation'.)

Chest radiograph — The chest radiograph is usually normal or demonstrates the findings of an associated pulmonary condition (eg, parenchymal disease, air leak, or CDH). The heart size typically is normal or slightly enlarged. Pulmonary blood flow may appear normal or reduced.

DIAGNOSIS — The definitive diagnosis of PPHN is made by echocardiography. Echocardiography is an essential test in any infant with unremitting cyanosis that is unexplained by parenchymal lung disease, to exclude structural heart disease and confirm a diagnosis of PPHN.

In PPHN, echocardiography demonstrates normal structural cardiac anatomy with evidence of pulmonary hypertension (PH) (eg, flattened or displaced ventricular septum). Doppler studies show right-to-left shunting through the patent ductus arteriosus and/or foramen ovale. Continuous-wave Doppler measurement of the velocity of a tricuspid regurgitation (TR) jet (if present) using a modified Bernoulli equation can be used to estimate right ventricular (RV) systolic pressure. In the absence of RV outflow obstruction, pulmonary artery systolic pressure can be calculated (peak pressure difference = 4 x [peak TR velocity]2), which is elevated in patients with PPHN [6].In addition, echocardiography may be used to assess ventricular function, which may be impaired.

Severity of PH — Echocardiography can also provide estimation of the severity of the pulmonary hypertension (PH).

Estimation of right ventricle pressure (RVp), using assessments of TR jet and/or changes in septal position, is compared with systemic blood pressure (BP), and the degree of atrial and/or patent ductus arteriosus shunting is determined. Estimations of severity are as follows:

Mild to moderate PPHN – Estimated RVp is between one-half to three-quarters systemic BP

Moderate to severe PPHN – Estimated RVp is greater than three-quarters systemic BP but less than systemic BP

Severe PPHN – Estimated RVp greater than systemic BP

Evidence of RV dysfunction suggests severe PH

Evidence of biventricular dysfunction may represent global insult (eg, perinatal depression)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PPHN includes:

Cyanotic congenital heart disease (CHD), which is distinguished from PPHN by echocardiography. (See "Cardiac causes of cyanosis in the newborn" and "Diagnosis and initial management of cyanotic heart disease in the newborn".)

Primary isolated parenchymal lung disease such as neonatal pneumonia, meconium aspiration syndrome, transient tachypnea of the newborn (TTN), and respiratory distress syndrome (RDS). These disorders are usually differentiated from PPHN by the clinical setting and chest radiography. However, as noted above, most patients with PPHN will also have an associated lung disorder. In these patients, echocardiography confirms the diagnosis of PPHN. (See "Overview of neonatal respiratory distress and disorders of transition", section on 'Clinical features' and "Overview of neonatal respiratory distress and disorders of transition", section on 'Chest imaging'.)

Sepsis is distinguished by the clinical setting, positive blood cultures, and echocardiography. However, PPHN may occur as a component of sepsis in a neonate. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Clinical manifestations'.)

Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD-MPV) is a rare disorder that may have a similar presentation as severe PPHN of severe hypoxia that is refractory to general supportive care. However, infants with ACD-MPV typically have initial period of stability and develop severe hypoxemia later than PPHN after the first few hours or days of life. If a diagnosis of ACD-MPV is suspected further evaluation including catheterization and lung biopsy are needed to confirm the diagnosis. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Alveolar capillary dysplasia with or without misalignment of the pulmonary veins' and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)", section on 'Diagnostic approach'.)

MANAGEMENT — The management of PPHN consists of the following:

General supportive cardiorespiratory care.

In severe cases, or in those that fail to respond to supportive measures, further interventions include the use of vasodilatory agents (eg, inhaled nitric oxide [iNO]) that reduce the ratio of pulmonary to systemic vascular resistance (PVR/SVR), or extracorporeal membrane oxygenation (ECMO) that provides adequate tissue oxygenation until PVR falls.

Specific treatment for any associated parenchymal lung disease (eg, antibiotic therapy for pneumonia, or surfactant for neonatal respiratory distress syndrome [RDS]). (See "Neonatal pneumonia", section on 'Management' and "Management of respiratory distress syndrome in preterm infants".)

Assessment of severity using oxygenation index — The oxygenation index (OI) is used to assess the severity of hypoxemia in PPHN and to guide the timing of interventions, such as iNO administration or ECMO support. The OI is calculated as follows (calculator 1):

OI = [mean airway pressure x FiO2 ÷ PaO2] x 100

In most cases when the OI is used, the infant is receiving a fraction of inspired oxygen (FiO2) of 1 and is being mechanically ventilated. Thus, the OI can be calculated easily from the mean airway pressure (MAP) displayed on the ventilator and the arterial partial pressure of oxygen (PaO2).

A high OI indicates severe hypoxemic respiratory failure. A term or late preterm infant with an OI ≥25 should receive care in a center where high-frequency oscillatory ventilation (HFOV), iNO, and ECMO are readily available in addition to general supportive care [17].

In patients with OI <25, general supportive care is typically adequate and no further invasive intervention is usually required.

General supportive care — The general approach to care is similar for all infants and begins with identification of risk factors and anticipation of potential illness. Infants depressed at birth should be resuscitated promptly and monitored closely to ensure adequate oxygenation and ventilation. Because sepsis may be associated with PPHN, blood cultures should be obtained and empiric antimicrobial therapy initiated. All ill-appearing newborns should be cared for in a neutral thermal environment to minimize oxygen consumption. (See "Overview of neonatal respiratory distress and disorders of transition".)

General cardiorespiratory measures may reverse or prevent further increase in pulmonary vasoconstriction and include the following:

Supplemental oxygen

Mechanical ventilation

Fluid therapy and inotropic agents for circulatory support

Correction of acidosis

Oxygen — Oxygen is a pulmonary vasodilator and it should be initially administered in a concentration of 100 percent to infants with PPHN in an attempt to reverse pulmonary vasoconstriction. The initial mode of oxygen administration (nasal cannula or CPAP) depends on the infant's underlying pulmonary condition and degree of respiratory distress. Most infants with moderate to severe PPHN require intubation and mechanical ventilation. However, because the administration of high oxygen concentrations, even for a short time period, may cause lung injury and there is no advantage to maintaining an elevated PaO2, oxygen concentration should be adjusted to maintain preductal oxygen saturation target of 90 to 95 percent. Although uncommon in PPHN, persistent hyperoxemia should be avoided.

If the oxygen saturation cannot be maintained above 90 percent, other interventions to preserve adequate tissue oxygenation include maintenance of a hemoglobin concentration between 15 and 16 g/dL and optimizing circulatory function. If these measures do not result in adequate oxygenation (assessed by calculating the oxygenation index), more directed/invasive measures (eg, iNO or ECMO) are required.

Assisted ventilation — Because hypercarbia and acidosis increase PVR, we initially attempt to establish and maintain normal ventilation (arterial partial pressure of carbon dioxide [PaCO2] 40 to 45 mmHg). As the infant's oxygenation and ventilatory status become more stable, we maintain PaCO2 in the range of 40 to 50 mmHg to minimize lung injury associated with high tidal volumes.

The strategy of ventilator support depends upon the presence or absence of pulmonary parenchymal disease, and the infant's response to treatment.

In infants with no associated lung disease, hypoxemia is caused by right-to-left shunting rather than ventilation-perfusion imbalance. As a result, hypoxemia may not respond to conventional ventilator maneuvers. In this circumstance, strategies that elevate MAP may actually impede cardiac output and increase PVR. Thus, we minimize MAP by using low inspiratory pressures and short inspiratory times or volume targeted ventilation. However, it is essential to maintain adequate lung recruitment with modest levels of positive end-expiratory pressure (PEEP).

When PPHN is associated with lung disease, atelectasis and the resulting maldistribution of ventilation may exacerbate high PVR. Assisted ventilation with PEEP is used to recruit atelectatic segments, maintain adequate resting lung volume, and ensure appropriate oxygenation and ventilation. When lung disease is severe, or ventilator peak pressures reach 28 to 30 cm H2O, we usually use HFOV. In a randomized trial of HFOV and iNO in patients with severe PPHN, combined therapy with HFOV and iNO was more effective than treatment with HFOV or iNO only, with a lower rate of death or ECMO treatment [18]. (See "Overview of mechanical ventilation in neonates".)

Infants with PPHN may breathe out of synchrony with the ventilator which may cause worsening hypoxemia. A patient-triggered ventilator mode may improve synchrony. If asynchrony persists, we add an opioid analgesic, (See 'Sedation' below.)

Sedation — Pain and agitation cause catecholamine release, resulting in increased PVR and increased right-to-left shunting. In addition, agitation may result in ventilator asynchrony which can worsen hypoxemia. In patients with agitation and asynchrony that persists on a patient-triggered ventilator mode, we add an opioid analgesic. Therapeutic choices include intravenous (IV) morphine sulfate (loading dose of 100 to 150 mcg/kg over one hour followed by a continuous infusion of 10 to 20 mcg/kg per hour) or fentanyl (1 to 5 mcg/kg per hour). (See "Prevention and treatment of neonatal pain", section on 'Opioid therapy'.)

If dyssynchronous breathing and severe hypoxemia persist and a specific cause cannot be identified (eg, airway obstruction or air leak), we may use neuromuscular blockade. However, we avoid this intervention if at all possible because of potential adverse effects [1,19].

Circulatory support — In patients with PPHN, right-to-left shunting increases as cardiac output and systemic blood pressure (BP) decrease. Thus, maintaining optimal cardiac output and systemic BP is important to reduce the right-to-left shunting and to maintain adequate tissue oxygenation. Systemic BP targets are set at the upper limits of normal (mean BP 45 to 55 mmHg; systolic BP 50 to 70 mmHg) because the pulmonary arterial pressure in patients with PPHN is at or near normal systemic levels. This is accomplished by:

Adequate vascular volume should be maintained with IV fluids. Transfusion of packed red blood cells usually is required to replace blood lost from sampling and to optimize tissue oxygen delivery, especially in patients with marginal oxygenation. In general, we maintain hemoglobin concentration above 15 g (hematocrit above 40 to 45 percent).

Vasopressor support usually is needed in patients with PPHN [20]. Dopamine has been the most commonly used medication in neonates requiring pharmacologic inotropic support. In our centers, we begin with IV infusion of dopamine at a starting dose of 2.5 mcg/kg per minute and titrate the infusion rate (usually to a maximum dose of 20 mcg/kg per minute) to maintain the mean arterial BP at a targeted level that minimizes right-to-left shunting. Little evidence exists comparing the effects of dopamine with other alternative inotropic agents in PPHN. Dobutamine may improve cardiac output if ventricular dysfunction is present, but does not reliably increase BP in neonates. Epinephrine can increase both systemic BP and left ventricular (LV) output [21] but increased LV afterload due to increased PVR may exacerbate right ventricle (RV) afterload.

If the echocardiography demonstrates RV or LV dysfunction, IV milrinone in conjunction with iNO may facilitate reduction in PVR while enhancing myocardial performance and forward flow of blood [22]. However, evidence of safety or efficacy of milrinone is lacking in neonates with PPHN and it is unclear whether this agent should be used in treating PPHN. Of note, hypotension is a contraindication for use. (See 'Severity of PH' above.)

Correction of acidosis — Acidosis increases PVR and attempts should be made to maintain partial pressure of carbon dioxide (PCO2) values between 40 and 50 mmHg and improve metabolic acidosis by cautious correction of a severe base deficit, if present. Sodium acetate may be added to infused IV fluids at a dose of 2 to 3 mEq/kg per day. Rapid infusion of sodium bicarbonate in face of impaired ventilation may worsen intracellular acidosis and is not recommended [23,24]. (See "Approach to the child with metabolic acidosis", section on 'Intravenous bicarbonate therapy'.)

Evidence of benefit of alkali therapy in neonatal respiratory disease remains lacking [25,26]. Hyperventilation and/or IV administration of high doses of alkali therapy (eg, sodium bicarbonate) to maintain "controlled" alkalosis is not recommended, as persistent alkalosis may be associated with reduced cerebral blood flow and impaired release of oxygen from hemoglobin.

Surfactant — Surfactant therapy does not appear to be effective when PPHN is the primary diagnosis [27]. However, it should be considered in patients with associated parenchymal lung disease, in whom there is either a suspected surfactant deficiency (eg, neonatal RDS) or impairment (meconium aspiration syndrome [MAS]) [27,28]. For infants with severe disease, the addition of surfactant to inhaled nitric oxide may be beneficial, especially in patients with parenchymal lung disease [29]. (See "Meconium aspiration syndrome: Prevention and management", section on 'Surfactant' and "Management of respiratory distress syndrome in preterm infants", section on 'Surfactant therapy'.)

Interventions for severe cases — In severe cases, general supportive care is often insufficient to maintain adequate oxygenation. Infants with OI greater than 25 despite the use of HFOV are candidates for iNO therapy or other vasodilatory agents that decrease PVR. Patients who fail to respond to these agents may require ECMO. (See 'Assessment of severity using oxygenation index' above.)

Inhaled nitric oxide

Efficacy — Inhaled nitric oxide (iNO) improves oxygenation and reduces the need for ECMO in term and late preterm infants with severe PPHN (defined as an OI ≥25 (calculator 1)) as illustrated by the following clinical trials [18,30-35].

In a NICHD Neonatal Research Network trial of 235 infants with gestational age (GA) ≥34 weeks who had severe hypoxic respiratory failure (OI ≥25) and did not have congenital diaphragmatic hernia (CDH), infants randomly assigned to iNO (initial dose 20 ppm) had a reduction in the composite primary endpoint of death within 120 days or need for ECMO therapy compared with controls who received 100 percent oxygen (46 versus 64 percent; relative risk [RR] 0.72, 95% CI 0.57-0.91) [30]. This difference was entirely due to a decreased requirement for ECMO (39 versus 54 percent), as there was no difference in mortality between groups.

In another trial of 248 neonates (GA >34 weeks) with severe respiratory failure (OI >25), the use of ECMO was lower in patients who received iNO compared with controls (38 versus 64 percent) [32]. The 30-day mortality rate was similar for both groups.

Additional evidence of the benefit of iNO was provided by a systematic review of the literature that showed the beneficial effect of iNO therapy compared with placebo in near-term and term infants with respiratory failure [35]. One limitation of this review regarding its application to PPHN is that it included all trials for infants with respiratory failure, and echocardiographic evidence of PPHN was not always available. Nevertheless, the authors concluded that the following results were not affected by whether there was or was not clear echocardiographic evidence of PPHN.

There was a reduction in the combined outcome of death or need for ECMO. However, this reduction was due to a reduction in use of ECMO and there was no difference in mortality between the two groups.

Oxygenation improved in 50 percent of infants who received iNO. The OI decreased by a weighted mean value of 15.1 within 30 to 60 minutes after commencing iNO therapy, and there was also a mean increase in arterial partial pressure of oxygen (PaO2) of 53 mmHg.

iNO therapy did not appear to be beneficial in patients with CDH.

However, iNO may not be effective in patients with milder PPHN. In a randomized trial, early initiation of iNO in infants with mild to moderate respiratory impairment with OI between 15 and 25 compared with routine initiation at OI >25 did not reduce the incidence of mortality or the need for ECMO therapy [36]. It also did not affect the outcomes of neurodevelopment and hearing of surviving infants evaluated at 18 to 24 months of age [37]. As a result, iNO is not recommended for infants with moderate respiratory distress and should be reserved for infants with severe respiratory failure with an OI >25.

Mode of action — Endogenous NO regulates vascular tone by causing relaxation of vascular smooth muscle. Exogenous iNO is a selective pulmonary vasodilator that acts by decreasing the pulmonary artery pressure and pulmonary-to-systemic arterial pressure ratio [38]. Oxygenation improves as vessels are dilated in well-ventilated parts of the lung, thereby redistributing blood flow from regions with decreased ventilation and reducing intrapulmonary shunting. In the circulation, NO combines with hemoglobin and is rapidly converted to methemoglobin and nitrate. As a result, there is little effect on SVR and systemic blood pressure.

Potential toxicity — Potential toxicity of iNO includes methemoglobinemia secondary to excess iNO concentrations or impaired metabolism, pulmonary injury related to increased levels of nitrogen dioxide during administration, and contamination of ambient air. However, iNO appears to be safe when administered in the established therapeutic dosing range for PPHN and with appropriate monitoring [35,39]. Bleeding times are prolonged in newborns treated with iNO because of inhibition of platelet function, although clinically significant bleeding has not been observed in term or late preterm infants [40]. (See 'Our approach' below.)

Congenital diaphragmatic hernia — iNO does not appear to be of long-term benefit in infants with CDH and it use in neonates with CDH is discussed separately. (See "Congenital diaphragmatic hernia in the neonate", section on 'Postnatal management'.)

Preterm infants — Routine use of iNO for respiratory failure in preterm infants <34 weeks gestation is not recommended [41,42]. Respiratory failure in most such infants is a result of primary lung disease with ventilation/perfusion mismatch due to surfactant deficiency. However, because pulmonary hypertension does occur in a small proportion of very low birth weight (VLBW) infants (BW <1500 g), it has been thought that select VLBW infants with hypoxic respiratory failure (OI >25) with echocardiographic evidence of PPHN, who are unresponsive to surfactant therapy and conventional respiratory care, may benefit from iNO therapy [15,34]. But iNO was not found to be beneficial in a retrospective large case control study of mechanically ventilated preterm infants born at 22 to 29 weeks gestation [42]. In this study that matched infants based on propensity score to patients who did not receive iNO, there was no difference in mortality. A subanalysis of patients with PPHN showed no effect of iNO on mortality. Of note, iNO exposure was associated with higher mortality for patients with RDS alone. (See "Management of respiratory distress syndrome in preterm infants", section on 'Inhaled nitric oxide'.)

As a result, until there is further information that identifies a subset of preterm infants for whom iNO is beneficial, iNO is not recommended for preterm infants as it remains an unproven and expensive intervention.

Our approach — We begin iNO therapy in term or late preterm infants (GA ≥34 weeks) with severe hypoxemic respiratory failure, defined as an OI ≥25 with maximum respiratory support using conventional mechanical ventilation or HFOV. Prior to initiating treatment, we perform echocardiography to confirm the diagnosis of PPHN and exclude congenital heart disease (CHD). (See 'Diagnosis' above.)

We recommend an initial iNO dose of 20 ppm [30,31,43]. We do not recommend doses above this level because higher doses have not been accompanied by improved response, but have been associated with elevated methemoglobin and nitrogen dioxide levels. In infants who respond, an improvement of approximately 20 percent in PaO2 or arterial oxygen saturation (SaO2) levels typically occurs within 15 to 20 minutes. The iNO concentration is decreased slowly as oxygenation improves [44]. In general, we initially wean supplemental oxygen concentration, maintaining SaO2 greater than 90 percent; when supplemental oxygen concentration is at or less than 60 percent, we begin to wean iNO concentration. Patients who respond to iNO typically require treatment for three to four days, although some require longer courses.

Our centers also follow the recommendations published by the American Academy of Pediatrics (AAP) for the use of iNO in infants with severe hypoxemic respiratory failure [17]:

Care of patients in centers with personnel experienced with multiple modes of respiratory support, rescue therapies, and use of iNO.

Availability of ECMO at the center, or an established mechanism for timely transfer of infants to an ECMO center.

Performance of an echocardiogram to exclude the diagnosis of CHD.

Use of iNO according to the indications, dosing, administration, and monitoring guidelines on the product label.

Although some centers measure methemoglobin levels, we routinely do not measure methemoglobin, as the risk of toxicity is low when using a maximum iNO concentration of 20 ppm.

Extracorporeal membrane oxygenation — Approximately 40 percent of infants with severe PPHN remain hypoxemic on maximal ventilatory support despite administration of iNO [30]. In these patients who fail to respond to iNO, ECMO therapy should be considered. The goal of this treatment is to maintain adequate tissue oxygen delivery and avoid irreversible lung injury from mechanical ventilation while PVR decreases and pulmonary hypertension resolves.

Criteria for institution of ECMO include an elevated OI that is consistently ≥40. However, because MAPs are higher on HFOV than conventional ventilation, some clinicians wait until OI is ≥60 when HFOV is used.

Most patients with PPHN are weaned from ECMO within seven days [45]. However, two or more weeks occasionally may be necessary for adequate remodeling of the pulmonary circulation in severe cases. Patients who fail to improve may have an irreversible condition, such as alveolar capillary dysplasia (ACD) [46] or severe pulmonary hypoplasia.

In one large series from a single institution from 2000 to 2010, the survival rate following ECMO support was 81 percent [45].

Other vasodilatory agents — Although iNO and ECMO have improved outcome for many infants with PPHN, there still remain those who do not respond to these interventions. In addition, these modalities are expensive and unavailable in many regions of the world.

Sildenafil — Sildenafil, a phosphodiesterase inhibitor type 5, is an agent that has been shown to selectively reduce pulmonary vascular resistance in both animal models and adult humans. It has also been reported to be successful in the treatment of infants with PPHN [47-52].

In a systematic review that included five trials, meta-analysis of three trials that included 77 patients showed enteral sildenafil therapy compared with placebo was associated with a reduction in mortality (RR 0.20, 95% CI 0.07-0.57) and improved oxygen levels [53]. These studies were performed in resource-limited settings, in which iNO and high frequency ventilation were not available.

An open-label dose-escalation trial of a continuous IV infusion of sildenafil was conducted in 36 neonates between 48 hours and 7 days of age with PPHN and an OI >15 [54]. In patients who received higher doses of sildenafil, OI improved from 28.7 to 19.3 after four hours of continuous infusion. There was one death (which was not considered related to sildenafil), and one patient required ECMO. Six of seven infants given sildenafil prior to treatment with iNO survived to discharge with no need for iNO or ECMO. Six treatment-related adverse events were reported in five patients, including five hypotensive episodes (three of which required discontinuation of therapy) and the development of patent ductus arteriosus with left-to-right shunting in one patient.

In 2012, the US Food and Drug Administration (FDA) issued a warning that sildenafil not be prescribed to children with pulmonary arterial hypertension (PAH) because of reports of associated mortality with administration of high doses of sildenafil in children between 1 and 17 years of age, and that low doses of this drug were not effective in improving the exercise ability in these children [55].

However, guidelines from the American Heart Association/American Thoracic Society (AHA/ATS) concluded that sildenafil may be a reasonable adjunctive therapy for infants with PPHN who are refractory to iNO [22].

Because data regarding efficacy and safety are insufficient, we do not recommend enteral sildenafil as initial therapy if iNO is available. It may be considered in a resource-limited setting.

Agents not recommended — The following agents have been used in the management of PPHN, but are not recommended for routine use because of the lack of data regarding efficacy and safety.

Prostacyclin – Inhaled or IV prostacyclin is a potential intervention in patients who fail NO therapy, but is no longer commonly used with the exception of infants who fail to respond to iNO [56-58].

Bosentan – The scant data available on bosentan, an endothelin-1 receptor antagonist, are conflicting regarding efficacy.

A single trial of 47 neonates with PPHN in a setting where iNO and ECMO are unavailable showed bosentan (1 mg/kg given through orogastric tube twice a day) was more effective than placebo in improving OI and oxygen saturation, and in decreasing the time of mechanical ventilation [59].

In contrast, a small trial of 21 infants with PPHN reported no improvement in oxygenation or other outcomes in the group treated with enteral bosentan compared with those who received placebo [60]. This trial was terminated early because of slow recruitment.

However, the small number of subjects and significant differences in study design between the two reports make it difficult to ascertain whether or not there is a role for bosentan, particularly in centers in which iNO and ECMO are not available.

Milrinone – There are no published clinical trials using milrinone, a selective inhibitor of type III cyclic adenosine monophosphate (cAMP) phosphodiesterase isoenzyme in cardiac and vascular muscle with both positive inotrope and vasodilator effects, in the treatment of PPHN [61]. Two small case series from a single tertiary center suggest that milrinone improved oxygenation without compromise of systemic blood pressure [62,63]. As a result, the efficacy and safety of milrinone in the treatment of PPHN are not known. We do not recommend the routine use of milrinone for infants with PPHN.

OUTCOME — The estimated mortality rate in developed countries is between 7 and 10 percent [1,64,65].

In a report based on a state-wide dataset of records from 2005 to 2012, the discharge mortality during birth hospitalization was 6.5 percent and one-year postdischarge mortality was 0.7 percent [65]. There was a 28.6 percent readmittance rate to the hospital within the first year of life for survivors with PPHN compared with 9.8 percent of infants without PPHN. Approximately one-third of readmissions were due to respiratory disease. Adjusted analysis (gestational age, sex, birth weight, and ethnicity) showed survivors compared with controls without PPHN were more likely to have died postdischarge or be readmitted to the hospital within the first year of life (adjusted relative risk [aRR] 3.5, 95% 3.3-3.7). In a subgroup analysis, infants with mild PPHN (no evidence of positive pressure ventilation) were also more likely than those without PPHN to have died or be readmitted within the first year of life (aRR 2.2, 95% CI 2.0-2.5). Of note, infants with congenital pulmonary anomalies (eg, diaphragmatic hernia) who have a higher risk of mortality and morbidity were included in this analysis. As a result, the risk of mortality and readmission may be lower in term infants without congenital pulmonary anomalies. Nevertheless, these data underscore the need for close follow-up for all survivors, even those with mild disease, and ongoing research efforts to identify measures that will prevent PPHN.

Survivors of severe PPHN and/or extracorporeal membrane oxygenation (ECMO) treatment are at increased risk of developmental delay, motor disability, hearing deficits, and chronic health problems compared with individuals without PPHN [66-72]. Inhaled nitric oxide (iNO) does not appear to increase the risk of adverse outcomes, including risk of neurodevelopmental impairment or pulmonary function [66,73,74].

These data draw attention to the need for ongoing follow-up, especially in the first year of life, due to the increased risk of mortality and morbidity even in patients with mild disease.

FOLLOW-UP — As noted above, all survivors of PPHN are at risk for postdischarge mortality and morbidity. As a result, both primary care providers and parents need to be aware of the increased vulnerability of this group of patients. These patients may require more frequent primary care visits than are routinely scheduled. All infants with severe PPHN who have been treated with inhaled nitric oxide (iNO) and/or extracorporeal membrane oxygenation (ECMO) should have neurodevelopmental follow-up [17]. Assessment should be performed through infancy at 6- to 12-month intervals, and longer if abnormalities are present. Hearing should be tested prior to hospital discharge and at 18 to 24 months corrected age. (See "Care of the neonatal intensive care unit graduate".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Persistent pulmonary hypertension in a newborn (The Basics)")

SUMMARY AND RECOMMENDATIONS — Persistent pulmonary hypertension of the newborn (PPHN) occurs when pulmonary vascular resistance (PVR) remains elevated after birth, resulting in right-to-left shunting of blood through fetal circulatory pathways (figure 1) that leads to hypoxemia, which in some cases may be severe and not responsive to conventional respiratory support.

PPHN occurs primarily in term or late preterm infants (gestational age [GA] ≥34 weeks). It is caused by abnormalities of the pulmonary vasculature that include underdevelopment, maldevelopment (ie, abnormally thick pulmonary arteriolar musculature), and maladaption (abnormal vasoconstriction that interferes with the normal postnatal fall in PVR). (See 'Pathogenesis' above.)

Infants with PPHN generally present with cyanosis and respiratory distress (eg, tachypnea). PPHN is associated with prenatal risk factors (fetal heart rate abnormalities and meconium-stained amniotic fluid), and a variety of primary respiratory disorders, such as meconium aspiration syndrome (MAS), pneumonia, respiratory distress syndrome (RDS), congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. (See 'Clinical manifestations' above.)

Initial testing includes pulse oximetry assessment, which may demonstrate a significant difference (>10 percent) between pre- and postductal oxygen saturation, chest radiograph, which is typically normal in patients without another pulmonary condition, and an echocardiogram. (See 'Initial laboratory tests' above.)

The diagnosis of PPHN should be considered in any neonate, especially term infants, with severe cyanosis, and is confirmed by echocardiography. In PPHN, the echocardiogram demonstrates normal structural cardiac anatomy and evidence of pulmonary hypertension (ie, flattened or displaced ventricular septum, or evidence of elevated pulmonary arterial pressure). (See 'Diagnosis' above.)

The differential diagnosis of PPHN includes cyanotic congenital heart disease (CHD), primary pulmonary disorders, and sepsis. (See 'Differential diagnosis' above.)

The management of PPHN consists of general supportive cardiorespiratory care, therapy directed towards associated pulmonary conditions, and in patients with severe PPHN, pulmonary vasodilatory agents (eg, inhaled nitric oxide [iNO]) and extracorporeal membrane oxygenation (ECMO).

Our approach to treating infants with PPHN includes the following:

Because oxygen is a pulmonary vasodilator, we recommend that supplemental oxygen should be initially administered in a concentration of 100 percent to infants with PPHN in an attempt to reverse pulmonary vasoconstriction (Grade 1A). PaO2 should be maintained subsequently in the range of 50 to 90 mmHg (preductal oxygen saturation 90 to 95 percent) to minimize lung toxicity. The oxygenation index (OI) is used to assess the severity of hypoxemia in PPHN and is used to determine whether additional interventions (eg, iNO and ECMO) are warranted (calculator 1). (See 'Oxygen' above.)

Mechanical ventilation to initially maintain PaCO2 between 40 and 50 mmHg, as hypercarbia and acidosis increase PVR. (See 'Assisted ventilation' above.)

Maintenance of adequate systemic blood pressure by providing sufficient vascular volume and the use of inotropic agents. (See 'Circulatory support' above.)

In term and preterm infants with a gestational age greater than 34 weeks and who have severe PPHN, defined as an OI ≥25, we recommend that iNO be administered at a dose of 20 ppm (Grade 1B). (See 'Inhaled nitric oxide' above.)

Because data regarding efficacy and safety are insufficient, we do not recommend enteral sildenafil as initial therapy if iNO is available (Grade 1C). It may be considered in a resource-limited setting. (See 'Sildenafil' above.)

In patients who have an OI ≥40 despite the use of iNO and high ventilatory support, we recommend ECMO (Grade 1C). (See 'Extracorporeal membrane oxygenation' above.)

We recommend that blood cultures should be obtained and empiric antimicrobial therapy initiated (Grade 1C). (See 'General supportive care' above and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Evaluation and initial management'.)

Survivors of severe PPHN and/or ECMO treatment are at increased risk of developmental delay, motor disability, and hearing deficits; and require medical and neurodevelopmental follow-up. (See 'Outcome' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Adams, Jr., MD, who contributed to an earlier version of this topic review.

  1. 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; 105:14.
  2. Mandell E, Kinsella JP, Abman SH. Persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 2021; 56:661.
  3. Levin DL. Morphologic analysis of the pulmonary vascular bed in congenital left-sided diaphragmatic hernia. J Pediatr 1978; 92:805.
  4. Geggel RL, Murphy JD, Langleben D, et al. Congenital diaphragmatic hernia: arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr 1985; 107:457.
  5. Murphy JD, Rabinovitch M, Goldstein JD, Reid LM. The structural basis of persistent pulmonary hypertension of the newborn infant. J Pediatr 1981; 98:962.
  6. Dhillon R. The management of neonatal pulmonary hypertension. Arch Dis Child Fetal Neonatal Ed 2012; 97:F223.
  7. Abman SH. Impaired vascular endothelial growth factor signaling in the pathogenesis of neonatal pulmonary vascular disease. Adv Exp Med Biol 2010; 661:323.
  8. Christou H, Adatia I, Van Marter LJ, et al. Effect of inhaled nitric oxide on endothelin-1 and cyclic guanosine 5'-monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension. J Pediatr 1997; 130:603.
  9. 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; 344:1832.
  10. Van Marter LJ, Leviton A, Allred EN, et al. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996; 97:658.
  11. 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 2001; 107:519.
  12. Van Marter LJ, Hernandez-Diaz S, Werler MM, et al. Nonsteroidal antiinflammatory drugs in late pregnancy and persistent pulmonary hypertension of the newborn. Pediatrics 2013; 131:79.
  13. Curtis J, Kim G, Wehr NB, Levine RL. Group B streptococcal phospholipid causes pulmonary hypertension. Proc Natl Acad Sci U S A 2003; 100:5087.
  14. Steurer MA, Jelliffe-Pawlowski LL, Baer RJ, et al. Persistent Pulmonary Hypertension of the Newborn in Late Preterm and Term Infants in California. Pediatrics 2017; 139.
  15. Aikio O, Metsola J, Vuolteenaho R, et al. Transient defect in nitric oxide generation after rupture of fetal membranes and responsiveness to inhaled nitric oxide in very preterm infants with hypoxic respiratory failure. J Pediatr 2012; 161:397.
  16. Nakanishi H, Suenaga H, Uchiyama A, et al. Persistent pulmonary hypertension of the newborn in extremely preterm infants: a Japanese cohort study. Arch Dis Child Fetal Neonatal Ed 2018; 103:F554.
  17. American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics 2000; 106:344.
  18. Kinsella JP, Truog WE, Walsh WF, et al. Randomized, multicenter trial of inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent pulmonary hypertension of the newborn. J Pediatr 1997; 131:55.
  19. Bhutani VK, Abbasi S, Sivieri EM. Continuous skeletal muscle paralysis: effect on neonatal pulmonary mechanics. Pediatrics 1988; 81:419.
  20. Seri I. Circulatory support of the sick preterm infant. Semin Neonatol 2001; 6:85.
  21. Dempsey EM, Barrington KJ. Treating hypotension in the preterm infant: when and with what: a critical and systematic review. J Perinatol 2007; 27:469.
  22. Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation 2015; 132:2037.
  23. Ostrea EM Jr, Odell GB. The influence of bicarbonate administration on blood pH in a "closed system": clinical implications. J Pediatr 1972; 80:671.
  24. Aschner JL, Poland RL. Sodium bicarbonate: basically useless therapy. Pediatrics 2008; 122:831.
  25. Corbet AJ, Adams JM, Kenny JD, et al. Controlled trial of bicarbonate therapy in high-risk premature newborn infants. J Pediatr 1977; 91:771.
  26. Lawn CJ, Weir FJ, McGuire W. Base administration or fluid bolus for preventing morbidity and mortality in preterm infants with metabolic acidosis. Cochrane Database Syst Rev 2005; :CD003215.
  27. Lotze A, Mitchell BR, Bulas DI, et al. 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; 132:40.
  28. Findlay RD, Taeusch HW, Walther FJ. Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996; 97:48.
  29. González A, Bancalari A, Osorio W, et al. Early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn: a randomized controlled trial. J Perinatol 2021; 41:32.
  30. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997; 336:597.
  31. 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; 101:325.
  32. 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; 342:469.
  33. Roberts JD Jr, Fineman JR, Morin FC 3rd, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med 1997; 336:605.
  34. Kinsella JP, Steinhorn RH, Krishnan US, et al. Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension. J Pediatr 2016; 170:312.
  35. Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2017; 1:CD000399.
  36. 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; 113:559.
  37. Konduri GG, Vohr B, Robertson C, et al. Early inhaled nitric oxide therapy for term and near-term newborn infants with hypoxic respiratory failure: neurodevelopmental follow-up. J Pediatr 2007; 150:235.
  38. Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet 2001; 357:118.
  39. Hamon I, Gauthier-Moulinier H, Grelet-Dessioux E, et al. Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants. Acta Paediatr 2010; 99:1467.
  40. George TN, Johnson KJ, Bates JN, Segar JL. The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates. J Pediatr 1998; 132:731.
  41. Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics 2011; 127:363.
  42. Carey WA, Weaver AL, Mara KC, Clark RH. Inhaled Nitric Oxide in Extremely Premature Neonates With Respiratory Distress Syndrome. Pediatrics 2018; 141.
  43. FDA prescibing information for iNO for hypoxic respiratory faliure. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020845s014lbl.pdf (Accessed on April 24, 2013).
  44. Davidson D, Barefield ES, Kattwinkel J, et al. Safety of withdrawing inhaled nitric oxide therapy in persistent pulmonary hypertension of the newborn. Pediatrics 1999; 104:231.
  45. 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; 177:263.
  46. Somaschini M, Bellan C, Chinaglia D, et al. Congenital misalignment of pulmonary vessels and alveolar capillary dysplasia: how to manage a neonatal irreversible lung disease? J Perinatol 2000; 20:189.
  47. García Martínez E, Ibarra de la Rosa I, Pérez Navero JL, et al. [Sildenafil in the treatment of pulmonary hypertension]. An Pediatr (Barc) 2003; 59:110.
  48. Karatza AA, Narang I, Rosenthal M, et al. Treatment of primary pulmonary hypertension with oral sildenafil. Respiration 2004; 71:192.
  49. Keller RL, Hamrick SE, Kitterman JA, et al. Treatment of rebound and chronic pulmonary hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia. Pediatr Crit Care Med 2004; 5:184.
  50. Baquero H, Soliz A, Neira F, et al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117:1077.
  51. 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; 95:F109.
  52. He Z, Zhu S, Zhou K, et al. Sildenafil for pulmonary hypertension in neonates: An updated systematic review and meta-analysis. Pediatr Pulmonol 2021; 56:2399.
  53. Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2017; 8:CD005494.
  54. Steinhorn RH, Kinsella JP, Pierce C, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009; 155:841.
  55. FDA Drug Safety Communication: FDA recommends against use of Revatio in children with pulmonary hypertension. http://www.fda.gov/Drugs/DrugSafety/ucm317123.htm (Accessed on August 31, 2012).
  56. Kelly LK, Porta NF, Goodman DM, et al. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. J Pediatr 2002; 141:830.
  57. Golzand E, Bar-Oz B, Arad I. Intravenous prostacyclin in the treatment of persistent pulmonary hypertension of the newborn refractory to inhaled nitric oxide. Isr Med Assoc J 2005; 7:408.
  58. Ahmad KA, Banales J, Henderson CL, et al. Intravenous epoprostenol improves oxygenation index in patients with persistent pulmonary hypertension of the newborn refractory to nitric oxide. J Perinatol 2018; 38:1212.
  59. Mohamed WA, Ismail M. A randomized, double-blind, placebo-controlled, prospective study of bosentan for the treatment of persistent pulmonary hypertension of the newborn. J Perinatol 2012; 32:608.
  60. Steinhorn RH, Fineman J, Kusic-Pajic A, et al. Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial. J Pediatr 2016; 177:90.
  61. Bassler D, Kreutzer K, McNamara P, Kirpalani H. Milrinone for persistent pulmonary hypertension of the newborn. Cochrane Database Syst Rev 2010; :CD007802.
  62. McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. J Crit Care 2006; 21:217.
  63. McNamara PJ, Shivananda SP, Sahni M, et al. Pharmacology of milrinone in neonates with persistent pulmonary hypertension of the newborn and suboptimal response to inhaled nitric oxide. Pediatr Crit Care Med 2013; 14:74.
  64. Lipkin PH, Davidson D, Spivak L, et al. Neurodevelopmental and medical outcomes of persistent pulmonary hypertension in term newborns treated with nitric oxide. J Pediatr 2002; 140:306.
  65. Steurer MA, Baer RJ, Oltman S, et al. Morbidity of Persistent Pulmonary Hypertension of the Newborn in the First Year of Life. J Pediatr 2019; 213:58.
  66. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up of the neonatal inhaled nitric oxide study group (NINOS). J Pediatr 2000; 136:611.
  67. Ellington M Jr, O'Reilly D, Allred EN, et al. Child health status, neurodevelopmental outcome, and parental satisfaction in a randomized, controlled trial of nitric oxide for persistent pulmonary hypertension of the newborn. Pediatrics 2001; 107:1351.
  68. Rosenberg AA, Kennaugh JM, Moreland SG, et al. Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension. J Pediatr 1997; 131:70.
  69. Robertson CM, Finer NN, Sauve RS, et al. Neurodevelopmental outcome after neonatal extracorporeal membrane oxygenation. CMAJ 1995; 152:1981.
  70. Cohen DA, Nsuami M, Etame RB, et al. A school-based Chlamydia control program using DNA amplification technology. Pediatrics 1998; 101:E1.
  71. Fligor BJ, Neault MW, Mullen CH, et al. Factors associated with sensorineural hearing loss among survivors of extracorporeal membrane oxygenation therapy. Pediatrics 2005; 115:1519.
  72. Eriksen V, Nielsen LH, Klokker M, Greisen G. Follow-up of 5- to 11-year-old children treated for persistent pulmonary hypertension of the newborn. Acta Paediatr 2009; 98:304.
  73. Rosenberg AA, Lee NR, Vaver KN, et al. School-age outcomes of newborns treated for persistent pulmonary hypertension. J Perinatol 2010; 30:127.
  74. Dobyns EL, Griebel J, Kinsella JP, et al. Infant lung function after inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn. Pediatr Pulmonol 1999; 28:24.
Topic 5045 Version 43.0

References