Clinical features and diagnosis of meconium aspiration syndrome

Author Joseph A Garcia-Prats, MD Section Editor Steven A Abrams, MD Deputy Editor Melanie S Kim, MD

Last literature review version 19.1: January 2011 | This topic last updated: October 6, 2010 (More)

INTRODUCTION Meconium aspiration syndrome (MAS) is defined as respiratory distress in newborn infants born through meconium-stained amniotic fluid (MSAF) whose symptoms cannot be otherwise explained [1]. MAS can present with varying degrees of severity from mild respiratory distress to life-threatening respiratory failure.

The clinical features and diagnosis of MAS will be discussed here. The management and complications of MAS are discussed elsewhere. (See "Prevention and management of meconium aspiration syndrome".)

EPIDEMIOLOGY In the United States, a retrospective multi-center study of 162,075 term infants born between 1997 and 2007 reported 1.8 percent of infants had an admission diagnosis of MAS [2].

MAS occurs in about 2 to 10 percent of infants born through MSAF. This was illustrated in a study from a single tertiary center of 20,047 live births between 1994 and 1998 that reported MSAF occurring in 9.2 percent and MAS in 0.1 percent of all live births [3].

This ten-fold difference in the incidence of MAS may be due to differences between the two studies in the rigor that MAS was diagnosed and measures used to prevent MAS.

(See "Prevention and management of meconium aspiration syndrome", section on 'Prevention'.)

The reported incidence of MSAF rises with increasing gestational age as follows [4]:

Preterm infants (<37 weeks gestation): 5 percentTerm infants: 7 to 22 percentPost term (>42 weeks gestation): 23 to 52 percent

The risk of MAS and MSAF is greatest in postmature infants and small for gestational age [5]. Changes in obstetric care, especially a reduction in postmature births, appear to be associated with a decrease in the incidence of MAS. This was illustrated in the following studies:

In a prospective study of 1365 infants 37 weeks gestational age born through MSAF at a single center from 1990 to 1998, MAS decreased nearly fourfold (5.8 to 1.5 percent in 1990 to 1992 and 1997 to 1998, respectively) [6]. This was associated with a significant reduction in births 41 weeks gestation (42 to 28 percent), as well as increased use of amnioinfusion, diagnosis of nonreassuring fetal heart rate patterns, and cesarean delivery. A significant decrease in the incidence of severe MAS (requiring intubation and mechanical ventilation) was also noted over an eight-year period in Australia and New Zealand from 1995 to 2002 [7]. The lowest incidence was 0.35 per 1000 live births in 2002. The lower incidence was attributed to improving obstetrical management with fewer deliveries beyond 41 weeks gestation and fewer infants with five-minute Apgar scores of less than seven (calculator 1). These two changes accounted for approximately 62 percent of the reduction in severe MAS cases.

PATHOPHYSIOLOGY The pathophysiology of MAS involves intrauterine passage of meconium, aspiration, and pulmonary disease, which results in hypoxemia and acidosis (figure 1). Persistent pulmonary hypertension of the newborn (PPHN) frequently accompanies severe MAS and contributes to hypoxemia [8]. (See "Persistent pulmonary hypertension of the newborn".)

Birth depression occurs in 20 to 33 percent of infants born through MSAF [9-11] and likely is caused by pathologic intrauterine processes, primarily chronic asphyxia and infection. This intrauterine stress leads to the passage and aspiration of meconium by the fetus.

Composition of meconium Meconium is a thick, black-green, odorless material first demonstrable in the fetal intestine during the third month of gestation. Meconium results from the accumulation of debris, including desquamated cells from the intestine and skin, gastrointestinal mucin, lanugo hair, fatty material from the vernix caseosa, amniotic fluid, and intestinal secretions. It contains blood group-specific glycoproteins and a small amount of lipid and protein that decreases during gestation [12,13]. The black-green color results from bile pigments.

Meconium is sterile. However, when aspirated into the lung, it may stimulate the release of cytokines and other vasoactive substances that lead to cardiovascular and inflammatory responses in the fetus and newborn [14,15]. In patients with MAS, pulmonary function improves with the fall of pro-inflammatory cytokines over the first 96 hours of life [16]. There is also animal data that implicates pancreatic phospholipase A2 as a potential source of the lung [17].

Meconium passage Passage of meconium occurs early in the first trimester of pregnancy [18]. Fetal defecation slows after 16 weeks gestation and becomes infrequent by 20 weeks, concurrent with innervation of the anal sphincter [19]. From approximately 20 to 34 weeks, fetal passage of meconium remains infrequent [20]. Almost all fetuses and newborn infants who pass meconium are at term or postterm gestation.

Meconium passage may be caused by increased peristalsis and relaxation of the anal sphincter due to increased vagal outflow associated with umbilical cord compression or increased sympathetic inflow during hypoxia [21-24]. In one study, fetuses that passed meconium prior to birth had higher motilin levels in cord blood compared to those who did not [24]. The higher levels of motilin, a regulatory intestinal peptide, were thought to be related to increased parasympathetic tone due to fetal hypoxia. (See "Overview of the development of the gastrointestinal tract", section on 'Hormonal regulation'.)

Aspiration Meconium in amniotic fluid can be aspirated during fetal gasping or in the initial breaths after delivery. Normally, fetal breathing activity results in movement of lung fluid out of the trachea [25]. However, as shown in animals, prolonged hypoxia stimulates fetal breathing and gasping that can lead to inhalation of amniotic fluid [2529]. Pathologic evidence suggests that this process also occurs in humans. Meconium has been found in the lungs of infants who were stillborn [30] or who died soon after birth without a history of aspiration at delivery [31,32].

Meconium that remains in the hypopharynx or trachea after delivery can be aspirated during the initial breaths. This is more likely to occur in a depressed infant.

Pulmonary disease Aspirated meconium can interfere with normal breathing by several mechanisms. They include airway obstruction, chemical irritation and inflammation, infection, and surfactant inactivation. However, it is likely that most cases of severe MAS are primarily caused by intrauterine pathologic processes, primarily asphyxia and infection, rather than the aspiration of meconium by itself [33].

Airway obstruction Airway obstruction can be complete or partial. Complete obstruction leads to distal atelectasis. Partial airway obstruction occurs when particulate meconium partly occludes the airway. Because the airway diameter is larger in inspiration, gas can enter around the partial obstruction. However, as the airway narrows during exhalation, the meconium plug occludes the airway completely, trapping the gas distally. This process is known as a ball valve effect and can lead to overdistention of the lung and alveolar rupture, with resulting pneumothorax or other air leak complications [34,35]. (See "Pulmonary air leak in the newborn".)

Chemical irritation and inflammation Components of meconium cause inflammation of the lung that is apparent 24 to 48 hours after inhalation. Direct injury and inflammation result in an exudative and inflammatory pneumonitis with epithelial disruption, proteinaceous exudation with alveolar collapse, and cellular necrosis [35-39]. In animal studies, pancreatic phospholipase A2 appears to directly contribute to lung injury [17].

Infection MSAF is a risk factor for bacterial infection of the amniotic cavity and should alert the clinician to the potential for increased neonatal morbidity [40-42] Although meconium is sterile, the mucopolysaccharide component provides an excellent growth medium for microorganisms, especially Escherichia coli [43]. Meconium also may inhibit phagocytosis by polymorphonuclear cells and their oxidative burst [44]. (See "Neonatal pneumonia".)

Surfactant Several studies have shown the deleterious effects of meconium on surfactant metabolism.

Increased inactivation Animal models of meconium aspiration demonstrate inactivation of surfactant with increased surface tension, and decreased lung volume, compliance, and oxygenation [45-49]. In human infants, concentrations of surfactant inhibitors (eg, total protein, albumin, membrane-derived phospholipid) were higher in lung lavage fluid in those with MAS than in controls [36]. However, surfactant phospholipid and surfactant protein A levels were not different. In addition, several meconium components (eg, free fatty acids) have a higher minimal surface area and may displace surfactant from the alveolar surface. Decreased synthesis In a small study, there was a trend toward lower surfactant synthesis in neonates with MAS or persistent pulmonary hypertension (PPHN) who required extracorporeal membrane oxygenation, compared to control infants who required ventilatory support for nonpulmonary indications [50]. Lower tracheal aspirate concentrations of

phosphatidylcholine (PC), a component of surfactant, and lower incorporation of radiolabeled carbon in PC were seen in infants with MAS or PPHN compared to controls.

Hypoxemia Hypoxemia results from several causes, including decreased alveolar ventilation related to lung injury, and ventilation-perfusion imbalance with continued perfusion of poorly ventilated lung units. PPHN frequently accompanies MAS, with rightto-left shunting caused by increased pulmonary vascular resistance, and resultant hypoxemia. (See "Persistent pulmonary hypertension of the newborn".)

CLINICAL FEATURES In addition to the pulmonary manifestations of MAS, the following features are seen:

A history of MSAF or evidence of meconium staining on physical examination of the infant. The vernix, umbilical cord, and nails may be meconium-stained, depending upon how long the infant has been exposed in utero [51]. In general, nails will become stained after six hours and vernix after 12 to 14 hours of exposure.Birth depression occurs in 20 to 33 percent of infants born through MSAF [9-11,52]. These infants have neurologic and/or respiratory depression at birth typically due to hypoxia or shock [52]. (See "Etiology, clinical manifestations, and evaluation of neonatal shock".)Affected infants are frequently small for gestational age or postmature [5]. Characteristic findings of postmaturity include peeling skin, long fingernails, and decreased vernix. (See "Small for gestational age infant" and "Postterm infant".)

Pulmonary findings Infants with MAS typically have respiratory distress with marked tachypnea and cyanosis. Reduced pulmonary compliance and use of accessory muscles of respiration are evidenced by intercostal and subxiphoid retractions and abdominal (paradoxical) breathing, often with grunting and nasal flaring.

Infants who develop MAS exhibit signs of respiratory distress immediately after birth. In a study of 394 term infants with MSAF, MAS developed in 18 patients with Apgar scores <8 (19 percent) and in one patient with an Apgar score 9 (0.3 percent) *53+. All 19 patients had signs of respiratory distress within 15 minutes of birth, which required ventilatory support in 16 of the infants. These results demonstrate that full-term infants with MSAF without any sign of respiratory distress or depression immediately after birth are unlikely to develop MAS.

Affected infants typically have a barrel-shaped chest with an increased anteriorposterior diameter caused by overinflation. Auscultation reveals rales and rhonchi. These signs usually are seen immediately after birth. However, some patients are asymptomatic at birth and develop worsening signs of pulmonary decompensation as the meconium moves from the large airways into the lower tracheobronchial tree.

In patients with severe MAS, pneumothorax and pneumomediastinum are common findings. Patient with severe disease are at risk for respiratory failure, which is often associated with persistent pulmonary hypertension (PPHN). Infants with pulmonary hypertension and right-to-left shunting may have a gradient in oxygenation between preductal and postductal arterial blood samples. In addition, echocardiography may demonstrate right-to-left shunting. (See "Pulmonary air leak in the newborn", section on 'Risk factors' and "Persistent pulmonary hypertension of the newborn", section on 'Maladaptation'.)

DIAGNOSIS The diagnosis of MAS is made by the following clinically based findings:

There is evidence of meconium-stained amniotic fluid (MSAF) or infant (See 'Clinical features' above.)Respiratory distress at birth or shortly after birth (See 'Pulmonary findings' above.)Characteristic radiographic features. The initial chest film may show streaky, linear densities similar in appearance to transient tachypnea of the newborn. As the disease progresses, the lungs typically appear hyperinflated with flattening of the diaphragms [54-56]. Diffuse patchy densities may alternate with areas of expansion. In infants with severe disease who require high concentrations of supplemental oxygen and mechanical ventilation, the lungs may develop an appearance of homogeneous density similar to respiratory distress syndrome. Radiographic changes resolve over the course of 7 to 10 days but sometimes persist for several weeks. Air leak occurs in 10 to 30 percent of infants with MAS [10,57]. (See "Transient tachypnea of the newborn" and "Pulmonary air leak in the newborn", section on 'Risk factors'.)If the infant requires intubation because of depression, the diagnosis is made by the presence of meconium in the trachea. (See "Prevention and management of meconium aspiration syndrome", section on 'Neonatal care'.)

Although arterial blood gas measurements typically demonstrate hypoxemia and hypercarbia, these findings are nonspecific and are not used to diagnosis MAS. However, arterial blood gas measurements and pulse oximetry are used to assess the respiratory status of the infant. (See 'Evaluation' below.)

DIFFERENTIAL DIAGNOSIS The differential diagnosis of MAS includes other causes of neonatal respiratory distress, which occur in 4 to 9 percent of infants born through MSAF [52]. They include:

Transient tachypnea of the newborn (60 percent) Delayed transition from fetal circulation (18 percent) Sepsis or pneumonia (11 percent) Persistent pulmonary hypertension of the newborn (3 percent) Miscellaneous conditions, including pulmonary edema, pneumothorax, hypovolemia, blood aspiration (8 percent)

MAS is distinguished from these based on the history, clinical course, and radiographic findings as follows:

Transient tachypnea of the newborn (TTN) is a frequent cause of respiratory distress in late preterm infants (34 to 37 weeks gestation), whereas MAS is most frequently seen in postmature infants (>41 weeks gestation). In addition, patients with TTN improve quickly in contrast to those with MAS. (See "Transient tachypnea of the newborn".)Infants with delayed transition from fetal circulation improve quickly in comparison to those with MAS. (See "Physiologic transition from intrauterine to extrauterine life".)Respiratory distress syndrome (RDS) generally occurs in preterm infants, whereas MAS usually occurs in postmature infants. (See "Pathophysiology and clinical manifestations of respiratory distress syndrome in the newborn", section on 'Clinical manifestations'.)Pneumonia may be difficult to differentiate from MAS. As a result, infants with presumed MAS are treated with antibiotics while awaiting the results of cultures. (See "Neonatal pneumonia" and "Prevention and management of meconium aspiration syndrome" and "Prevention and management of meconium aspiration syndrome", section on 'Antibiotics'.)Congenital cyanotic heart disease is differentiated from MAS by physical examination, chest radiography, and echocardiography. (See "Evaluation and initial management of cyanotic heart disease in the newborn".)Isolated air leaks such as pneumothorax is differentiated from MAS by history (absence of meconium-stained amniotic fluid) and chest radiography. (See "Pulmonary air leak in the newborn", section on 'Risk factors'.)

EVALUATION The evaluation for suspected MAS includes the following:

Chest

radiograph

is

used

in

confirming

the

diagnosis

of

MAS

(See

'Diagnosis' above.)Arterial blood gas is used to assess the respiratory status of the affected neonate. It is used to determine whether mechanical ventilation is indicted in patients with severe respiratory distress. Pulse oximetry is used to continue to monitor the infants oxygenation. (See "Mechanical ventilation in neonates", section on 'Indications for ventilation' and "Oxygen monitoring and therapy in the newborn", section on 'Pulse oximetry'.) Echocardiography may be indicated in patients with severe respiratory distress to exclude the diagnosis of structural heart disease, and to identify patients with persistent pulmonary hypertension (PPHN). In PPHN, echocardiography demonstrates normal structural anatomy with evidence of pulmonary hypertension (eg, flattened or displaced ventricular septum) and right-to-left shunting. (See "Persistent pulmonary hypertension of the newborn", section on 'Electrocardiogram'.)Because it is difficult to differentiate MAS from pneumonia, blood cultures and, if possible, tracheal aspirate cultures are obtained. Empiric antibiotic therapy is started while awaiting culture results. (See "Treatment and outcome of sepsis in term and late preterm infants", section on 'Empiric antibiotic therapy'.)

SUMMARY AND RECOMMENDATIONS Meconium aspiration syndrome (MAS) is defined as respiratory distress in an infant born through meconium-stained amniotic fluid (MSAF) whose symptoms cannot be otherwise explained. MAS can present with varying degrees of severity from mild respiratory distress to life-threatening with respiratory failure.

With changes in obstetric care, the incidence of MAS has declined to about 0.1 to 1.8 percent of live births in developed countries. Risk factors for MAS include postmaturity and small for gestational age. (See 'Epidemiology' above.)The pathophysiology of MAS involves intrauterine passage of meconium, aspiration, and pulmonary disease resulting in hypoxemia, acidosis, and potentially pulmonary hypertension (figure 1). Pulmonary disease is a result of aspirated meconium interfering with normal lung function due to airway obstruction, chemical irritation and inflammation, and deleterious effects on surfactant metabolism (ie, inactivation and reduced production). (See

'Pathophysiology' above.)Infants with MAS typically have a history of MSAF or evidence

of meconium staining on physical examination. They are frequently small for gestational age or postmature. Many infants with MAS also have neurologic or respiratory depression due to perinatal hypoxia. (See 'Clinical features' above.)Patients present with respiratory distress with marked tachypnea, cyanosis, intercostal and subxiphoid retractions, abdominal breathing, grunting, and nasal flaring. The chest appears barrelshaped (increase anterior-posterior diameter) due to overinflation. In patients with severe MAS, complications include air leaks (eg, pneumothorax) and persistent pulmonary hypertension (PPHN). (See 'Pulmonary disease' above and "Pulmonary air leak in the newborn" and "Persistent pulmonary hypertension of the newborn".)The diagnosis of MAS is based on the clinical findings of MSAF or meconium-stained infant, respiratory distress, and characteristic radiographic features. The radiologic findings are initially streaky, linear densities, followed by hyperinflation, and alternating diffuse patchy densities with areas of expansion. In patients who require intubation, the diagnosis is established by the presence of meconium in the trachea. (See 'Diagnosis' above.)MAS is differentiated from other causes of neonatal respiratory distress (eg, transient tachypnea of the newborn, neonatal pneumonia, and congenital cyanotic heart disease) based upon the history, physical examination, clinical course, and radiographic findings. (See 'Differential diagnosis' above.)The evaluation of suspected MAS includes chest radiography, arterial blood gas and pulse oximetry, blood cultures, and if possible, tracheal aspirate cultures. In patients with more severe disease, an echocardiography may be indicated to exclude structural heart disease and/or PPHN. (See 'Evaluation' above.)

A newer version of UpToDate is now available, and the information in this version may no longer be current.Persistent pulmonary hypertension of the newborn

Authors James M Adams, Jr, MD Ann R Stark, MD Section Editor Joseph A Garcia-Prats, MD Deputy Editor Melanie S Kim, MD

Last literature review version 19.1: January 2011 | This topic last updated: September 23, 2010 (More)

INTRODUCTION 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. 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].

PHYSIOLOGY The fetal circulation operates in parallel. Both the right and left ventricles eject blood into the aorta with subsequent perfusion of the placenta, the fetal organ of respiration (figure 1). The right ventricle 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 postnatal (adult) 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 adult 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 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 oxygenation, 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.

PATHOPHYSIOLOGY 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 [2-4].

Underdevelopment In abnormalities of underdevelopment, the cross sectional area of the pulmonary vasculature is reduced, resulting in a relatively fixed elevation of PVR. Underdevelopment occurs with pulmonary hypoplasia associated with a variety of conditions. They include congenital diaphragmatic hernia (CDH), cystic adenomatoid malformation of the lung, renal agenesis, oligohydramnios accompanying obstructive uropathy, and intrauterine 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.

Maldevelopment Maldevelopment occurs in the setting of normal development of the lung, including branching and alveolar differentiation, and the normal number of pulmonary vessels. However, the muscle layer of the pulmonary arterioles is abnormally thick and extends into small vessels that normally have thin walls and no muscle cells [4]. 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 to 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) [5].

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 had lower plasma concentrations of arginine, a precursor of NO and a urea cycle intermediate, and NO metabolites than control infants with respiratory distress [6]. 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 pulmonary hypertension, than in the general population.

Conditions associated with PPHN caused by vascular maldevelopment include post-term delivery, meconium staining, and meconium aspiration syndrome. In these disorders, the pulmonary vasculature responds poorly to stimuli that normally result in a decrease in PVR, such as increased oxygen levels and the establishment of ventilation. (See "Clinical features and diagnosis of meconium aspiration syndrome".)

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 antiinflammatory drugs) or foramen ovale, high placental vascular resistance, and total anomalous pulmonary venous drainage. Use of nonsteroidal antiinflammatory drugs (NSAIDs) in pregnancy is associated with PPHN, probably caused by ductal constriction in the fetus. In a case-control study, PPHN was significantly associated with the presence in meconium of aspirin (odds ratio [OR] 8.1, 95% CI 3.3-20.1), ibuprofen (OR 12.9, 95% CI 3.9-42.3), naproxen (OR 3.3, 95% CI 1.29.3), or at least one NSAID (aspirin, ibuprofen, naproxen, indomethacin) (OR 21.5, 95% CI 7.1-64.7) [7].

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, pulmonary hypertension was induced by infusion of cardiolipin and phosphatidylglycerol, phospholipids located primarily in the cell wall of GBS [8]. (See "Group B streptococcal infection in neonates and young infants".)

CLINICAL FEATURES The clinical features of PPHN were described in a study of 385 infants with the disorder admitted to the neonatal intensive care units of the participating centers in the National Institute of Child Health and Human Development Neonatal Research Network [1]. The diagnosis of PPHN was documented by echocardiogram or a difference between the preductal and postductal arterial oxygen tension. Infants included in the study received 50 percent inspired oxygen concentration and/or mechanical ventilation.

Many of the newborns were considered to be at high risk for an abnormal initial course [1]. Amniotic fluid was meconium-stained in 50 percent of cases, and fetal heart rate abnormalities occurred in 49 percent of those who had antenatal monitoring. Delivery was by cesarean delivery in 51 percent and without labor in approximately one-third. Infants often were depressed at birth. Apgar scores were 5 at one and five minutes in 54 and 21 percent, respectively.

The majority of infants had respiratory diagnoses associated with PPHN, although the condition was considered idiopathic in 17 percent [1]. The primary respiratory diagnoses were:

Meconium aspiration syndrome (41 percent)Pneumonia (14 percent)Respiratory distress syndrome (RDS, 13 percent)Pneumonia and/or RDS, when they could not be distinguished (14 percent)Congenital diaphragmatic hernia (CDH, 10 percent)Pulmonary hypoplasia (4 percent)

In utero exposure of selective serotonin receptor inhibitors (SSRIs) during the second half of pregnancy has been associated with a six-fold increased risk of PPHN compared to nonexposed infants. (See "Infants with antenatal exposure to serotonin reuptake inhibitors", section on 'Persistent pulmonary hypertension'.)

DIAGNOSIS The diagnosis of PPHN should be considered in any infant with severe cyanosis. In affected patients, arterial oxygenation typically improves little or not at all in response to 100 percent inspired oxygen concentration, increased mean airway pressure with continuous positive airway pressure, or high inspiratory pressures with positive pressure ventilation. Other diagnoses that must be considered include uncomplicated pulmonary parenchymal disease, infection, structural heart disease, and myocardial dysfunction.

Physical examination The physical examination usually is not helpful in establishing the diagnosis, although it may show signs of associated conditions, such as respiratory disorders or meconium staining of skin and nails. Infants with PPHN may have 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.

Chest radiograph As with the physical examination, the chest radiograph is more helpful in identifying associated pulmonary disorders, such as parenchymal disease, air leak, or CDH. The heart size typically is normal or slightly enlarged. Pulmonary blood flow may appear normal or reduced.

Electrocardiogram The electrocardiogram may be normal for age, with right ventricular predominance. Signs of myocardial ischemia, such as ST segment elevation, may be present in infants with perinatal depression.

Arterial blood gas An arterial blood gas sample typically will show low partial pressure of oxygen (PaO2 below 100 mmHg in 100 percent inspired oxygen concentration). 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 PCO2 is normal in infants without accompanying lung disease.

A right-to-left shunt through the ductus arteriosus can be documented by a difference in oxygen tension between preductal and postductal arterial blood gas samples. These samples usually are obtained from the right radial artery and the umbilical artery, after

placement of an umbilical artery catheter. Alternatively, a transcutaneous oxygen monitor can be used. A difference between preductal and postductal (right thumb and either great toe) oxygen saturation also supports the diagnosis. (See "Oxygen monitoring and therapy in the newborn".)

It is important to recognize that the absence of a preductal 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 ductus arteriosus.

Echocardiography The definitive diagnosis of PPHN is made by echocardiography. Echocardiography is essential in any infant with severe and unremitting hypoxemia to exclude the diagnosis of structural heart disease and detect myocardial dysfunction, if present.

In PPHN, echocardiography demonstrates normal structural anatomy with evidence of pulmonary hypertension, such as a flattened or displaced ventricular septum. Doppler studies show right-to-left shunting through the ductus arteriosus and/or foramen ovale. Continuous-wave Doppler sampling of the velocity of a jet of tricuspid insufficiency, if present, can be used to estimate pulmonary artery pressure.

MANAGEMENT The management of PPHN is largely supportive. It is directed toward promoting a progressive decline in the ratio of PVR to SVR and to maintaining adequate tissue oxygenation until PVR falls. Specific treatment is provided for any associated parenchymal lung disease.

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. All ill newborns should be cared for in a neutral thermal environment to minimize oxygen consumption. (See "Overview of neonatal respiratory distress: Disorders of transition".)

Oxygen Oxygen is a pulmonary vasodilator and initially should be administered in a concentration of 100 percent to infants with PPHN in an attempt to reverse pulmonary vasoconstriction. However, there is no advantage to maintaining an elevated PaO2. Thus, the PaO2 should be kept in the range of 50 to 90 mmHg (oxygen saturation >90 percent) to provide adequate tissue oxygenation and avoid lung injury that may result from continued administration of high concentrations of oxygen. Particular care should be taken to avoid persistent hyperoxemia in the occasional premature infant with PPHN.

Assisted ventilation Because hypercarbia and acidosis increase PVR, we initially attempt to establish and maintain normal ventilation (PaCO2 35 to 40 mmHg). In the above study of practice and outcomes in PPHN prior to the availability of inhaled nitric oxide (iNO), hyperventilation was used in two-thirds of patients, although this intervention has not been tested in a controlled trial [1]. As the infant's ventilatory status becomes 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 ventilationperfusion imbalance. As a result, hypoxemia may not respond to conventional ventilator maneuvers. In this circumstance, strategies that elevate mean airway pressure may impede cardiac output and increase PVR. Thus, we minimize mean airway pressure by using low inspiratory pressures and short inspiratory times.When PPHN is associated with lung disease, atelectasis and the resulting maldistribution of ventilation may exacerbate high PVR. Assisted ventilation is used to recruit atelectatic segments, maintain adequate resting lung volume, and ensure appropriate oxygenation and ventilation. When lung disease is severe, we usually use high-frequency oscillatory ventilation (HFOV). In a randomized trial of HFOV and iNO in severe PPHN, 23 percent of patients initially assigned to HFOV recovered without crossover to iNO with conventional mechanical ventilation or to iNO with HFOV [9]. (See below).

Surfactant Surfactant should be administered to infants with RDS. It also should be considered for improvement of alveolar recruitment in infants with other pulmonary conditions (eg, sepsis, pneumonia, or meconium aspiration syndrome) in which surfactant function may be impaired [10,11]. In a randomized trial in term infants with severe respiratory failure, surfactant administration significantly reduced the need for ECMO therapy (29 versus 40 percent with placebo), without increasing the risk of complications [11]. However, there seemed to be no effect when PPHN was the primary diagnosis (30 versus 32 percent).

Sedation Infants with PPHN may breathe out of synchrony with the ventilator and be agitated. Agitation may cause catecholamine release that results in increased PVR. Thus, we use an opioid analgesic such as morphine sulfate (loading dose of 100 to 150 mcg/kg over one hour, then 10 to 20 mcg/kg per hour, IV) or fentanyl (1 to 5 mcg/kg per hour).

If dyssynchronous breathing persists and a specific cause cannot be identified (eg, airway obstruction or air leak), we use neuromuscular blockade with pancuronium (0.1 mg/kg IV push, as needed). However, we limit this intervention as much as possible because of potential adverse effects. In the survey of practice variation and outcome, neuromuscular blockade appeared to be associated with increased risk of death (odds ratio 2.8, 95% CI 1.1-7.2) that exceeded the mortality risk associated with either HFOV or extracorporeal membrane oxygenation (ECMO); however, the difference did not remain significant when infants with CDH were removed from the analysis [1]. Prolonged skeletal muscle paralysis may also reduce functional residual capacity and pulmonary compliance [12].

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:

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

In most cases when the OI is used, the infant is receiving an inspired oxygen concentration (FiO2) of 1.0. Thus, the OI can be calculated easily from the mean airway

pressure displayed on the ventilator and the 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 HFOV, iNO, and ECMO are readily available [13].

Circulatory support Because PVR is elevated in PPHN, decreased SVR or poor cardiac output that result in decreased mean systemic blood pressure can increase right-to-left shunting. Thus, circulatory support usually is needed in severely affected patients. An adequate vascular volume should be maintained with intravenous 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 [14]. Dopamine has been the most commonly used medication use in neonates requiring pharmacologic inotropic support. We begin with dopamine (2.5 to 10 mcg/kg per min IV) and titrate the infusion rate to maintain the mean arterial blood pressure at a level that minimizes right-to-left shunting (typically >50 mmHg). Alternative agents include dobutamine [15] and norepinephrine [16].

Correction of acidosis Acidosis increases PVR and should be corrected. However, alkali infusion to maintain alkalosis is not recommended. In the study of practice and outcomes, alkali infusion was used in 74 percent of patients [1]. However, infants treated with alkali infusion compared to those treated with hyperventilation appeared to be more likely to need ECMO and require oxygen supplementation at 28 days. It is unclear if these observations reflect an adverse effect of alkali therapy or increased severity of disease in those who received alkali therapy [17-27].

Inhaled nitric oxide Endogenous NO regulates vascular tone by causing relaxation of vascular smooth muscle. When inhaled, NO is a selective pulmonary vasodilator.

Administration of inhaled NO (iNO) decreases the pulmonary artery pressure and pulmonary-to-systemic arterial pressure ratio [17]. 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.

Inhaled NO improves oxygenation and reduces the need for ECMO in term and late preterm infants with severe PPHN and does not appear to have toxicity [9,18-22]. A large and well-designed multicenter trial was conducted by the Neonatal Research Network in 235 infants with gestational age 34 weeks who had severe hypoxic respiratory failure (OI 25) and did not have CDH *18+. Echocardiography was performed in most infants before randomization and demonstrated pulmonary hypertension in 78 percent. Infants were randomly assigned to iNO (initial dose 20 ppm) or control (100 percent oxygen). Fewer infants treated with iNO died within 120 days or received ECMO therapy, (46 versus 64 percent; relative risk 0.72, 95% CI 0.57-0.91) compared to control. This difference was entirely due to decreased requirement for ECMO (39 versus 54 percent); there was no difference between groups in mortality.

Similar findings (less requirement for ECMO and no difference in mortality) were noted in another large randomized trial [20] and in a systematic review by the Cochrane database of 12 randomized controlled trials [22]. In the Cochrane review, iNO improved oxygenation in approximately one-half of infants who received the drug [22]. Within 30 to 60 minutes of beginning therapy, PaO2 increased by a mean of 53 mmHg and OI decreased by a mean of 15.1. Outcome did not appear to be affected by whether infants had echocardiographic evidence of PPHN, but no benefit was noted in those with congenital diaphragmatic hernia. (See 'Congenital diaphragmatic hernia' below.)

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 relatively safe if high iNO doses are avoided and appropriately monitored [22,28]. 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 [23].

In a randomized trial, early initiation of iNO in infants with mild to moderate respiratory impairment with OI between 15 and 25 compared to routine initiation at OI > 25 did not reduce the incidence of mortality or the need for ECMO therapy [24]. It also did not affect the outcomes of neurodevelopment and hearing of surviving infants evaluated at 18 to 24 months of age [25]. 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.

Congenital diaphragmatic hernia Inhaled NO does not appear to be of long-term benefit in infants with CDH [22,26]. In the one trial that specifically addressed this issue, 53 infants with CDH and hypoxemic respiratory failure (OI 25) and 34 weeks gestational age were randomly assigned to receive iNO (20 ppm) or control (100 percent oxygen). Death before 120 days or need for ECMO was not significantly different in iNO or control groups (96 versus 82 percent, respectively). ECMO use occurred significantly more in the iNO group (80 versus 54 percent, respectively), although the proportion of infants who died was not different (48 versus 43 percent, respectively). No significant changes in PaO2 or OI were detected 30 minutes after starting iNO. However, a transitory improvement occurred in approximately one-half of the infants treated with iNO, suggesting that this intervention might be helpful in stabilizing some patients for transport and initiation of ECMO.

Recommendations Recommendations for the use of iNO in infants with severe hypoxemic respiratory failure have been published by the American Academy of Pediatrics [13]. They include:

Care of patients in centers with personnel experienced with multiple modes of respiratory support, rescue therapies, and use of iNOAvailability of ECMO at the center, or an established mechanism for timely transfer of infants to an ECMO centerPerformance of an echocardiogram to exclude the diagnosis of congenital heart disease.Use of iNO according to the indications, dosing, administration, and monitoring guidelines on the product label.

We begin iNO therapy in term or late preterm infants (gestational age 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.

The initial dose of iNO is 20 ppm. In infants who respond, an improvement of approximately 20 percent in PaO2 or SaO2 typically occurs within 15 to 20 minutes. The iNO concentration is decreased slowly as oxygenation improves [27]. Patients who respond to iNO typically require treatment for three to four days, although some require longer courses. We monitor for potential toxic effects by measuring the serum methemoglobin concentration, levels of nitrogen dioxide at the airway opening, and ambient air contamination.

Extracorporeal membrane oxygenation Approximately 40 percent of infants with severe PPHN remain hypoxemic on maximal ventilatory support with iNO and require ECMO [18]. The goal of this treatment is to maintain adequate tissue oxygen delivery and avoid irreversible lung injury while PVR decreases and pulmonary hypertension resolves.

Criteria for institution of ECMO include an elevated OI. In most cases, ECMO is started when the OI is consistently 40. However, because mean airway pressures 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 five to seven days. 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 [29] or severe pulmonary hypoplasia.

Other potential 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, 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 (mostly in case reports) to be successful in the treatment of infants with PPHN [30-34].

In one small randomized controlled study of 13 infants with severe PPHN (oxygenation index, OI 40), oral sildenafil was associated with improved OI compared to controls [33]. Six of seven infants treated with sildenafil survived compared to 1 of 6 placebotreated infants.In an open-label dose-escalation trial of 36 infants with PPHN and an OI>15, intravenous sildenafil was continuously administered for at least 48 hours and up to 7 days [35]. Twenty-nine infants were already receiving nitric oxide. In the overall group, OI improved from a mean of 27.2 to 11.3 after 24 hours of sildenafil infusion. In the infants who received higher doses of sildenafil (loading dose greater than 0.05 mg/kg and infusion rate greater than 0.06 mg/hour), the OI improved from a mean of 28.7 to 19.3 after four hours of infusion. Thirty-five infants survived. In five patients, hypotension and blood pressure liability were reported as adverse events related to sildenafil, and sildenafil was discontinued in four of the infants.

Although these results are promising, larger randomized controlled studies are needed to show whether sildenafil is effective and safe in the treatment of PPHN. (See "Treatment of pulmonary hypertension".)

Inhaled prostacyclin is another potential intervention in patients who are fail NO therapy [36].

OUTCOME Survivors of severe PPHN and/or ECMO treatment are at increased risk of developmental delay, motor disability, and hearing deficits [37-43]. In one study, survivors of PPHN compared to a matched control group were more likely to have sensorineural hearing loss based upon audiologic evaluation and chronic health

problems (eg, cerebral palsy, developmental delay, the use of bronchodilator therapy, and remedial education) by parental report at 5 to 11 years of age [43].

iNO does not appear to increase the risk of adverse outcomes.

In one report, 87 percent of surviving infants enrolled in the Neonatal Research Network trial of iNO were evaluated at 18 to 24 months of age [37]. Approximately one-third of the infants had at least one disability. Abnormal outcomes included sensorineural hearing loss (14 percent) and moderate to severe cerebral palsy (7.5 percent), but were not different between groups. Mental and psychomotor developmental scores also were not different.In a report from a single tertiary center, 109 of 187 children who were term infants treated for PPHN were evaluated at school age (mean age 7.1 years) [44]. Overall, 9 percent of the cohort had an IQ score less than 70, and 7 percent had an IQ score between 70 to 84. There was no difference in the medical and neurodevelopmental outcome between the 77 children who had received iNO, of whom 12 were also treated by ECMO, and those who did not receive iNO.

Treatment with iNO does not appear to alter lung function in later infancy, as illustrated in a study in which 22 infants who had severe PPHN (15 treated with iNO) and 18 healthy controls were evaluated 4 to 12 months after discharge from the neonatal intensive care unit [45]. No differences between groups were detected in functional residual capacity or respiratory system compliance.

All infants with severe PPHN who have been treated with INO and/or ECMO should have neurodevelopmental follow-up [13]. 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.