Embryology

The vascular network of the developing endodermal pair of lung buds is derived from the surrounding mesenchyme of the splanchnic mesoderm beginning at 4 weeks of gestation. These vessels accompany the developing airways, differentiate into arteries, and join the larger pulmonary arteries that originate from the sixth aortic arch. The veins arise separately within the loose mesenchyme of the lung septa and subsequently connect to the developing left atrium.

Distinctions can be recognized between the proximal and distal pulmonary vasculature both in terms of their embryonic origins and the morphogenetic processes by which they develop. The sixth branchial arch is the embryonic origin of the proximal pulmonary vasculature, and it develops by the process of vasculogenesis. Vasculogenesis is the differentiation and segregation of angioblasts within the mesenchyme, which forms early vascular channels (arteries, veins, and lymphatics), depending on local influences from the epithelium and the mesenchyme. The lung mesenchyme is the embryonic origin of the distal vasculature, which develops by angiogenesis. Angiogenesis is the formation of new vessels from preexisting vascular channels by proliferation and migration of endothelial cells at the tips, which form multiple capillary sprouts. Abnormal maturation or maturational arrest in pulmonary arterial development is reflected in functional derangement that can appear in the newborn period. Persistent pulmonary hypertension of the newborn (PPHN) has been reported in association with pulmonary arterial maturational arrest at week 5 of gestation.¹ Normal growth and development of the pulmonary circulation in utero is critical for achieving successful transition to postnatal life.

Multiple factors influence development and growth of pulmonary vasculature in utero, including growth factors. Growth factors such as vascular endothelial growth factor² and fibroblast growth factor³ appear to be responsible for orderly growth and branching morphogenesis of blood vessels. Quantity, timing, and location are critical determinants of the net effects of these agents. The mechanical stress that endothelial cells must withstand may be the predominant force responsible for development of large vessels after onset of circulation.⁴

Vascular Smooth Muscle

In the normal fetal and term lung, fully muscularized thick-walled preacinar arteries extend to the level of terminal bronchioles, whereas the intra-acinar arteries (i.e., those accompanying respiratory bronchioles) are partially muscular (surrounded by a spiral of muscle) or nonmuscular. Arteries at alveolar ducts and alveolar walls are nonmuscular. Preacinar arteries in the fetus late in gestation and in the newborn have thicker coats of smooth muscle relative to the arterial diameter than do similar arteries in adults, although the fetus actually has less distal extension of smooth muscle in smaller arteries than do older children or adults.⁵ Figure 48-1 shows the diagrammatic representation of the extension of arterial smooth muscle within the acinus in a normal term newborn and in infants with severe PPHN.⁶ An increase in intrauterine vascular smooth muscle, resulting from peripheral extension of smooth muscle into vessels that do not normally contain muscle layers, may contribute to the pathophysiology of PPHN⁷ (see Figure 48-1). Increased muscularization of the pulmonary arteries has been described in infants with severe meconium aspiration syndrome (MAS) with PPHN.⁸ Neonates who die of PPHN may have a striking distal extension of smooth muscle in the intra-acinar region, thickening of the media and adventitia, and excessive accumulation of the matrix protein in the pulmonary vessels.⁹ The increase in vascular smooth muscle and its peripheral extension can occur either prenatally or postnatally. In utero ductal ligation 1 to 2 weeks prior to delivery results in severe PPHN at birth associated with distal extension of vascular smooth muscle in newborn lambs¹⁰ (Figure 48-2) similar to the changes seen in human infants dying with severe PPHN.

Figure 48–1 Diagrammatic representation of a normal pulmonary artery from a term newborn infant showing a fully muscular media to the level of the terminal and respiratory bronchiole. A partial muscular layer extends further distally but the terminal portion of the arterial tree is devoid of smooth muscle. A pulmonary artery in an infant with severe persistent pulmonary hypertension of the newborn shows an increase in the thickness of the muscular layer and distal extension of muscle.

(Copyright Satyan Lakshminrusimha.)

Figure 48–2 Histology (hematoxylin and eosin stain) showing increased muscularization surrounding pulmonary arteries (blue arrow) following antenatal ductal ligation in lambs resulting in persistent pulmonary hypertension of the newborn (B). Control twin lamb (A) with a normal pulmonary artery (red arrow) is shown for comparison. The cartoon (C) shows increased muscularization and distal extension of muscle in persistent pulmonary hypertension of the newborn.

(Copyright Satyan Lakshminrusimha.)

Hemodynamic Features of Fetal Circulation

Oxygenated blood (PaO₂ approximately 30 to 40 mm Hg) returning from the placenta in the umbilical vein¹¹ splits in the liver with slightly more than half passing through the ductus venosus to the inferior vena cava (IVC). The oxygenated blood streams along the medial aspect of the IVC as it enters the right atrium (Figure 48-3). Approximately two thirds of the IVC flow is directed toward the foramen ovale by the eustachian valve and the septum primum and enters the left atrium. The remaining third of the IVC flow mixes with the blood from the superior vena cava and enters the right ventricle. The majority of the right ventricular (RV) output enters the ductus arteriosus and the descending aorta. A small portion enters the lungs via the pulmonary arteries.¹² The ratio of blood flow to the pulmonary arteries to the flow that traverses the ductus arteriosus is determined by the fetal pulmonary vascular resistance (PVR).

Figure 48–3 Fetal circulation showing the shunting of blood at the ductus venosus, foramen ovale, and ductus arteriosus.

(Copyright Satyan Lakshminrusimha.)

The fetal pulmonary circulation fulfills a unique function. Close to term, fetal lungs in the lamb receive about 5% to 10% of combined ventricular output to meet the metabolic demands of an actively growing organ. More recent data in human fetuses using Doppler echocardiography suggest that approximately 25% of combined ventricular output may enter the lungs near term.¹³ The presence of large fetal shunts, the foramen ovale and the ductus arteriosus (see Figure 48-3), allows the fetal lung to regulate the amount of blood flow it receives by active vasoconstriction. The distribution of combined ventricular output, measured in fetal lambs ranging from 60 to 150 days gestational age, indicates that the lungs receive only about 3.5% of total output at 0.4 term, but the fraction increases to almost 8% at term.¹⁴ This remarkable increase in fetal pulmonary perfusion presumably is related to growth of the fetal lung. The lung increases in weight by sixfold from midgestation to term, and the number of pulmonary vessels increases more than tenfold.^15,16 Thus the tremendous increase in cross-sectional area of pulmonary vasculature permits pulmonary blood flow (Qp) to increase throughout gestation. However, Qp remains relatively constant when corrected for wet lung weight with advancing gestation.¹⁷ A gradual increase in pulmonary arterial pressure (PAP), accompanied by a relatively constant flow per unit lung tissue, results in increasing fetal PVR with advancing gestation.¹⁷ A major part of this increase comes from elevated pulmonary vascular tone associated with low PO₂ in the fetal lung.^18,19 Maintaining high PVR in utero is important because the function of gas exchange is performed not by the lungs but by the placenta.

Regulation of Pulmonary Vascular Tone in Utero

Low oxygen tension and various mediators play a crucial role in maintaining elevated fetal PVR.²⁰ Vasoconstriction in response to low oxygen tension contributes to high PVR in the fetal lamb as it approaches term.^18,19 Decreasing oxygen tension in fetuses at 103 to 104 days of gestation does not increase PVR, but it doubles resistance in fetuses at 132 to 138 days. Conversely, increasing oxygen tension does not change PVR before 100 days of gestation, but it decreases resistance markedly and increases blood flow to normal newborn levels at 135 days of gestation.¹⁷

Arachidonic acid metabolites are some of the most powerful vasoconstrictors known. Prostaglandin (PG) F_2α and thromboxane A₂ (TXA₂) are synthesized by the fetal lung via the cyclooxygenase pathway²¹ and are pulmonary vasoconstrictors in the fetal and newborn lungs. However, TXA₂ does not appear to be responsible for maintenance of high PVR in the fetus.²² Blocking PG or thromboxane synthesis does not decrease fetal PVR but prevents the decrease in PVR in response to rhythmic distension of the lung in fetal lambs.²³ The cytochrome P450 metabolism of arachidonic acid results in the formation of epoxyeicosatrienoic acids, dihydroxyeicosatetraenoic acids, and 20-hydroxyeicosatetraenoic (HETE) acids. Of these compounds, HETE acids have been shown to constrict pulmonary circulation in newborn piglets.²⁴ However, inhibition of 20-HETE did not reduce basal PVR in fetal lambs.²⁵ Thus it does not appear that cyclooxygenase and CYP450 metabolites of arachidonic acid cause the high vascular tone of the fetal lung.

Leukotrienes are formed from arachidonic acid through the 5-lipooxygenase pathways. Lipoxygenase activity has been demonstrated in human fetal lung as early as 12 to 18 weeks of gestation.²⁶ Leukotriene inhibition has been shown to decrease PVR in fetal lambs by 45%.²⁷ It also reverses hypoxic pulmonary vasoconstriction in newborn lambs but not in newborn piglets.^28,29 The specific role of leukotrienes in maintaining high PVR in immature fetuses is unclear. It is possible that they play a role in pathologic states such as hypoxia or inflammation.

Endothelins (ETs) are 21-residue peptides^30,31 whose role in regulating vascular tone and vasomotor responses has been studied intensively in the past decade. Three distinct ET isoforms have been described: endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3), cleaved from ET precursors big ET-1, big ET-2, and big ET-3, respectively, by an ET-converting enzyme. ET-1 synthesized by vascular endothelial cells is a potent vasoconstrictor,³² and its effects in both animal and human studies vary with the tone of the pulmonary vessels, dose of ET-1, and the maturation of vessels.^33,34 Of the ETs, ET-1 is the best characterized, and its actions of fetal pulmonary circulation are best studied. Both ET-1 and ET-2 have been shown to dilate the fetal (normally high tone) pulmonary vasculature and constrict the bed when the tone is reduced by ventilation.³⁵ Thus it appears that the response of the pulmonary vasculature to ETs is tone-dependent. In contrast, infusion of big ET-1, the precursor of ET-1, into fetal lambs causes sustained pulmonary vasoconstriction,³⁶ suggesting that this might be the predominant effect of endogenous ET-1.³⁷ Currently at least two receptor subtypes, ET_A and ET_B, are thought to mediate responses to ETs (Figure 48-4). The ET_B receptor plays a role in vasodilation and the ET_A receptor plays a role in vasoconstriction. Selective blockade of the ET_A receptor causes fetal pulmonary vasodilation.^38–40 Some investigators suggest a significant role for an endothelial ET_B receptor in vasodilation and a smooth muscle ET_B receptor and ET_A receptor in vasoconstriction.^41,42 Vasoconstriction induced by ET-1 is mediated by calcium,⁴³ whereas the vasodilator properties are mediated by endothelium-derived nitric oxide (NO).^42,44 ET-1 may play a role in the change that occurs in the pulmonary vasculature at birth. It is possible that prenatally, endogenous ET-1 primarily stimulates ET_A receptors to cause vasoconstriction and that ET_B receptors are less active in fetal life.³⁸ However, ET_B receptors mediate the vasodilator responses to ET-1 in the fetus, and there is a suggestion that an abundance of ET_B receptors may be of physiologic importance in decreasing PVR at birth.⁴⁰

Figure 48–4 Endothelin and nitric oxide pathways in pulmonary arterial endothelial and smooth muscle cells. ATP, Adenosine triphosphate; BNP, B-type natriuretic peptide; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; ET-A and ET-B, endothelin A and B receptors; GMP, guanosine monophosphate; IP₃, inositol triphosphate; Kv, voltage gated potassium channel; O2.–, superoxide anions; pGC, particulate guanylate cyclase; sGC, soluble guanylate cyclase; SR, sarcoplasmic reticulum.

(Copyright Satyan Lakshminrusimha.)

Factors Responsible for Decrease in Pulmonary Vascular Resistance at Birth

The onset of ventilation with rhythmic inflation of the lungs at birth with a resultant increase in oxygen tension in the lungs leads to a decrease in PVR. Each of these stimuli has been shown to decrease vascular resistance and increase blood flow in the lungs of fetal lambs.⁴⁵ Increasing oxygen tension alone by using a hyperbaric chamber decreased PVR and increased Q_p by tenfold in mature fetal lambs.¹⁷ Inflation of lungs with gas may decrease resistance, at least in part by mechanical effects. Oxygen may dilate in part by direct effects on vascular endothelial and smooth muscles.^20,47

The drop in PVR soon after birth is accompanied by production of prostacyclin (PGI₂) and NO. Arachidonic acid metabolites such as PGs, generated through the cyclooxygenase pathway, are potent pulmonary vasodilators in the fetus. PGI₂ synthesized by endothelial cells appears to relax smooth muscle by producing cyclic adenosine monophosphate (cAMP). PGI₂ and its metabolites are more potent vasodilators than PGE₂. Even though blockade of PG synthesis, either by indomethacin^48,49 or meclofenamate,²³ blunts the decrease in PVR, it does not completely disrupt the transition to gas exchange. In addition, cyclooxygenase through the PGE₂ pathway plays an important role in maintaining patency of the ductus arteriosus. PPHN has been observed in infants of mothers receiving aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit cyclooxygenase activity.⁵⁰ In this situation, the inhibitor acts through prenatal constriction of the ductus arteriosus or by decreasing PGI₂ synthesis at birth.⁵¹ The cAMP signal transduction pathway is shown in Figure 48-6.

Figure 48–6 Prostaglandin pathway in the pulmonary arterial endothelial and smooth muscle cells. AMP, Adenosine monophosphate; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase enzyme; IP, prostacyclin receptor; PDE 3, phosphodiesterase 3 enzyme; PGG₂ and PGH₂, prostaglandins; PGI₂, prostacyclin; PLA₂, phospholipase A2.

(Copyright Satyan Lakshminrusimha.)

Acetylcholine,⁵² bradykinin,⁵³ and histamine⁵⁴ are fetal pulmonary vasodilators, which in many species act by an endothelium-dependent mechanism (see Figure 48-4). They stimulate the production of NO by vascular endothelium. NO activates soluble guanylate cyclase to produce the second messenger cyclic guanosine monophosphate (cGMP). cGMP induces relaxation of vascular smooth muscle through activation of a cGMP-dependent protein kinase that produces a lowering of cytosolic ionic calcium, in part through activation of potassium channels.⁵⁵ There is strong evidence that NO is an important mediator of the decrease in PVR at birth. NO is a potent dilator of the fetal pulmonary circulation.⁵⁶ The dilation of the fetal pulmonary circulation caused by an increase in oxygen tension is mediated in large part by endogenous synthesis of NO.⁵⁷ In late gestation lambs, prolonged administration of nitric oxide synthase (NOS) inhibitors, which blocks endogenous NO synthesis, does not affect basal PVR but markedly blunts the decrease in PVR observed at birth.⁵⁸

Evidence suggests that many other mediators can act as pulmonary vasodilators during fetal life and at birth. The purines adenosine triphosphate and adenosine are potent pulmonary vasodilators in the fetal lamb that may also be involved at birth.^59–63 Natriuretic peptides such as atrial natriuretic peptide, B-type natriuretic peptide, and C-type natriuretic peptide dilate fetal pulmonary vasculature by increase cGMP through particulate guanylate cyclase.⁶⁴ Arachidonic acid metabolites such as epoxyeicosatrienoic acids, which are generated through the cytochrome P450 pathway, are potent pulmonary vasodilators.⁶⁵ Because pulmonary vasodilation at birth is a vital step in establishing postnatal life, it is logical that there would be sufficient redundant vasodilators to compensate for failure or inadequacy of any single pathway.³⁷

Pathophysiology

Elevated pulmonary to systemic vascular resistance ratio (PVR/SVR) resulting from either vasoconstriction, structural remodeling of the pulmonary vasculature, intravascular obstruction, or lung hypoplasia (Figure 48-7) characterizes PPHN. This leads to right-to-left shunting of blood across the foramen ovale and ductus arteriosus, resulting in hypoxemia. Numerous disease states with diverse etiologies can result in a similar final pathophysiology. About 10% of cases with PPHN are idiopathic, with no associated pulmonary airspace pathology. However, PPHN is usually associated with other acute respiratory conditions, such as MAS, respiratory distress syndrome (RDS), pneumonia, or congenital diaphragmatic hernia (CDH) (Figure 48-8). Hypoxemia in these conditions can be due to ventilation/perfusion (V/Q) mismatch and intrapulmonary, as well as extrapulmonary, right-to-left shunting of blood. In some newborns with hypoxic respiratory failure, a single mechanism predominates (e.g., extrapulmonary right-to-left shunting in idiopathic PPHN). However, more commonly, several of these mechanisms contribute to hypoxemia. In MAS, obstruction of the airways by meconium results in decreasing V/Q ratios and increasing intrapulmonary right-to-left shunt. Other segments of the lungs may be overventilated relative to perfusion, causing increased physiologic dead space. The same patient also may have severe PPHN with extrapulmonary right-to-left shunting at the ductus arteriosus and foramen ovale. The PPHN in patients with MAS may result from the alveolar hypoxia, from inflammatory mediators, or from abnormal pulmonary vascular muscularization.

Figure 48–7 Mechanisms of persistent pulmonary hypertension of the newborn.

(Copyright Satyan Lakshminrusimha.)

Figure 48–8 Clinically common conditions associated with persistent pulmonary hypertension of the newborn.

(Copyright Satyan Lakshminrusimha.)

Pneumonia or meconium aspiration may release inflammatory mediators that induce vasoconstriction. Vasoconstrictors such as leukotrienes, platelet-activating factor, thromboxanes,⁶⁶ and ET-1⁶⁷ have been found to be elevated in patients with PPHN. Chronic intrauterine ET_A receptor blockade following ductal ligation decreases pulmonary arterial pressure in utero and decreases RV hypertrophy, and distal muscularization of small pulmonary arteries increases the fall in PVR at delivery in newborn lambs with PPHN.³⁹ Thus ET-1 acting through the ET_A receptor stimulation might contribute to the pathogenesis and pathophysiology of PPHN. Derangements in the NO pathway of vasodilation also can result in the physiologic characteristics of PPHN. Pulmonary endothelial nitric oxide synthase (eNOS) gene and protein expression and enzyme activity are decreased in fetal lambs with PPHN induced by antenatal ductal ligation.⁶⁸ In addition, the response to stimulators of eNOS is lost.⁶⁹ In these lambs with PPHN, the vascular response to NO itself is also diminished,⁷⁰ whereas the response to cGMP is normal. Thus the decreased responsiveness appears to result from decreased vascular smooth muscle sensitivity to NO at the level of soluble guanylate cyclase. The cGMP pathway of signal transduction is shown in Figure 48-4. Because NO both vasodilates and inhibits vascular smooth muscle growth, diminished eNOS expression may contribute to both abnormal vasoreactivity and excessive muscularization of pulmonary vessels in patients with PPHN.

PH sometimes occurs because of an abnormal pulmonary vascular bed despite the absence of alveolar hypoxia and hypercapnia and of lung inflammation. These infants can be grouped according to the degree of muscularization and the number of pulmonary arteries.⁷¹ In infants with hypoplastic lungs, as in those with congenital heart disease (CHD) and oligohydramnios sequence, PPHN may arise primarily as a consequence of a decreased number of vessels causing a decreased cross-sectional area of the pulmonary vascular bed, leading to flow restriction (see Figure 48-7). Patients with alveolar capillary dysplasia may have a similar vascular hypoplasia. These cases may be complicated by increased muscularization of the vessels.

Antenatal exposure to NSAIDs such as aspirin and ibuprofen has been associated with PPHN.⁵⁰ More recently, an association between the use of selective serotonin reuptake inhibitor class of antidepressants after 20 weeks of gestation and PPHN has been found.^72,73 Prenatal exposure to fluoxetine (a selective serotonin reuptake inhibitor) induced fetal PH in rats.⁷⁴ The exact mechanism of this association is not clear. Polycythemia and hyperviscosity also may increase PVR and contribute to PPHN. Similarly, hypothermia, acidosis, and hypoxemia can aggravate PPHN.

Clinical Presentation

PPHN must be included in the differential diagnosis of hypoxic respiratory failure in term or near-term infants. Prenatal and perinatal history may provide clues to the etiology of PPHN. These clues include the presence of meconium, acidosis, and asphyxia at delivery, maternal risk factors for infection such as prolonged rupture of membranes, maternal fever, or positive group B streptococcus status. Maternal use of over-the-counter medications that contain PG synthesis inhibitors such as aspirin may be important. Postmaturity also appears to be a risk factor.

Labile hypoxemia is the hallmark of PPHN (Figure 48-9). A newborn infant who is extremely labile, with frequent desaturation episodes and wide swings in arterial PO₂ without changes in ventilator settings, should suggest the possibility of PPHN. Lability also can occur in the face of significant parenchymal disease when V/Q mismatch is severe. Auscultation of the heart in babies with PPHN may reveal a single S2, which can be loud, and a systolic murmur of tricuspid regurgitation. Chest radiograph findings may vary depending on the etiology of PPHN. Hypoxemia out of proportion to the degree of parenchymal disease severity on chest radiography should suggest PPHN. Measurement of preductal and postductal arterial oxygenation can confirm PPHN. A difference in arterial PO₂ 20 mm Hg or greater or oxygen saturation 10% or greater should be considered significant. Minimal or no difference in oxygen tension does not exclude PPHN because shunting at the atrial level produces no ductal gradient and probably is the most common site of shunting. Thus in clinical practice, the gold standard in defining PPHN rests on the echocardiographic findings of right-to-left shunting of blood at the foramen ovale and/or the ductus arteriosus, as well as estimates of PAP. Doppler measurements of atrial and ductal level shunts provide essential information when managing a newborn with hypoxic respiratory failure.⁷⁵ For example, left-to-right shunting at the foramen ovale and ductus arteriosus with marked hypoxemia suggests predominant intrapulmonary shunting, and interventions should be directed at optimizing lung inflation. Similarly, presence of right-to-left shunting at the ductal level and left-to-right shunting at the atrial level suggests PPHN with left ventricular dysfunction with some pulmonary venous hypertension (see Table 48-1). This finding may be associated with CHD.⁷⁶

Figure 48–9 Physiology of labile oxygenation in persistent pulmonary hypertension of the newborn. When systemic vascular resistance (SVR) is higher than pulmonary vascular resistance (PVR), there is no right-to-left shunt. When PVR is close to or exceeds SVR, variable right-to-left shunt at foramen ovale and ductal levels results in labile hypoxemia.

(Copyright Satyan Lakshminrusimha.)

Table 48–1 Differential Diagnosis of Hypoxemia in a Neonate Based on the Direction of Shunt at Atrial and Ductal Level on Echocardiography

Treatment

Lung Recruitment Strategies

Surfactant

Clinical reports suggest that surfactant therapy improves oxygenation in term infants with RDS, pneumonia, and MAS.^93,94 Surfactant administration results in reduced need for ECMO in infants of 36 weeks or greater gestation at birth. Near-term and term infants delivered by elective repeat cesarean section may be one subset of patients who are at risk for deficiency or dysfunction of surfactant and progressive hypoxic respiratory failure.⁹⁵ If the cause of PPHN is parenchymal lung disease such as RDS, meconium aspiration or pneumonia, exogenous surfactant may be beneficial in improving oxygenation and reducing the need for ECMO.⁹⁴

High-Frequency Ventilation

Many clinicians use HFV to manage infants with PPHN. Considering the important role of parenchymal lung disease in specific disorders resulting in PPHN, adequate lung inflation and optimal ventilation are as essential as pharmacologic vasodilator therapy. In the case of inhaled vasodilators, optimal inflation and ventilation may be necessary for drug delivery.⁹⁶ Infants with PPHN from a variety of causes have been successfully treated with HFV.⁹⁷ High-frequency oscillatory ventilation (HFOV) decreases PaCO₂ and increases oxygenation in infants with PPHN. HFOV may improve oxygenation through safer use of higher mean airway pressures to maintain lung volume and prevent atelectasis. Two studies have evaluated the effectiveness of HFV compared with conventional ventilation in rescuing infants with respiratory failure and PPHN from potential ECMO therapy.^98,99 Neither mode of ventilation was more effective in preventing ECMO in these infants. In clinical pilot studies using iNO, combination of HFOV and iNO resulted in the greatest improvement in oxygenation in some newborns who had severe PPHN complicated by diffuse parenchymal lung disease and underinflation.¹⁰⁰ A randomized controlled trial demonstrated that treatment with HFOV and iNO was often successful in patients who failed to respond to HFOV or iNO alone in severe PPHN, and the differences in responses were related to the specific disease associated with PPHN. Infants with RDS and MAS benefit most from a combination of HFOV and iNO therapy.^101,102

Nitric Oxide

In 1996 the Food and Drug Administration (FDA) approved iNO for use in neonates who are 35 weeks’ gestation and older with PPHN. The physiologic rationale for using iNO for treatment of PPHN^103,104 is based on its ability to achieve potent and selective pulmonary vasodilation without decreasing systemic vascular tone (Figure 48-9). Once iNO enters the intravascular space, it combines with hemoglobin to form methemoglobin and does not exert a vasodilator effect on the systemic circulation. Inhaled NO also exerts a microselective effect and reduces V/Q mismatch. Being an inhaled vasodilator, NO enters only ventilated alveoli and redirects pulmonary blood by dilating adjacent pulmonary arterioles and reduces V/Q mismatch (Figure 48-10). Studies in newborn lambs have shown that prolonged administration of NO increased survival rates without increasing the incidence of acute lung injury in lambs with PPHN.¹⁰⁵

Figure 48–10 Selective and microselective action of inhaled nitric oxide (NO). Inhaled NO is a selective dilator of the pulmonary circulation without any significant systemic vasodilation because it combines with hemoglobin to form methemoglobin (MHb). Because it is an inhaled vasodilator, it selectively goes to the well-ventilated alveoli and improves blood flow to these alveoli and reduces ventilation/perfusion mismatch (microselective effect).

(Copyright Satyan Lakshminrusimha.)

Three randomized trials on the use of iNO in newborns with PPHN and respiratory failure were published in 1997. In a randomized controlled clinical trial of patients with PPHN reported by Roberts and colleagues,¹⁰⁶ oxygenation doubled in 58% of treated patients in response to 80 ppm iNO. In addition, twice the proportion of the treated group avoided ECMO compared with the control group. In the Neonatal Inhaled Nitric Oxide Study, 235 infants older than 34 weeks’ gestation who were diagnosed with hypoxic respiratory failure were randomly assigned to receive 20 ppm iNO or were assigned to a control group. Infants whose partial pressure of arterial oxygen increased by 20 mm Hg or less were studied for a response to 80 ppm iNO or control gas. The end point of this trial was death or ECMO. Although the mortality rate was no different in either treatment arm, there was a 40% reduction in the need for ECMO among infants treated with iNO compared with control subjects.¹⁰⁷ Only 6% of infants who failed to respond to treatment with 20 ppm of iNO responded to the higher dose in this study. In a study by Kinsella and colleagues,¹⁰² 205 infants with PPHN were randomly assigned to receive iNO and conventional ventilation or to receive HFOV alone. Those who did not respond to either therapy received the combination of iNO and HFOV. Treatment with HFOV in combination with iNO was successful in some patients who did not respond to one treatment alone. The differences were partly related to the specific disease (RDS and MAS) associated with PPHN.¹⁰² Because adequate lung inflation appears to be necessary for optimal response to iNO, lung recruitment strategies with HFOV should augment the response to iNO. Clark and colleagues¹⁰⁸ reported a 38% reduction in ECMO and no difference in mortality among 248 infants randomly assigned to receive 20 ppm iNO for 24 hours followed by 5 ppm for no more than 96 hours. A meta-analysis of the results of seven randomized trials of iNO use in newborns with PPHN demonstrated that 58% of hypoxic near-term and term infants responded to iNO within 30 to 60 minutes.¹⁰⁹ Mortality was not reduced in any of the NO studies analyzed, but use of ECMO as a rescue therapy in nonresponders was significantly decreased.

Inhaled NO by itself is toxic at higher concentrations. Potential adverse effects include methemoglobinemia, pulmonary edema, and platelet dysfunction. NO reacts with superoxide anion to form peroxynitrite, which causes lipid peroxidation and other oxidative injury to cell membranes. NO₂ is even more toxic. Careful monitoring of both NO and NO₂ levels during administration is mandatory. Because the optimal dosing and timing of iNO administration remains unclear and the potential toxicities are dose-related, lower doses might afford both safety and efficacy in the management of these infants. Two studies using 2 ppm iNO yielded contradictory results. In one study, 2 ppm iNO diminished the clinical response to 20 ppm.¹¹⁰ In the other study, the initial exposure to a very low dose did not compromise the response to higher doses.¹¹¹ In a study involving direct measurements of PAP during cardiac catheterization, iNO produced peak improvement in oxygenation at 5 ppm, whereas peak improvement in the pulmonary-to-systemic arterial pressure ratio did not occur until an iNO dose of 20 ppm, which suggests that an initial dose of 20 ppm is optimum for the treatment of PPHN.¹¹² The use of higher doses of iNO is associated with increased methemoglobin levels, especially at 80 ppm but not at 40 or 20 ppm.¹¹³ The results of randomized controlled trials support the use of iNO at starting does of 20 ppm in near-term and term infants. In summary, iNO offers substantial benefit to a large proportion of near-term and term newborns with hypoxic respiratory failure who do not respond to ventilatory support, lung recruitment, and oxygen.

The timing of initiation of iNO in patients with hypoxic respiratory failure is not clear. Severity of hypoxemia in neonates is measured by oxygenation index (OI = Mean airway pressure in cm of water × FIO₂ × 100/PaO₂ [in mm Hg]). An OI of 40 is often used as an indication for ECMO therapy. An OI of 25 is associated with a 50% risk of requiring ECMO or dying.³⁷ Thus the acceptable indication for treatment with iNO include an OI greater than 25 with echocardiographic evidence of PPHN or a higher OI with or without evidence of right-to-left shunt. However, it has been suggested that initiating iNO at a lower OI may be associated with reduced need for ECMO.¹¹⁴ Konduri and colleagues¹¹⁵ randomly assigned neonates who were born at 34 weeks’ gestation or later, required assisted ventilation, and had an OI of 15 or greater and less than 25 to receive early iNO or to receive simulated initiation of iNO (control). Infants who had an increase in OI to 25 or more were given iNO as standard therapy. Arterial oxygen tension increased by more than 20 mm Hg in 73% of infants who received early iNO (n = 150) and in 37% of infants in the control group (n = 149) after study gas initiation. Infants in the control group received standard iNO and deteriorated to an OI score greater tha 40 more often than did infants who were given early iNO. The incidence of death (early iNO group, 6.7% vs. control group, 9.4%), ECMO (10.7% vs. 12.1%), and their combined incidence (16.7% vs. 19.5%) were similar in both groups.¹¹⁵ Follow-up evaluations showed no differences between the 2 groups in the incidence of neurodevelopmental impairment (early iNO group, 27%; control group, 25%) and hearing impairment (early iNO group, 23%; control group, 24%). Mental development index scores were similar in the two groups; however, psychomotor developmental index scores were significantly higher in the control group (early iNO group, 89 ± 17.7; control group, 93.5 ± 18.4).¹¹⁶ These findings suggest that caution must be exercised while initiating iNO at lower OI levels.

Inhaled NO should be weaned gradually to avoid rebound PH.¹¹⁷ A flow diagram showing the protocol for weaning iNO at The Women and Children’s Hospital of Buffalo is shown in Figure 48-11.

Figure 48–11 Weaning protocol for inhaled nitric oxide in use at The Women and Children’s Hospital of Buffalo, NY.

The outcome of infants treated with iNO collectively supports both the efficacy and safety of this mode of treatment. Reports identify significant medical and neurodevelopmental sequelae of PPHN with or without iNO and point out the necessity for coordinated multidisciplinary follow-up for these infants. The overall rate of neurodevelopmental handicap in infants treated with NO was 46%, with 25% mildly affected and 21% severely affected at age 1 year in one study.¹¹⁸ In another study, mild and severe neurodevelopmental handicaps were 14% and 12% at age 1 year and 9% and 12% at age 2 years.¹¹⁹ In these studies sensorineural hearing loss was present in 6% to 19% of infants with PPHN treated with iNO. No difference was noted between control and treatment groups for these outcomes. Published reports on the use of iNO in ECMO centers have not substantiated early concerns that iNO would adversely affect outcome by delaying ECMO utilization. Inhaled NO treatment may play an important role in stabilizing patients before ECMO is initiated, thus improving the chances of ECMO cannulation without further clinical deterioration. The Committee on the Fetus and Newborn of the American Academy of Pediatrics has suggested that iNO use be limited to tertiary care centers where ECMO is available.¹²⁰ In non-ECMO centers, a system should be in place to continue iNO during transport even if a response occurs, because not all physiologic responders avoid ECMO. For the same reason, the combination of HFOV and iNO should be used cautiously in non-ECMO centers.

Inhaled NO is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of blood (such as hypoplastic left heart syndrome). Also, patients with preexisting left ventricular dysfunction treated with iNO, even for short durations, have a high risk of pulmonary edema (package insert, INOmax, 2009).