120: Persistent Pulmonary Hypertension of the Newborn

Persistent pulmonary hypertension of the newborn (PPHN) is a condition characterized by marked pulmonary hypertension resulting from elevated pulmonary vascular resistance (PVR) and altered pulmonary vasoreactivity, leading to right-to-left extrapulmonary shunting of blood across the foramen ovale and the ductus arteriosus, if it is patent. It is associated with a wide array of cardiopulmonary disorders that may also cause intrapulmonary shunting. When this disorder is of unknown cause and is the primary cause of cardiopulmonary distress, it is often called “idiopathic PPHN” or persistent fetal circulation.

2–6 per 1000 live births.

PPHN may be the result of underdevelopment of the lung together with its vascular bed (eg, congenital diaphragmatic hernia and hypoplastic lungs), maladaptation of the pulmonary vascular bed to the transition occurring around the time of birth (eg, various conditions of perinatal stress, hemorrhage, aspiration, hypoxia, and hypoglycemia), and maldevelopment of the pulmonary vascular bed in utero from a known or unknown cause. It is convenient to think in terms of this basic pathologic classification. However, the clinical manifestations of PPHN are often not attributable to a single physiologic or structural entity, and many disorders exhibit more than one underlying pathology. Often, even when there is evidence of perinatal or postnatal stress (eg, meconium aspiration), the underlying cause of PPHN had been secondary to an in utero process of some duration.

Preacinar arteries are already present in the lungs by 16 weeks' gestation; thereafter, respiratory units are added with further growth of the appropriate arteries. Muscularization, differentiation, and growth of the peripheral pulmonary arteries are influenced by numerous trophic factors (eg, fibroblast growth factors) and by changes that occur in the connective tissue matrix. The lungs of infants with PPHN contain many undilated precapillary arteries, and pulmonary arterial medial thickness is increased. There may be extension of muscle in small and peripheral arteries that are normally nonmuscular. After a few days, there is already evidence of structural remodeling with connective tissue deposition.

In the fetus, PVR is high, and only 5–10% of the combined cardiac output flows into the lungs, with most of the right ventricular output crossing the ductus arteriosus to the aorta. After birth, with expansion of the lungs, there is a sharp drop in PVR and pulmonary blood flow increases ∼10-fold. The factors responsible for maintaining high PVR in the fetus and for effecting the acute reduction in PVR that occurs after birth are incompletely understood. Fetal and neonatal pulmonary vascular tone is modulated through a balance between vasoconstrictive and vasodilatory stimuli. Vasoconstrictive stimuli include various products of arachidonic acid metabolism (eg, thromboxane) and the endothelins (ETs). The hemodynamic effect of the ETs are mediated by at least 2 receptors; ET-A and ET-B. The fetal lung also produces a number of cyclooxygenase (COX)–dependent metabolites that function as pulmonary vasodilators (eg, PGI2, PGE1, and PGE2). It has also become clear that the endothelium (and its interaction with vascular smooth muscle cells) plays a crucial role in regulating pulmonary vascular tone. Nitric oxide (NO), a potent vasodilator, is synthesized from L-arginine by endothelial nitric oxide synthase (eNOS). NO stimulates soluble guanylate cyclase (sGC), which produces cGMP and causes vasodilation. cGMP, in turn, is hydrolyzed by cyclic nucleotide phosphodiesterases (PDEs), and manipulation of these control the intensity and duration of cGMP action. Various isoenzymes of PDE have been identified, and inhibition of PDE-5 (by, eg, sildenafil) causes pulmonary vasodilation.

In summary, for successful pulmonary circulatory transition to occur, various mechanical, physiologic, and biochemical factors, which maintain high fetal PVR, must be eliminated or reversed. Major events are the replacement of the fluid-filled lung of the fetus with the air-filled postnatal lung, the increase in oxygen tension, and the increase in pulmonary blood flow (which increases shear stress and thereby increases NO). At the same time, changes occur in the synthesis and release of various biochemical modulators of vascular tone, and there are interactions between the mechanical and biochemical events surrounding birth. Disturbances in this cascade of events may lead to PPHN. At the same time, manipulation of these pathways enables us to treat it.

The following factors or conditions may be associated with PPHN:

1. Lung disease. Meconium aspiration, respiratory distress syndrome (RDS), pneumonia, pulmonary hypoplasia, cystic lung disease (including congenital cystic adenomatoid malformation and congenital lobar emphysema), diaphragmatic hernia, and congenital alveolar capillary dysplasia.

2. Systemic disorders. Polycythemia, hypoglycemia, hypoxia, acidosis, hypocalcemia, hypothermia, and sepsis.

3. Congenital heart disease. Particularly, total anomalous venous return, hypoplastic left heart syndrome, transient tricuspid insufficiency (transient myocardial ischemia), coarctation of the aorta, critical aortic stenosis, endocardial cushion defects, Ebstein anomaly, transposition of the great arteries, endocardial fibroelastosis, and cerebral venous malformations.

4. Perinatal factors. Asphyxia, perinatal hypoxia, and maternal ingestion of aspirin or indomethacin.

5. Miscellaneous. Central nervous system disorders, neuromuscular disease, and upper airway obstruction. Although still contentious, some observational studies have suggested that the use of selective serotonin reuptake inhibitors during the last half of pregnancy may be associated with PPHN in the newborn.

The primary finding is respiratory distress with cyanosis (confirmed by demonstrating hypoxemia). This may occur despite adequate ventilation. Other clinical findings are highly variable and depend on the severity, stage, and other associated disorders (particularly pulmonary and cardiac diseases).

1. Respiratory. Initial respiratory symptoms may be limited to tachypnea, and onset may be at birth or within 4–8 hours of age. In addition, in an infant with pulmonary disease, PPHN should be suspected as a complicating factor when there is marked lability in oxygenation. These infants may have significant decreases in pulse oximetry readings with routine nursing care or minor stress (eg, movement or noise). Furthermore, a minor decrease in inspired oxygen concentration may lead to a surprisingly large decrease in arterial oxygenation (eg, the AaDO₂ gradient changes more rapidly and is more labile than that seen in the normal course of progression of uncomplicated RDS or other pulmonary disease).

2. Cardiac signs. Physical findings may include a prominent right ventricular impulse, a single second heart sound, and a murmur of tricuspid insufficiency. In extreme cases, there may be hepatomegaly and signs of heart failure.

3. Imaging. The chest film may show either cardiomegaly or a normal-sized heart. If there is no associated pulmonary disease, the film may show normal or diminished pulmonary vascularity. If there is also a parenchymal lung disorder, the degree of hypoxemia may be out of proportion to the radiographic measure of severity of the pulmonary disease.

PPHN is essentially a diagnosis of exclusion.

1. Differential oximeter readings. In the presence of right-to-left shunting of blood via the PDA, the Pao₂ in preductal blood (eg, from the right radial artery) is higher than that in the postductal blood (obtained from left radial, umbilical, or tibial arteries). Hence simultaneous preductal and postductal monitoring of oxygen saturation is a useful indicator of right-to-left shunting at the ductal level. However, it is important to note that PPHN cannot be excluded if no difference is found because the right-to-left shunting may be predominantly at the atrial level (or the ductus may not be patent at all). A difference >5% between preductal and postductal oxygen saturations is considered indicative of a right-to-left ductal shunt. A difference >10–15 mm Hg between preductal and postductal Pao₂ is also considered suggestive of a right-to-left ductal shunt. Preductal and postductal oxygenation should be assessed simultaneously.

2. Hyperventilation test. PPHN should be considered if marked improvement in oxygenation (>30 mm Hg increase in Pao₂) is noted on hyperventilating the infant (lowering Paco₂ and increasing pH). When a “critical” pH value is reached (often ∼7.55 or greater), PVR decreases, there is less right-to-left shunting, and Pao₂ increases. This test may differentiate PPHN from cyanotic congenital heart disease. Little or no response is expected in infants with the latter diagnoses. It has been suggested that infants subjected to this test should be hyperventilated for 10 minutes. Prolonged hyperventilation is not recommended, however, particularly in premature infants (see later discussion).

3. Imaging. Clear lung fields or only minor disease in the face of severe hypoxemia is strongly suggestive of PPHN, if cyanotic congenital heart disease has been ruled out. In an infant with significant pulmonary parenchymal disease, a chest film is of little help in diagnosing PPHN (although it is indicated for other reasons). In an infant with rapidly worsening oxygenation, the major value of a chest film is in the exclusion of alternative diagnosis (eg, pneumothorax or pneumopericardium).

4. Echocardiography. Often essential in distinguishing cyanotic congenital heart disease from PPHN because the latter is frequently a diagnosis of exclusion. Furthermore, whereas all the other previously mentioned signs and tests are suggestive, echocardiography (together with Doppler studies) can provide confirmatory evidence that is often diagnostic. The first question that needs to be answered is whether the heart is structurally normal. Then the pulmonary artery pressure can be assessed indirectly by measuring the velocity of the tricuspid regurgitant jet when present. A flattened interventricular septum, or one that is bowing into the left ventricle, also supports the diagnosis of PPHN. Similarly, information about right-to-left shunting at the atrial and ductal levels support the diagnosis of PPHN. Echocardiography can also be used to assess ventricular output and contractility (both of which may be depressed in infants with PPHN).

1. Prevention. Adequate resuscitation and support from birth may presumably prevent or ameliorate, to some degree, PPHN when it may occur superimposed on a preexisting condition. An example is adequate and timely ventilation of an asphyxiated infant with appropriate attention to temperature control.

2. General management. Infants with PPHN clearly require careful and intensive monitoring. Fluid management is important because hypovolemia aggravates the right-to-left shunt. However, once normovolemia can be assumed, there is no known benefit to be gained from repeated administration of either colloids or crystalloids. Normal serum glucose and calcium should be maintained because hypoglycemia and hypocalcemia aggravate PPHN. Temperature control is also crucial. Significant acidosis should be avoided. It is useful to use 2 pulse oximeters: 1 preductal and 1 postductal.

3. Minimal handling. Because infants with PPHN are extremely labile with significant deterioration after seemingly “minor” stimuli, this aspect of care deserves special mention. Endotracheal tube suctioning, in particular, should be performed only if indicated and not as a matter of routine. Noise level and physical manipulation should be kept to a minimum.

4. Mechanical ventilation. Often needed to ensure adequate oxygenation and should first be attempted using “conventional” ventilation. The goal is to maintain adequate and stable oxygenation using the lowest possible mean airway pressures. The lowest possible positive end-expiratory pressure should also be sought. However, atelectasis should be avoided because it may aggravate pulmonary hypertension and also impair effective delivery of inhaled nitric oxide (iNO) to the lungs. Hyperventilation should be avoided, and as a guide, arterial Pco₂ values should be kept >30 mm Hg if possible; levels of 40–50 mm Hg, or even higher, are also acceptable if there is no associated compromise in oxygenation. Initially, it would be wise to ventilate with 100% inspired oxygen concentration. Weaning should be gradual and in small steps. In those infants who cannot be adequately oxygenated with conventional ventilation, high-frequency oscillatory ventilation (HFOV) should be considered early. In the presence of parenchymal lung disease, infants treated with HFOV combined with iNO were less likely to be referred for extracorporeal membrane oxygenation/extracorporeal life support (ECMO/ECLS) than those treated with either therapy alone.

5. Surfactant. In infants with RDS, administration of surfactant is associated with a fall in PVR. Surfactant may also be of benefit in various other pulmonary disorders (eg, meconium aspiration), although it is unknown whether its actions in these is related to a reduction in PVR. There is evidence for surfactant deficiency in some patients with PPHN.

6. Pressor agents. Some infants with PPHN have reduced cardiac output. In addition, increasing systemic blood pressure reduces the right-to-left shunt. Hence at least normal blood pressure should be maintained, and some recommend maintaining blood pressure of ≥40 mm Hg. Dopamine is the most commonly used drug for this purpose. Dobutamine has the disadvantage, in this context, that, although it may improve cardiac output, it has less of a pressor effect than dopamine. Milrinone, a type 3 phosphodiesterase inhibitor, is also sometimes employed to improve cardiac output. Milrinone reduces pulmonary hypertension in experimental animal models, and 2 small case series have reported on its beneficial effects in neonates with PPHN. However, the use of milrinone has been associated with occasional cases of systemic hypotension in adults and of higher heart rates in neonates. Hence more data are needed before widespread use of milrinone can be recommended.

7. Sedation. The lability of these infants has been mentioned previously, and hence sedation is commonly used. Pentobarbital (1–5 mg/kg) or midazolam (0.1 mg/kg) is frequently used, and analgesia with morphine (0.05–0.2 mg/kg) is also used.

8. Inhaled nitric oxide (iNO). See also Chapters 8 and 148.

   1. Background. Controlled clinical trials have shown that nitric oxide (NO), when given by inhalation, reduces PVR and improves oxygenation and outcomes in a significant proportion of term and near-term neonates with PPHN. The administration of iNO to infants with PPHN reduces the number requiring ECMO/ECLS without increasing morbidity at 2 years of age. In another large multicenter trial, iNO was demonstrated to reduce both the need for ECMO/ECLS and the incidence of bronchopulmonary dysplasia (BPD)/chronic lung disease (CLD). Oxygenation can also improve during iNO therapy via mechanisms additional to its effect of reducing extrapulmonary right-to-left shunting. iNO can also improve oxygenation by redirecting blood from poorly aerated or diseased lung regions to better aerated distal air spaces (which are better exposed to the inhaled drug), thereby improving ventilation-perfusion mismatching. Although the benefits of iNO have been demonstrated in full- and near-term neonates with pulmonary hypertension, iNO treatment of preterm infants is more controversial. In preterm neonates, the hope was that iNO would decrease the incidence of BPD/CLD and, possibly, mitigate other morbidities. However, results of clinical trials have been conflicted, and respiratory distress in premature infants is regarded as a controversial indication for which further studies are necessary.

   2. Physiology. NO is a colorless gas with a half-life of seconds. Exogenous iNO diffuses from alveoli to pulmonary vascular smooth muscle and produces vasodilation. Excess NO diffuses into the bloodstream, where it is rapidly inactivated by binding to hemoglobin and subsequent metabolism to nitrates and nitrites. This rapid inactivation thereby limits its action to the pulmonary vasculature. Dosage of iNO is measured as ppm (parts per million) of gas.

   3. Toxicity. NO reacts with oxygen to form other oxides of nitrogen and, in particular, NO₂ (nitrogen dioxide). The latter may produce toxic effects and hence must be removed from the respiratory circuit (which can be done by using an adsorbent). When NO combines with hemoglobin, it forms methemoglobin, and this is also of potential concern. In the several large trials that have been completed, methemoglobinemia has not been a significant complication at NO doses <20 ppm. The rate of accumulation of methemoglobin depends on both the dose and duration of NO administration. Even when using doses >20 ppm, clinically significant methemoglobinemia does not appear to be a frequent complication. NO inhibits platelet adhesion to endothelium. Hence another potential complication is the prolongation of bleeding time described at NO doses of 30–300 ppm. NO may also have an adverse effect on surfactant function, but this appears to require much higher doses than those relevant in clinical applications. On the contrary, low-dose NO also has antioxidant effects, and these may be potentially beneficial. Because of these potential complications, when administering NO, NO₂ levels should be monitored. Also, blood methemoglobin concentration should be measured. Follow-up studies in infants receiving iNO have not shown any adverse effects.

   4. Dosage and administration. Available evidence supports the use of doses of iNO beginning at 20 ppm. Among infants with a positive response to iNO, the response time is rapid. There is no agreement, however, about the duration of treatment and criteria for discontinuation; these vary and often reflect institutional preferences. Thus some recommend weaning once arterial Po₂ is >50 mm Hg; others suggest an oxygenation index <10 as an indications for weaning. Moreover, no evidence suggests the superiority of one weaning regimen over another. However, some observations are available to assist in weaning considerations. One point is, however, beyond contention: weaning should be done under careful and intensive monitoring of each step. Particular note should be made of the observation that sudden discontinuation of iNO can be associated with “rebound” pulmonary hypertension (see Section VII.H.4b).

      1. Initial dose. Start treatment with iNO at 20 ppm. Little is to be gained by administering higher doses because, at most, only a few patients will respond to these higher doses after not having responded to a dose of 20 ppm. Higher doses may significantly increase the rate of methemoglobinemia. Also, initial treatment with subtherapeutic low-dose iNO may diminish the subsequent response to iNO at 20 ppm. Among infants with a positive response to iNO, the response time is rapid.

      2. Weaning. Wean inspired oxygen concentration until Fio₂ <0.6. Then start weaning iNO concentrations in steps of 5 ppm until iNO is 5 ppm. Weaning may be initiated as early as 4–6 hours after starting treatment, or later, and should be attempted at least once per day, but may be done as frequently as every 30 minutes. Hemodynamic stability and adequate oxygenation should be monitored closely 30–60 minutes after each weaning step. Significant deterioration should be an indication of reversing the previous weaning step. Once iNO is at 5 ppm, weaning should be continued at a slower pace, in steps of 1 ppm, until iNO is 1 ppm. Once the patient has demonstrated stability at iNO of 1 ppm for a few hours, iNO may be discontinued. Some decline in oxygen saturation should be anticipated, and an increase of 10–20% in required inspired oxygen concentration may be considered reasonable when discontinuing iNO and need not be an indication for reinstating therapy. However, if an Fio₂ >0.75 is required to maintain adequate oxygenation, the patient may benefit from being placed back on iNO. Caution: Although there are various weaning regimens of iNO, evidence suggests that iNO should be discontinued from a dose of 1 ppm and not from a higher one. The rate of success is higher when discontinuation is done from a dose of 1 ppm than from 5 ppm or higher. Moreover, the phenomenon of rebound pulmonary hypertension should be kept in mind after discontinuation of iNO. Sudden discontinuation of iNO can be associated with “rebound” pulmonary hypertension, and this rebound can be severe and may occur even in infants who had initially failed to respond to iNO treatment when it was initiated. We should emphasize that this protocol is merely a suggestion and is compatible with data derived from trials and experience with the use of iNO. Many other regimens would be just as reasonable.

   5. Failure to respond to iNO or the need for prolonged administration. Patients not responding to iNO or those in whom iNO cannot be weaned after 5 days of treatment merit a reevaluation. Effective therapy requires adequate lung inflation, and an infant who fails to respond should be evaluated by chest radiograph for airway obstruction and atelectasis. Lung volume recruitment strategies may be required, as may surfactant treatment in appropriate circumstances. Pressor support or volume administration may be required because impaired cardiac output may render iNO treatment ineffective. An echocardiogram is warranted to rule out cardiac anomalies that may have been missed and to assess cardiac function. Consideration should be directed toward lung diseases that respond poorly to iNO, such as alveolar-capillary dysplasia or those associated with pulmonary hypoplasia. Fewer than 35% of infants with congenital diaphragmatic hernia respond to iNO or survive without ECMO/ECLS.

9. Sildenafil. The phosphodiesterase PDE5 is abundantly expressed in lung tissue and degrades cGMP. Sildenafil, a PDE5 inhibitor, prolongs the half-life of cGMP and would be expected to enhance the actions of both endogenous and exogenous nitric oxide. A few small randomized trials in infants have shown its effectiveness in treating pulmonary hypertension. Additional reports are in the form of case series. It has been successful in treating pulmonary hypertension in infants after cardiac surgery, and case series have shown it to be useful in attenuating the rebound pulmonary hypertension after withdrawal of iNO. In some patients sildenafil may confer benefit additional to that obtained by iNO alone. In some units, sildenafil is given prophylactically before the final step in weaning off iNO. Patients treated with sildenafil have not shown an increased propensity for systemic hypotension. Concern has been raised about possible adverse effects of this drug in those infants at risk for retinopathy of prematurity, although the putative association has been questioned. Larger trials will be required to address issues of risk and benefits. Although an intravenous (IV) preparation is available, the drug is mostly given enterally. Reported dosages vary and range from 1–3 mg/kg every 6 hours.

10. Prostacyclin. Prostacyclin (PGI₂) is a short-acting, potent vasodilator of both the pulmonary and systemic circulations. The greatest experience of its use is as a continuous IV infusion of epoprostenol. Trials in adults and older children with pulmonary hypertension have shown an improvement in symptoms and mortality. However, epoprostenol treatment is associated with various limitations. The drug has a very short half-life and requires continuous infusion. There are special storage requirements, and side effects include systemic hypotension. The data in neonates is sparse and consists of a few case reports of the drug's successful use in this patient population. Reported dosages have varied between 4 ng/kg/min to 40 ng/kg/min IV, and it is suggested that a low starting dose be initiated, with increasing dosage rate being titrated according to response. Higher doses are associated with increased risk of systemic hypotension, and blood pressure should be monitored.

11. Inhaled/nebulized PGI2 (Iloprost). This is a stable PGI₂ analogue with a longer half-life, and it acts by stimulating adenyl cyclase and increasing cAMP. It is gaining wider acceptance owing to its selective pulmonary vasodilation without decreasing systemic blood pressure. Randomized trials in adults have shown its effectiveness and safety, but the pediatric and neonatal literature consists of a few case series and case reports. The use of inhaled prostacyclin was reported in 4 neonates with PPHN refractory to iNO. All 4 infants showed a rapid improvement. One neonate subsequently deteriorated and was found to have alveolar-capillary dysplasia. No systemic vascular effects were noted. Dosage varies between reports but is mostly in the range of 0.25–2 mcg/kg per inhalation with inhalations being given over 5–10 minutes every 2–8 hours.

12. Bosentan. ET-1 is a potent vasoconstrictor and is increased in newborns with PPHN. Bosentan is an endothelin receptor antagonist that improves hemodynamics and quality of life in adults with pulmonary hypertension. Up to 10% of patients are affected by liver toxicity. Bosentan improved hemodynamics in a study of its use in pediatric patients with pulmonary hypertension. Its use also enabled a reduction of the epoprostenol dose. There is, however, little information on the use of bosentan in neonates with PPHN and the literature consists mostly of case reports. Bosentan is sometimes used anecdotally for refractory pulmonary hypertension in infants with congenital diaphragmatic hernia, severe BPD/CLD, and congenital heart diseases. There are no systematic data on its use and safety in neonates, either as a single therapy or as an adjunct in combination therapy. Reported dosage is 1–2 mg/kg twice per day.

13. Paralyzing agents. The use of these agents is controversial. Their use has been advocated in infants who have not responded to sedation and are still labile or who appear to “fight” the ventilator. In a retrospective survey, the use of paralysis was associated with increased mortality, although a causal relation cannot be inferred. Pancuronium is the drug most commonly used, although it may increase PVR to some extent and worsen ventilation-perfusion mismatch. Vecuronium (0.1 mg/kg) has also been used.

14. Alkalinization. In the past, it had been noted that hyperventilation, with the resulting hypocapnia, improved oxygenation secondary to pulmonary vasodilation. Subsequently, it was shown, in animal studies, that the beneficial effect of hypocapnia was actually a result of the increased pH rather than of the low Paco₂ values achieved. Furthermore, follow-up of infants with PPHN had suggested that hypocapnia was related to poor neurodevelopmental outcome (especially sensorineural hearing loss). Hypocapnia is known to reduce cerebral blood flow. The use of alkalinization is controversial, and there are no adequately controlled trials on its use to alleviate PPHN. If alkalinization is employed, it may be advisable to increase pH using an infusion of sodium bicarbonate (0.5–1 mEq/kg/h) if possible. Serum sodium should be monitored to avoid hypernatremia. Improvement in oxygenation has been anecdotally reported with arterial pH 7.50–7.55 (sometimes levels as high as 7.65 are required).

15. Magnesium sulfate. Magnesium causes vasodilation by antagonizing calcium ion entry into smooth muscle cells. A few small observational studies have suggested that MgSO₄ may effectively treat PPHN, but the evidence is conflicting, and there is some risk of systemic hypotension. The dose reported is a loading dosage of 200 mg/kg followed by an infusion of 20–150 mg/kg/h (the drug is given IV). Two small trials in neonates with PPHN have shown that sildenafil and iNO are each superior to IV MgSO_4.

16. Adenosine. Adenosine causes vasodilation by stimulation of adenosine receptors on endothelial cells and release of endothelial NO. A small randomized trial reported the effectiveness of adenosine infusion (25–50 mcg/kg/min) in treating PPHN in term babies. Subsequently a few further cases have been published. Despite initial favorable data, the drug has not attracted attention, and its use awaits further clinical trials.

17. ECMO/ECLS. (See Chapter 18.) ECMO/ECLS may be indicated for term or near-term infants with PPHN who fail to respond to conventional therapy and who meet ECMO/ECLS entry criteria. The survival rate with ECMO/ECLS is reportedly >80%, although only the most severely afflicted infants are referred for this treatment.

A significant number of cases of BPD/CLD exhibit pulmonary hypertension (PH). The pulmonary circulation in BPD/CLD exhibits elevated pulmonary vascular resistance and increased vasoreactivity, vascular remodeling, and decreased and disrupted growth. The disruption in angiogenesis also impairs alveolarization, and, furthermore, there is formation of bronchial and other systemic-to-pulmonary collateral vessels. The presence of PH complicating the course of BPD/CLD is associated with significantly increased mortality and morbidity. The rationale for aggressively diagnosing and treating PH complicating BPD/CLD is the hope that it would affect the increased mortality. Which patients with BPD/CLD should be screened for the presence of PH? There are no data to indicate an optimal approach, but a few guidelines have been suggested. Patients still requiring ventilatory assistance or significant supplemental oxygen at 36 weeks' postconceptional age might benefit from an echocardiographic evaluation. Furthermore, infants with severe respiratory disease that fails to improve, those with respiratory disease out of proportion to the expected course or radiologic findings, those with recurrent and persistent cyanotic spells or respiratory deteriorations, and those with repeated need for diuretic administration might also benefit of screening for PH. Screening for PH in patients with BPD/CLD may require serial interval echocardiograms. The echocardiographic evaluation of PH is far from perfect, and certain patients may require cardiac catheterization for diagnosis of PH and to assess its severity and response to treatment. The therapeutic options most commonly used are iNO, sildenafil, and bosentan. However, treatment of PH should always occur in a context whereby attempts have been made to optimize ventilatory support and complicating factors (eg, reflux and aspirations) have been considered and treated, if necessary.

The overall survival rate is >70–75%. There is, however, a marked difference in survival and long-term outcome according to the cause of the PPHN. More than 80% of term or near-term neonates with PPHN are expected to have an essentially normal neurodevelopmental outcome. Abnormal long-term outcome in PPHN survivors (and a high incidence of sensorineural hearing loss) has been reported to correlate with duration of hyperventilation. However, the relationship may not be causal because prolonged hyperventilation may simply be a marker for the severity of PPHN and hypoxic insult. Survivors of idiopathic PPHN usually have no residual lung or heart disease. Very low birthweight infants with PPHN accompanying severe RDS have a much higher rate of mortality, and there are few data on the long-term outcome of the survivors.