Looking beyond PPHN: The Unmet Challenge of Chronic Progressive Pulmonary Hypertension in the Newborn

Abstract

Infants with forms of pulmonary hypertension (PH) that persist or develop beyond the first week of life are an understudied group of patients with up to 40%–60% mortality. The clinical management of the progressive PH that develops in these infants is challenging because of the nonspecific signs and symptoms of clinical presentation, the limited diagnostic sensitivity of standard echocardiographic techniques, and the lack of proven therapies. The signaling mechanisms that underlie the structural and functional abnormalities in the pulmonary circulation of these infants are not yet clear. The ability to improve outcomes for these patients awaits technological advances to improve diagnostic capabilities and therapeutic discoveries made in basic science laboratories that can be tested in randomized clinical trials.

Keywords

bronchopulmonary dysplasia chronic lung disease of infancy congenital diaphragmatic hernia

INTRODUCTION

When queried about their clinical experience with pulmonary hypertension, neonatologists are quick to expound about the successful management of patients suffering from persistent pulmonary hypertension of the newborn (PPHN), a syndrome characterized by the failure to transition from the high fetal pulmonary vascular resistance (PVR) to the lower PVR of the normal newborn lung. By definition, PPHN presents in the first moments and days of life. Infants suffering from PPHN have historically garnered a lot of attention, in part because of the acute and life-threatening presentation of the disorder. Significant progress has been made in the past 2 decades in the care of infants with severe respiratory failure and PPHN. Research from basic science laboratories led to randomized clinical trials culminating in the approval of inhaled nitric oxide (iNO) in late 1999 for the treatment of PPHN in newborns at 35 weeks' gestation and older. However, up to 40% of infants with PPHN fail to respond to iNO,¹ and this condition continues to carry a 10% mortality and a 25% risk of long-term neurodevelopmental morbidity.² Results of randomized clinical trials also support the use of extracorporeal membrane oxygenation (ECMO)³ and surfactant⁴ as therapies to improve outcomes for infants with respiratory failure, many of whom have PPHN. However, ECMO is an invasive therapy, and not all infants respond to either surfactant or iNO. Without question, research efforts are still needed to improve therapies for infants with PPHN (Table 1).

Table 1.

Spectrum of neonatal pulmonary hypertension

Type of neonatal pulmonary hypertension	Most common etiologies	Evidence-based therapies	Outcomes
Persistent pulmonary hypertension of the newborn (PPHN)	Meconium aspiration syndrome, pneumonia, sepsis, idiopathic PPHN	iNO surfactant ECMO	10% mortality, 25% risk of long-term morbidity
Chronic, progressive pulmonary hypertension	BPD, CDH, congenital heart disease, pulmonary hypoplasia, interstitial pneumonia	None	40%–60% mortality, long-term morbidity unknown

Note: PPHN: persistent pulmonary hypertension of the newborn; iNO: inhaled nitric oxide; ECMO: extracorporeal membrane oxygenation; BPD: bronchopulmonary dysplasia; CDH: congenital diaphragmatic hernia.

Less scientific and clinical attention has been given to infants with forms of pulmonary hypertension (PH) that persist or develop beyond the first week of life (Table 1). The need to recognize the entire spectrum of PH in infants is highlighted by the recent development and publication of clinical and functional classification systems for children with PH.^5,6 Inherent to the classification of pediatric PH is the knowledge that due to congenital anomalies of the heart or lungs, some infants never complete the transition to a normal postnatal pulmonary circulatory pattern in the first days of life. Some of these infants, including those with congenital diaphragmatic hernia and lung hypoplasia, develop progressive and worsening PH over weeks and months. Other infants may undergo an initial normal pulmonary circulatory adaptation in the first hours and days of life but subsequently experience adverse conditions that lead to postnatal development of PH. These include premature and term infants with chronic lung diseases, such as bronchopulmonary dysplasia (BPD) and interstitial pneumonia. Unlike PPHN, there have been no randomized clinical trials for any therapy in infants with chronic PH. This review will discuss the pathophysiology, clinical presentation, assessment, and management of infants with persistent and progressive PH in early infancy. Attention will be given to common causes of progressive PH in infants, specifically, chronic lung disease (CLD) of prematurity, bronchopulmonary dysplasia (BPD), and congenital diaphragmatic hernia (CDH). The major intent is to delineate our knowledge deficits and identify areas in need of basic and translational research.

DISCUSSION

Chronic lung disease and pulmonary hypertension

General comments, epidemiology, and pathobiology The vast majority of newborns with CLD are premature infants with BPD, currently defined as the need for supplemental oxygen at 36 weeks' corrected age of gestation. Although it has long been known that infants with BPD are at risk of developing cardiovascular complications, information about the prevalence of PH in BPD is both scarce and inadequate. Recently, it was reported that echocardiographic evidence of PH could be found in 25%–37% of patients with BPD.^7,8 However, these findings reflect the retrospective analysis of echocardiograms obtained in subsets of patients with BPD; that is, not all infants with BPD had studies to evaluate the presence or absence of PH. The true prevalence of PH in infants and children with BPD will require studies that are designed to prospectively evaluate the presence of PH in all premature infants at risk of developing BPD.

Determining the prevalence of PH in BPD will be challenging. One issue is that the timing and frequency of assessment for PH in patients with BPD have not been studied or defined. In a prospective study, 6.2% of infants with birth weights <1,000 g who survived to postnatal day 28 had evidence of PH on echocardiograms performed soon thereafter.⁹ Notably, the prevalence of PH increased to 17.9% when subsequent echocardiograms were performed in those patients with severe lung disease or clinical signs suggestive of right-sided heart failure. It is clear that a one-time echocardiographic assessment will not be sufficient to determine the prevalence of PH in patients at risk for or with established BPD.

Limitations in the sensitivity of standard echocardiographic assessments in making an accurate diagnosis of PH and knowledge that PVR is dynamic, that is, influenced by the infant's mood, level of sedation, and whether the infant is acutely ill, add to the difficulty in determining the prevalence of PH in infants with BPD. In fact, there is evidence that the prevalence of subclinical PH in infants with BPD may be as high as 39%.^10,11

Another challenge will be the application of new information about the prevalence/diagnosis of PH to the therapy and prognosis for the individual patient. This is because the increased PVR may resolve over time in many infants with BPD.^7,12,13 Yet, once diagnosed with PH, the outcome for infants with BPD can be quite dismal, a fact that has not changed in 3 decades. In the 1980s, echocardiographic evidence of PH persisting beyond the first few months of life was associated with up to 40% mortality in infants with CLD.^14,15 In the 2000s, the estimated survival rate of infants with PH and CLD is 64% at 6 months and 53% at 2 years.¹² We clearly have made no progress since the 1980s. Moreover, for the specific subset of infants with BPD requiring prolonged positive pressure ventilation, mortality is increased nearly 4-fold for those with PH compared to those with BPD but without PH.⁸

At present, when an infant is diagnosed with BPD and coexisting PH, there is no reliable way to predict the clinical outcome. In particular, it is not possible to differentiate between those who will resolve their high PVR and those who will suffer a progressive course ultimately accompanied by right-sided heart failure or cor pulmonale (Fig. 1). There is growing awareness that adult diseases have fetal and neonatal origins and that disruptions in vascular/lung development that take place in infancy may place the child/adult at greater risk for subsequent vascular diseases.¹⁶ Moreover, it is quite probable that once evidence of right-sided heart failure is present, a significant amount of the pulmonary circulation is involved, so that complete resolution of the PH may no longer be possible. Thus, although the long-term significance of subclinical or resolving PH is not known, it seems prudent to try to determine the true prevalence of PH in infants with BPD, to do so early in the disease course, and to design effective therapies to reverse or prevent the process, reestablishing a normal pattern of cardiopulmonary development.

Figure 1.

Pathobiology of progressive neonatal hypertension. The question marks denote knowledge deficits that need to be addressed in order to improve outcomes for these patients. One question mark: What signaling mechanisms underlie the structural and functional changes in the pulmonary circulation? Two question marks: What technological advances can be made to detect/diagnose pulmonary hypertension before the pulmonary circulation is substantially compromised? Three question marks: What forms of evaluation (biomarkers, genetic tests, etc.) need to be discovered and utilized to predict which infants will develop and then resolve their pulmonary hypertension and which will follow a course culminating in right-sided heart failure?

Despite decades of research, the pathogenesis of BPD is not completely understood.¹⁷ Therefore, it is perhaps not surprising that why and when some infants with BPD develop clinically significant PH remain unclear. Even term infants have lungs that are not fully developed at birth. Between birth and approximately 2–4 years of life, significant alveolar development takes place,¹⁸ with recent evidence suggesting that this process continues into adolescence¹⁹ and is impaired in infants and toddlers with CLD.²⁰ It is critical to remember that under normal circumstances, the number of intra-acinar vessels also continue to increase after birth.¹⁸ When exposed to injurious stimuli, both alveoli and intra-acinar vessels may fail to develop normally,^21,22 such that vascular rarefaction, which reduces the total cross-sectional area of the pulmonary circulation, is a logical component of PH in infants with BPD.^23,24 However, reports of the presence of marked angiogenesis in lungs of ventilated preterm infants shed some uncertainty on the role of intra-acinar vascular growth arrest in the pathogenesis of PH in infants with BPD.²⁵

Structural and functional changes in the distal pulmonary circulation are uncontested vascular abnormalities that increase PVR and contribute to PH in BPD (Fig. 1).^21,26,27 In addition, there is growing awareness that stiffness of the entire pulmonary circulation, that is, loss of compliance in both distal and proximal pulmonary arteries, also contributes to right ventricular afterload and thereby contributes to PH.^28,29 Some of the structural changes in the pulmonary vasculature of infants with BPD are similar to those found in many types of PH in older children and adults and include distal extension of smooth muscle, thickening of the media and adventitia, and excessive accumulation of matrix protein in the pulmonary vessel walls.^21,26,27 Unlike adults with PH, intimal hyperplasia and plexiform lesions are not commonly found in the pulmonary vasculature of infants with BPD.³⁰

The precise stimuli responsible for pulmonary vascular remodeling, abnormal tone, and vascular rarefaction in infants with BPD are not known but include hyperoxia, oxidative injury, and inflammation, the most cited factors currently implicated in maldevelopment and damage to the airways and alveoli. Prolonged or intermittent hypoxia is thought to play a prominent role in the pathogenesis of PH in infants with BPD.^27,31 Diminished intra-acinar vessel development in infants with BPD could contribute to PH not only by reducing the cross-sectional area of the vascular bed but also by impairing gas exchange, leading to a vicious cycle. Although it is clear that a number of injurious conditions contribute to the structural and functional changes in the pulmonary circulation of these infants, the precise signaling mechanisms mediating these changes remain unclear (Fig. 1).

Animal models have been used to study the aberrant signaling underlying PH in infants with BPD. Based on findings with animal models, abnormalities in NO signaling have been strongly implicated in the pathogenesis of the impaired alveolar and vascular growth.^24,32–35 Genetic mouse models hold promise for providing mechanistic information about the molecular signals leading to decreased alveolarization and angiogenesis in BPD. However, not all components of the vascular abnormalities found in PH are manifest in mice.³⁶ In particular, mice exhibit minimal pulmonary vascular remodeling in response to hypoxia, a stimulus that is known to be associated with the development of PH.³⁶ Thus, a variety of animal models will be needed to tease out all the mechanisms contributing to the vascular disease found in PH in human infants. Accordingly, it should be noted that studies with newborn sheep and pigs have provided evidence that NO signaling abnormalities are involved in the development of the increased pulmonary vascular tone and aberrant pulmonary vascular responsiveness that are hallmarks of PH in infants.^32,37,38

Altered production of other known vasoactive mediators, including prostanoids and endothelin (ET)–1,^39,40 have also been found in newborn animal models of PH. Alterations in any of these vasoactive agents could impact both vasomotor tone and vascular remodeling, the latter via an influence on smooth muscle cell mitogenesis. The relative contributions of vasomotor tone and vascular remodeling in animal models of PH or in human infants with BPD are not known. Inhibiting ET-1 signaling was shown to ameliorate pulmonary vascular remodeling but had minimal effect on the development of PH in chronically hypoxic newborn piglets.⁴⁰ This latter study, among others, indicates that although remodeling may be important, the contribution from vasomotor tone should not be discounted and must continue to be considered when devising therapies for preventing the development of PH in infants with BPD.

Clinical presentation

Clinical symptoms and signs of PH in infants with BPD are nonspecific and difficult to distinguish from the underlying CLD. An awareness of the risk of PH in any infant with developing or established BPD is crucial. In particular, infants who have persistent oxygen requirements, recurrent cyanotic episodes, poor growth, or chronic aspiration or those who are unable to wean from ventilatory support should be considered at high risk for developing PH.

Diagnosis

There are no established standards for diagnosing PH in neonates with BPD. Cardiac catheterization, the standard method for assessing pulmonary vascular disease in older children and adults, is considered too invasive for routine use in the neonatal population. Cardiac catheterization is generally reserved for those BPD patients with severe cardiorespiratory disease, concern for significant PH despite optimal clinical management, or to exclude or document anatomic cardiac lesions and is typically performed late in the clinical course for such infants. Echocardiography is commonly used to screen for and follow PH in infants with BPD. Unfortunately, there is poor correlation between echocardiographic and cardiac catheterization findings. Of great concern, the absence of tricuspid regurgitant jet velocity on echocardiographic evaluation does not rule out the presence of severe PH diagnosed by cardiac catheterization.⁴¹ Technological advances, such as myocardial tissue Doppler^42,43 or right ventricular strain measurement by speckle tracking echocardiography,^44,45 might increase the utility of echocardiography in diagnosing PH. In addition, once adapted for use in infants, pulmonary vascular impedance measurements to assess both PVR and stiffness hold promise to improve our ability to predict clinical outcomes in patients with PH.⁴⁶ Last, there is growing appreciation that some infants with BPD and PH can develop progressive pulmonary vein stenosis,⁴⁷ an echocardiographic finding that is associated with very high mortality.

Treatment

There are no randomized clinical trials that have evaluated therapies for PH in infants with BPD. For decades the treatment has been to try to resolve the underlying respiratory disorder and provide optimal nutrition for lung growth and development. Although ineffective in reversing PH in all patients with BPD, the importance of the preceding therapeutic goals cannot be overstated. The other long-standing therapy has been the use of oxygen as a vasodilator. The amount of oxygen to use and the appropriate oxygen saturation targets are not known. The desire to achieve a maximal decline in pulmonary arterial pressure must be counterbalanced by cognizance of oxygen toxicity, particularly because oxygen therapy may not only worsen parenchymal lung disease and promote free-radical mediated pulmonary vascular injury but also contribute to the development of retinopathy of prematurity in the at-risk infant. Oxygen saturations of approximately 95% are commonly targeted.^48,49 This target is based in part on one study in infants with BPD and PH that showed that during cardiac catheterization, the maximal decrease in pulmonary arterial pressure was achieved when the oxygen saturation exceeded 95%.⁵⁰ Another study found little improvement in pulmonary arterial pressure when oxygen saturations increased from 93% to 98%.⁵¹ Longitudinal controlled studies comparing progression of PH at various levels of oxygen saturations are not available to guide therapy. Avoidance of hypoxemia and its associated acute increase in PVR is, however, a reasonable and commonly accepted goal of oxygen therapy. To achieve this, the knowledge that oxygenation varies with activity and feeding and during sleep must be considered. Accordingly and particularly relevant for outpatient management, the inability of brief pulse oximetry assessments to accurately evaluate pulmonary reserves and oxygen needs during stress must be kept in mind.⁵²

Despite absence of well-designed and appropriately powered randomized controlled trials, there is some limited experience with vasodilators other than oxygen to treat PH in infants with CLD. The response to iNO in infants with documented PH and BPD is variable, but some patients appear to clinically improve, at least temporarily.^53,54 Recent evidence from animal models reveals that reactive oxygen species (ROS) may explain, at least in part, the failure of iNO therapy to improve PH.⁵⁵ This is because ROS, which may be involved in the pathogenesis of BPD and PH, interact with and thereby reduce the bioavailability of iNO.⁵⁶ It should be noted that randomized controlled trials of iNO performed in preterm infants have not shown consistent efficacy of this drug in preventing BPD in human infants^57–60 and its use for this indication is not approved by the Food and Drug Administration (FDA). At this point, until more information is available, it seems prudent to restrict clinical use of iNO to the treatment of PPHN and hypoxic respiratory failure in human infants greater than 34 weeks^61,62 and to infants with other pulmonary vascular diseases enrolled in clinical studies.

The phosphodiesterase inhibitor sildenafil may be effective in infants with BPD and PH.⁶³ However, uncertainty about the utility of this therapy is raised by findings showing that acute reductions in right ventricular peak systolic pressure in infants with BPD receiving sildenafil were not accompanied by improvements in gas exchange.⁶⁴ Other therapies that manipulate the NO signaling pathway, such as the NO precursor citrulline, may hold promise for improving PH in this patient population.^65,66 Oral therapy with the nonselective endothelin receptor antagonist bosentan may also be beneficial, but concerns about liver toxicity limit the potential for widespread use of this agent and there is limited experience in the neonatal population.⁶³ No recommendations for routine clinical use can be made for any of these therapies as none have been adequately studied. In fact, the recent FDA warning about use of sildenafil in patients between 1 and 17 years of age brings to light the need to emphasize that all potential therapies be adequately studied in age-appropriate pediatric patients before their widespread use in patients with BPD and PH can be advocated.⁶⁷

Another issue relevant to dilator use in these patients is the possible contribution to PH from left-sided systolic or diastolic cardiac dysfunction or venoocclusive disease.^23,47,68 In these cases, the patient's clinical condition could worsen on dilator therapies. Therapy for these infants is further confounded by the realization that responses to various dilator therapies may vary with the stage of BPD and PH. This is, in part, due to the fact that the relative contribution of functional and structural changes to PH in infants with BPD is commonly believed to change with evolution of the disease process.^69,70 Nonetheless, there is evidence that high PVR continues to play a prominent role in older infants with BPD, based on studies showing their responsiveness to altered oxygen tension and iNO.^51,71 Awareness that a reactive component, responsive to dilator therapy, could be present should be kept in mind, even in infants with advanced stages of BPD. At all stages of disease, avoidance of vasoconstrictive stimuli, such as hypoxia, should play a prominent role in treating these infants. Vigilance for gastroesophageal reflux, dysphagia, and any potential cause of aspiration as well as prophylaxis for respiratory diseases, such as RSV, which could worsen the underlying lung disease as well as trigger pulmonary vasoconstriction, are warranted in these patients. Moreover, responses to all therapies must be carefully monitored and consideration for cardiac catheterization given to evaluate for pulmonary venous obstruction or left heart dysfunction and to assess pulmonary vascular reactivity in patients who have unexplained pulmonary edema and fail to respond to oxygen therapy alone.

Congenital diaphragmatic hernia and pulmonary hypertension

General comments, epidemiology, and pathobiology CDH is a life-threatening congenital anomaly resulting from failure of the posterolateral (Bochdalek) and anterior/midline (Morgagni) or crural (paraesophageal) diaphragm to fuse with the chest wall or, in the case of complete diaphragmatic agenesis, the complete absence of a muscular diaphragm. The incidence of CDH is approximately 1 : 2,500 live births.^72,73 Prenatal herniation of bowel loops and liver into the thorax leads to compression of the lungs, mediastinal shift, and hypoplasia of both the ipsilateral and contralateral lung. The morbidity and mortality from CDH is related to the timing of the herniation and resulting pulmonary and vascular hypoplasia and to the presence of other major anomalies, including cardiovascular defects, intestinal atresias, and chromosomal anomalies, not to the presence of the anatomic diaphragmatic defect per se. Even when considered separately from other possible anomalies, the degree of lung hypoplasia is so variable that it is not surprising that the CDH population is heterogeneous in physiology and complexity with a mortality rate that ranges from 8% to 80%.⁷⁴ The precise incidence of PH in infants with CDH is not known. However, it is well recognized that these infants are at great risk for PH and that the presence and persistence of PH contributes significantly to the extremely high rate of morbidity and mortality found in these infants.^75,76

Well-described structural abnormalities of the pulmonary vasculature in infants with CDH are associated with the development of PH in this population. These structural changes include a decreased number of pulmonary arteries per unit lung volume, an increase in total wall thickness of all arteries, and distal extension of smooth muscle out to the alveolar duct level.⁷⁷ In addition, extensive collagen deposition has also been found in the media and adventitia of pulmonary arteries from infants with CDH.⁷⁸ In utero lung compression acting either directly or indirectly (by decreasing pulmonary blood flow) to inhibit lung growth has been thought to be responsible for many of the pulmonary vascular structural changes. However, in utero compression may be too simplistic an explanation.^79,80 It is possible that abnormal development of the lung and fundamental alterations in the pulmonary circulation contribute to the pathobiology of PH in infants with CDH as a primary pathology that is not entirely attributable to lung compression.^79,80 This is supported by the knowledge that the impaired contralateral lung development may occur independently of compression by intrathoracic viscera. Indeed, there are some reports of altered expression of angiogenesis-related factors in lungs of infants with CDH.^81–83 In addition, several lines of investigation have implicated retinoids, which have been shown to play a role in lung and diaphragm development, in the pathogenesis of CDH.⁸⁴ Two small clinical studies of human infants with CDH showed that retinol and retinol-binding protein plasma levels were reduced in cord blood, whereas vitamin A status in mothers was comparable.^85,86 These findings support a search for candidate genes related to retinoid signaling as a genetic cause of CDH.⁸⁴ Unfortunately, the genetic basis and molecular mechanisms responsible for the abnormal lung and diaphragm development and any of the structural changes found in the pulmonary circulation of infants with CDH are not yet known or well studied.⁸⁷

It seems likely that functional changes in the pulmonary circulation contribute to PH in infants with CDH. Two animal models, a nitrofen-induced CDH model in the rat^88,89 and surgically induced CDH in fetal lambs,^90,91 have been used to evaluate functional abnormalities in the pulmonary circulation of animals with experimental CDH. Pulmonary vascular responses are abnormal in both CDH animal models.^90,92 Studies in the rat model have implicated functional pulmonary arterial abnormalities in the NO-cGMP pathway.^88,93,94 Some⁹⁵ but not all studies in the lamb model substantiate abnormalities in the NO-cGMP signaling pathway.^90,91 Elevated pulmonary expression of ET-1 and ET_A receptors⁸⁹ and exaggerated pulmonary arterial responses to ET-1 were found in the rat model.⁹⁶ Evidence has also been provided that ET-1 receptor activation favoring pulmonary vasoconstriction contributes to PH in the lamb model.^97,98

It is notable that elevated circulating levels of ET-1,⁹⁹ greater lung expression of ET_A than ET_B receptors,¹⁰⁰ decreased lung endothelial nitric oxide synthase expression,⁸³ elevated urine levels of the competitive NO synthase inhibitor, asymmetric dimethylarginine,¹⁰¹ and elevated levels of the prostanoid constrictor thromboxane^102,103 have been reported in human infants with CDH. In fact, the severity of PH in infants with CDH was recently shown to be associated with high ET-1 levels.¹⁰⁴ These latter reports provide support that an imbalance in vasodilators and vasoconstrictors, as suggested by the findings in animal models, are functionally relevant to PH in human infants. Moreover, via influences on smooth muscle cell mitogenesis, alterations in production of vasoactive mediators could contribute to the structural vascular abnormalities found in infants with CDH.⁷⁷

Clinical presentation

The clinical presentation of PH in infants with CDH is variable and not entirely predictable.^75,105,106 Infants with CDH may present with acute PPHN at birth due to inadequate gas exchange with hypoxia, hypercapnea, or respiratory acidosis. Surgical repair is generally delayed for at least 24 hours to allow for the stabilization of the infant and for a postnatal transitional decline in PVR to occur. However, some infants experience little to no postnatal decline in PVR. These infants may need to be placed emergently on ECMO preoperatively. Other infants may have marked improvements in respiratory function over the first few days to weeks of life, undergo nonurgent surgical repair, wean off ventilatory support, and recover from their initial PPHN, with or without use of iNO or other vasodilator therapy.¹⁰⁷ Other infants with underlying, unresolved, pulmonary vascular abnormalities do not completely recover from their initial PPHN and instead experience a protracted course of elevated pulmonary arterial pressure.^75,108 Not all of these infants do poorly in the long run. It has been estimated that, of those infants with a persistently elevated PVR, 50% slowly resolve their PH over weeks to months.⁷⁵ For other infants, the course of chronic PH is complicated and severe and can be accompanied by acute exacerbations of PH that necessitate a second course of ECMO or result in death. Moreover, there are reports of infants who are discharged home and months later are diagnosed with severe PH.^105,106 The variability and breadth of the clinical spectrum of PH in infants with CDH makes them a challenging group of patients to diagnose, treat, and study.

Diagnosis

In the presence of a patent ductus arteriosus, the diagnosis of PPHN in CDH can be presumptive on the basis of a pre/postductal saturation gradient of 5% or more. The absence of the pre/postductal saturation gradient does not preclude PPHN. An atrial level shunt alone will fail to produce a differential in preand postductal oxygen saturations but result in venous admixture and hypoxemia. Most clinicians rely on the use of two-dimensional echocardiography with color flow Doppler demonstrating a right-to-left shunt at the ductal and/or atrial level or other evidence of elevated pulmonary artery pressures with bowing of the atrial septum or tricuspid regurgitation to diagnose PPHN in infants with CDH. As with chronic PH in BPD, there are no established standards for diagnosis of protracted, late, or chronic PH in infants with CDH.

Treatment

The optimal strategy for medical and surgical treatment of CDH remains to be determined. Nonetheless, the potential for severe, acute PPHN in the first few hours and days of life and the knowledge that the course of PH may be protracted for days to months underlie many of the current, albeit unproven, clinical strategies used to treat infants with CDH. A common approach is to carefully manage the cardiorespiratory support of these infants, minimizing iatrogenic pulmonary damage while waiting for clinically significant PH to abate over time.^109,110 In accordance with this approach, the concept of gentle ventilation and permissive hypercapnia is a fundamental part of the treatment strategy used for these infants in many institutions.^76,111 To date, conventional ventilation is the most commonly used initial ventilation mode. High-frequency ventilation is sometimes incorporated as part of the gentle ventilation strategy and is used variably as the initial ventilation mode or as rescue therapy.^76,110,112 A randomized controlled trial comparing initial ventilator treatment with high-frequency oscillation versus conventional ventilation in infants with CDH is under way and will hopefully provide better insight into ventilation strategies in these patients.¹¹³

Unfortunately, PH, either acute, late, or chronic,¹⁰⁵ can be so severe that all conventional therapies fail, including all modes of ventilation. In these cases, the infant may be placed on ECMO as an alternative strategy to stabilize the infant while waiting for the PH to resolve. Placement on ECMO is done with the knowledge that the time period for resolution of PH is not known and may exceed the current limitation of this invasive supportive measure. Indeed, although nonrandomized studies support its use, there are no conclusive data in favor of or against the use of ECMO in infants with CDH.⁷⁴ As an additional supportive measure, pulmonary vasodilators are often used prior to, concomitant with, or following ECMO, even though none has yet been proven to impact important clinical outcomes.

Initial case reports suggested that iNO therapy could improve oxygenation in infants with CDH. It has been a disappointment that large randomized, controlled trials have not demonstrated that early administration of iNO reduced death or ECMO utilization in CDH patients.¹¹⁴ Limited evidence indicates that iNO may be useful in stabilizing the infant for transport or prior to initiating ECMO.^114,115 However, caution and careful evaluation of LV performance has been recommended when using iNO in patients with CDH.¹⁰⁵ This is because in some infants with CDH, left ventricular output is diminished, causing a right ventricular–dependent systemic circulation; iNO delivered by nasal cannula is a potential candidate for long-term treatment to enhance resolution of persistent PH in newborns with CDH.¹¹⁶

Information about the efficacy of other pulmonary dilators in infants with CDH is extremely limited and consists of case reports. Prostacyclin was reported to be helpful as a temporary bridge to ECMO.¹¹⁷ Some clinicians have advocated use of prostaglandin E₁ to open or maintain ductal patency to prevent right ventricular failure.^118,119 Milrinone, a phosphodiesterase-3 inhibitor, has been used both as a vasodilator and to treat the cardiac dysfunction that can accompany PH in infants with CDH.¹²⁰ The phosphodiesterase-5 antagonist sildenafil has been used to wean an infant from iNO¹⁰⁴ and to reduce PH in patients with CDH unresponsive to iNO.¹²¹ Combined use of sildenafil, prostacyclin, and iNO was reported to transiently improve oxygenation in an infant with severe PH and CDH.¹²² Another patient with CDH was noted to have severe intractable PH while being treated with iNO, sildenafil, and inhaled prostacyclin but showed gradual clinical improvement after treatment with the endothelin receptor antagonist bosentan and the platelet-derived growth factor receptor antagonist imatinib was added.¹²³ Whether any pulmonary vasodilators given solely or in combination will have long-term benefit in CDH patients with acute or chronic PH remains to be shown. Randomized controlled trials of oral sildenafil (Pfizer, NCT1069861/Keller, San Francisco, CA, NCT00133679) and of bosentan (Actelion, NCT01223352) in infants with CDH and severe PH are under way.¹²⁴ Long-term use of these and other agents warrants evaluation for efficacy in promoting lung growth and resolving vascular remodeling in PH, beyond their potential acute vasodilatory effects. Moreover, based on recent findings in animal models, another avenue that merits future exploration is antenatal treatment with agents such as sildenafil to promote lung growth and development and prevent or counteract vascular remodeling in utero.^125,126

CONCLUSIONS

Infants with chronic progressive PH associated with BPD and CDH are an understudied group of patients in need of effective therapies. Knowledge deficits in many aspects of the pathobiology of progressive PH serve as impediments to successfully managing these infants (Fig. 1). Improved outcomes for these infants will require multidisciplinary efforts including those from basic science laboratories whose discoveries can be tested in randomized clinical trials. Because of the limited number of patients with these disorders at any single institution, meaningful clinical trial design will require collaborative efforts. Relevant clinical and functional classification systems for children with PH have at long last been developed and should facilitate the pursuit of meaningful research.^5,6 With adequate funding of transdisciplinary research focused on this patient population, the knowledge needed to improve outcomes for infants with progressive forms of PH may be within our grasp.

Footnotes

Source of Support: This work was supported by RO1 HL97566 (to CDF).

Conflict of Interest: None declared.

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