Pulmonary Hypertension in the child with Bronchopulmonary Dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of prematurity resulting from complex interactions of perinatal factors that often lead to prolonged respiratory support and increased pulmonary morbidity. There is also growing appreciation for the dysmorphic pulmonary bed characterized by vascular growth arrest and remodeling, resulting in pulmonary vascular disease (PVD) and its most severe form, pulmonary hypertension (PH) in children with BPD. In this review, we comprehensively discuss the pathophysiology of PH in children with BPD, evaluate the current recommendations for screening and diagnosis of pulmonary hypertension, discern associated comorbid conditions, and outline the current treatment options.

Introduction

Bronchopulmonary dysplasia (BPD) was first described in the late 1960s as a chronic lung disease associated with high mortality that followed acute respiratory distress syndrome in premature infants¹. BPD patients have a spectrum of respiratory disease phenotypes². Pulmonary vascular disease and in its most severe form, BPD-associated PH (BPD-PH), are increasingly recognized disease phenotypes for premature infants². Over time, we have had a growing understanding of lung development and mechanisms of perinatal lung injury. The use of antenatal steroids, surfactant, refinement in ventilation strategies, enhanced nutrition, and other improvements in neonatal care practices have been significant advances in the care of extremely low gestational age newborns (ELGANs)³. With increased survival of these extremely premature infants and a steady incidence of BPD, it is important to have a detailed understanding of BPD-PH, as this disease phenotype associates with significant morbidity and mortality, especially in the first 6 months of life but also with potential for cardiopulmonary disease into adulthood^{4, 5}. BPD-PH patients can also present management challenges secondary to a complex hemodynamic profile and interplay of exacerbating and comorbid conditions. The objective of this review is to provide a comprehensive framework for clinicians treating patients with BPD-PH, with detail to pathophysiology, hemodynamics, diagnosis, screening, and management.

Definitions

Controversy persists regarding a formal definition for BPD, which is likely secondary to a spectrum of disease severity and clinical phenotypes. Clinically, BPD is generally defined as the use of supplemental oxygen at 36 weeks postmenstrual age (PMA) in infants born at or below 32 weeks gestation, per recommendations from a National Institutes of Health workshop in 2001⁶. BPD can be further classified into mild, moderate, or severe based on level of respiratory support⁶.

PH is a condition of elevated pulmonary vascular pressure which may occur in association with a wide variety of conditions, or in isolation. Historically, PH in children has been defined the same as that in adults. PH was previously arbitrarily defined as a mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest during right heart catheterization⁷. This definition has now been modified to a mPAP >20 mmHg⁸, following evidence in adult studies that even mild elevations in mPAP were found to be independent predictors of poor survival⁹. Hemodynamically, precapillary PH or pulmonary arterial hypertension (PAH) can be defined as mPAP >20 mmHg, indexed pulmonary vascular resistance (PVRi) >3 WU·m², and pulmonary arterial wedge pressure <15 mmHg in children over 3 months of age^{10, 11}. During fetal circulation, pulmonary vascular resistance is high and decreases following term delivery, reaching a level similar to adult physiology by 2 to 3 months of age¹⁰. The time course of this transition is less clear for an infant born prematurely.

There is an increasing recognition that PVD, including PH, is not a single entity in patients with BPD, just as BPD itself is not one distinct clinical phenotype in preterm infants¹². While each patient is different, in general, BPD-PH may be further delineated into ‘Early’, ‘Late’, and ‘Chronic’ PVD^{13, 14}. In the initial few weeks post-delivery, and early form of PH (‘Early PH) may present not only in term, but also preterm, infants. This early PVD phenotype is propelled by a delayed transition of the lung circulation post-birth in neonates, often accompanied by hypoxemia associated with right-to-left shunt of blood thus not oxygenated across the pulmonary vascular bed¹³. ‘Early PH’ in neonates is in contrast to a later form of PH (often termed ‘Late PH’ due to its presentation later in the neonatal and/or early infant course post-delivery), which may present over weeks to months either clinically or by evidence of PH on echocardiogram. The etiology of ‘Late PH’ is multifactorial, including but not limited to antenatal and postnatal influences, including reduced pulmonary vascular surface area, exaggerated constriction of the pulmonary vascular bed in response to insults, chronic and intermittent insults including infection, hypoxemia, mechanical ventilation-associated trauma and other forms of inflammation. Infants with Late PH are often burdened by additional challenges including substantial respiratory support needs, intermittent exacerbations of their cardiopulmonary status, and challenges with persistent and/or intermittent hypoxemic events. While Late PH may be limited, it may also persist beyond neonatal intensive care discharge. In some circumstances, Late PH will evolve into a persistent form (‘Chronic PH’), impacting formerly premature children in late infancy and beyond with more typical PH features including but not limited to reduced cardiopulmonary fitness and exercise tolerance, at times well into childhood¹³. Children with the ‘Chronic PH’ form of BPD-PH represent a significant percentage of patients followed in Pediatric PH Specialty Centers such as at Vanderbilt, where approximately 35% of our outpatients have this chronic form of BPD-PH. In addition, the Pediatric Pulmonary Hypertension Network (PPHNet) recently published overall results from their NIH-funded registry, noting a high percentage of patients with group 3 PH within their registry—most of these subjects had BPD-PH¹⁵. Finally, it should be noted that growing data suggest that an unknown percentage of asymptomatic adults born premature have elevated pulmonary pressures, elevated pulmonary vascular resistance, and right ventricular dysfunction particularly evident with exercise challenge¹⁶.

Prevalence and Prognosis

The reported prevalence estimates of BPD-associated PH (BPD-PH) vary in the literature. A meta-analysis of 25 selected publications, with median gestational age of <30 weeks, reported PH prevalence of 6% in infants with mild BPD, 12% in infants with moderate BPD, and 39% in infants with severe BPD¹⁷. This meta-analysis also found a prevalence of 2% in the absence of BPD, which highlights that prematurity in itself influences vascular development and subsequent PVD¹⁷.

There is a significant increase in both morbidity and mortality in those with BPD-PH compared to infants without PH. Severe BPD with PH has been associated with adverse outcomes including need for tracheostomy, gastrostomy, post-neonatal intensive care unit (NICU) home oxygen need, and hospital readmission prior to 1 year of corrected gestational age¹⁸. There is also additional concern for impaired neurodevelopmental outcomes and suboptimal somatic growth in those with BPD-PH^{19, 20}. Mortality rates are reported up to 4 times higher in those with BPD-PH compared to those with BPD alone^{17, 18, 21}. In contrast to other etiologies of PH, which are likely to be progressive, patients with BPD-PH can have improvement and even resolution of PH with time and lung growth²².

Pathophysiology

The pathogenesis of BPD-PH is multifactorial, with complex interactions between prenatal and postnatal factors, resulting in decreased growth, structure, and function of the premature lung. The inherent contribution of genetic and epigenetic variations are less well understood but may also contribute. There are five stages of fetal lung development: embryonic, pseudoglandular, canalicular, saccular, and alveolar²³, with alveolarization occurring after 36 weeks gestation. In extremely premature infants, there is disruption of the saccular phase and even late canalicular phase of lung development, which results in significant alveolar simplification, characteristic of what is often referred to as “new BPD”^{6, 24, 25}. This contrasts with the heterogeneity seen with “old BPD” with diffuse parenchymal fibrosis from surfactant deficiency and ventilation injury, characteristic of the pre-surfactant era¹. In addition to reduction in surface area for gas exchange, patients born premature also have a dysmorphic capillary bed with dysregulation of pulmonary vascular development, characterized by vascular growth arrest and an abnormal distribution of pulmonary capillaries²⁶. This fragile vascular system can be further influenced by hemodynamic stress, hyperoxia, and alveolar hypoxia, which leads to smooth muscle proliferation and integration myofibroblasts and fibroblasts into the vessel walls^27–31. Stated simply, BPD is morphologic disruption of all features of the lung, including airway, vascular, and lymphatics features. Molecular irregularities implicate a host of different perturbed pathways, including an imbalance in TGFβ/BMP and vascular endothelial growth factor (VEGF) signaling^32–34. The vascular alterations ultimately result in increased pulmonary vascular resistance, from vascular narrowing and decreased compliance, with eventual PH and right heart strain. Uncontrolled, right heart dysfunction and ultimately right ventricular (RV) failure may occur. Systemic arterial stiffness in patients with BPD can result in sufficient afterload to create high end-diastolic pressure and subsequent left ventricular (LV) hypertrophy and dysfunction³⁵, which can lead to pulmonary edema.

Risk Factors (Table 1)

Table 1.

Factors associated with BPD-PH which may contribute to the development of BPD-PH in the child born prematurely.

Prenatal Factors	Postnatal Factors
Maternal hypertensive vascular disease of pregnancy	Toxicity from prolonged hyperoxic exposure
Anomalies of the placenta	Toxicity from prolonged hypoxemic exposure
Intrauterine growth restriction and associated conditions (e.g., oligohydramnios and small for gestational age)	Physical trauma from mechanical ventilation and related support
Chorioamnionitis or other infections	Sepsis or other infections
Fetal and/or maternal epigenic changes	Hemodynamic alterations related to patent ductus arteriosus (PDA) or congenital heart disease
	Retinopathy of prematurity (ROP)
	Necrotizing enterocolitis (NEC)
	Stenosis of one or more pulmonary veins

Understanding maternal, perinatal, and postnatal risk factors for BPD-PH can inform diagnostic and therapeutic approaches in these infants. There is notable variability in which premature infants develop PH. It remains an important clinical question why an infant with severe BPD does not develop PH while an infant on less respiratory support does develop PH.

There is growing evidence that maternal vascular disease during pregnancy and placental maldevelopment increases the risk for BPD-PH³⁶. Infants born early due to maternal preeclampsia, especially when accompanied by reversed or absent end diastolic flow, and those with intrauterine growth restriction have been noted to be at high risk for development of PH³⁷. It remains unclear whether such premature risk factors prompt a distinct pathophysiologic cause of BPD-PH.

Several post-utero clinical variables have also been associated with development of PH in those with BPD. A 2016 meta-analysis found that longer invasive mechanical ventilation associated with the highest odds ratio for the development of PH³⁸. In addition, the length of NICU hospitalization, oligohydramnios with intrauterine growth restriction and/or small for gestational age (SGA) status, use of high frequency oscillatory ventilation (HFOV), sepsis, and severity of BPD were associated with PH³⁸. There have been also associations in the literature between BPD-PH and non-pulmonary conditions, such as retinopathy of prematurity (ROP) and necrotizing enterocolitis (NEC), with a notably strong association of NEC and BPD-PH¹⁷. The same meta-analysis suggested a weak association between having a patent ductus arteriosus (PDA) and PH¹⁷. Not surprisingly, ROP, NEC, and PDA all involve, to varying degrees, vascular dysplasia.

Diagnosis

The diagnosis of PH in patients with BPD requires a high level of clinical suspicion, as the presenting symptoms can be non-specific and have considerable overlap with other pulmonary etiologies³⁹. Clinical examination can be used to augment imaging findings to support the diagnosis of PH. The majority of patients present during their NICU course; however, presentation post-discharge, and even post infancy, is possible. Patients may present with supplemental oxygen need for hypoxemia or have intermittent desaturations and bradycardic events. In more severe cases, the infant may have respiratory deteriorations or have hypoxemic events with routine care, requiring sedation or paralysis. In the setting of moderate to severe PH, there may be right heart dysfunction, which when severe can present with hepatomegaly, facial edema, peripheral edema, or poor feeding. When performing a physical exam on an infant with suspected PH, one may detect abnormal heart sounds, such as a prominent S2, holosystolic murmur, or a hyperdynamic precordium. Palpation of the liver and spleen is an important part of the abdominal exam to assess for hepatosplenomegaly.

Screening

Despite published guidelines on evaluation and management of PH, and BPD-PH, there continues to be variation in practice based on the institution, even amongst experienced centers. There is continued need for high quality evidence regarding evaluation and management of these patients. In 2015, a joint report from the American Heart Association and the American Thoracic Society published guidelines for the care of pediatric PH patients, which included BPD-PH⁷. This work product remains an important contribution and guide for clinicians, as well as additional collaborative guidelines^{34, 40}. More specific recommendations for BPD-PH have since been provided by the Pediatric Pulmonary Hypertension Network (PPHNet), and from European specialists^34,41. These multidisciplinary panels of PH experts have each provided practical frameworks for diagnosis and management of infants with BPD-PH based on level of evidence and potential benefit (Table 2).

Table 2.

Comparison of published guidelines for screening and management of BPD-PH from the American Heart Association/American Thoracic Society (AHA/ATS), European Pediatric Pulmonary Vascular Disease Network (EPPVDN), and Pediatric Pulmonary Hypertension Network (PPHNet)^7,32,39.

	AHA/ATS	EPPVDN	PPHNet
Screening for PH by echocardiogram	Recommended in infants with established BPD	If severe respiratory compromise is present in any preterm infant <28 weeks gestation In any infant with established BPD at corrected age of 36 weeks and before discharge In any infant with prolonged oxygen requirement, poor growth, or unsatisfactory clinical improvement	Severe hypoxemic respiratory failure shortly after birth attributed primarily to persistent pulmonary hypertension of the newborn (PPHN) physiology despite optimal management of underlying lung disease Continued need for ventilator support at postnatal day 7, as echocardiogram evidence of PH at day 7 suggests high risk for BPD and may alter therapy With sustained need for significant respiratory support at any age, especially with recurrent episodes of hypoxemia. At the time of formal BPD diagnosis per current practice (36 weeks PMA)
Cardiac catheterization	For infants who have persistent signs of severe cardiorespiratory disease or clinical deterioration not directly related to airways disease Infants who are suspected of having significant PH despite optimal management of their lung disease and associated morbidities Infants who are candidates for long-term PH-specific drug therapy Infants who have unexplained, recurrent pulmonary edema	Should be considered before introduction of a second PH-specific medication Advised if PH worsens under dual PH-specific therapy or if an unsatisfactory response to PH-specific therapy is seen in any infant with PH at a corrected postnatal age of >3 months Additional indications include concern for vascular abnormalities (e.g., pulmonary vein stenosis), other features of an atypical response to therapy, and/or failure to thrive	To confirm the echocardiographic diagnosis of PH Determine disease severity Evaluate the potential contributions of shunt lesions, PVS, LV diastolic dysfunction, aortopulmonary collaterals, and close shunts if appropriate To define the need for the addition of combination drug therapy, especially systemic prostanoid therapy In the setting of clinical deterioration and echocardiographic evidence of increasing PH or decreasing ventricular function
Evaluation of comorbidities	Evaluation and treatment of lung disease, including assessments for hypoxemia, aspiration, structural airway disease, and the need for changes in respiratory support, are recommended in infants with BPD-PH before initiation of PH-specific therapy	Maximizing non-invasive respiratory support as much as possible in order to avoid mechanical ventilation and therefore aggravation of lung injury is advisable Treatment with diuretics may be considered in infants with severe BPD Infants with severe BPD have higher caloric requirements, which should be accounted for in their nutritional plans	Evaluation and treatment of comorbidities that impact the severity of lung disease should be undertaken with the diagnosis of BPD-PH infants before the initiation of PH-specific therapy Studies should include evaluation for intermittent or sustained hypoxemia, aspiration, gastroesophageal reflux disease, structural airways disease, pulmonary artery and vein stenosis, left ventricular diastolic dysfunction, and aortopulmonary collaterals
Management	Supplemental oxygen therapy is reasonable to avoid episodic or sustained hypoxemia and with the goal of maintaining O2 saturations between 92%−95% PH-specific therapy can be useful for infants with BPD-PH on optimal treatment of underlying respiratory and cardiac disease Treatment with iNO can be effective for infants with established BPD and symptomatic PH	Supplemental oxygen should be supplied when target oxygen saturations are >93% for infants with suspected and >95% for infants with proven PH PH-specific therapy should be considered if PH persists after optimizing ventilation strategies and oxygenation Infants with BPD-PH are prone to a sudden elevation of PVR when undergoing stressful procedures (“PH crisis”) and often require sufficient sedation or even analgesia/relaxation before such procedures are performed	Supplemental oxygen therapy should be used to avoid episodic or sustained hypoxemia and with the goal of maintaining O2 saturations between 92%−95% PH-specific therapy should be considered for infants with BPD-PH after optimal treatment of underlying respiratory and cardiac disease Pharmacologic therapy should be initiated in patients with evidence of significantly elevated pulmonary vascular resistance and right ventricular impairment not related to left heart disease or pulmonary vein stenosis iNO should be used for acute PH crises and weaned after stabilization
Follow-up	Infants should be followed up by serial echocardiograms, which should be obtained at least every 2 to 4 weeks with the initiation of therapy and at 4- to 6-month intervals with stable disease	Infants should be followed by clinical evaluation, echocardiogram, and repeat NT-proBNP every 1–4 weeks while initiating therapy.	Infants should have outpatient follow-up with a multidisciplinary PH team at intervals of 3–4 months with use of echocardiograms, biomarkers, hemodynamic studies, and sleep studies when indicated, depending on disease severity and clinical progress

At our Center, as a PPHNet member institution, we most strictly follow the PPHNet guidelines. A screening echocardiogram should be considered if severe hypoxemic respiratory failure is present shortly after birth despite optimal management of lung disease⁴¹, especially in infants with prenatal risk factors (Table 1). Prospective studies have suggested that features of PH by echocardiogram, as early as postnatal day 7, is strongly associated with development of BPD, but this remains to be definitively determined as to whether screening at this time point influences clinical care positively^{26, 42, 43}. While no studies have been conducted to assess the impact of early PH therapy on BPD-PH outcomes, early detection of PVD may change management, especially with respect to monitoring for hypoxemia, hypoventilation, and other exacerbating factors. Given this, it is worth considering pursuit of an echocardiogram in an infant with continued ventilator support at postnatal day 7⁴¹. Routine screening echocardiogram is recommended at the time of formal BPD diagnosis at 36 weeks PMA by most specialists including our group, even if previous echocardiograms have been reassuring against PH, especially in infants with moderate to severe BPD^{41, 42}. While subjects with BPD are at highest risk, we suggest a screening echocardiogram for all subjects born less than 32 weeks gestation at 36 weeks PMA or at the time of NICU discharge, whichever comes first. We feel that if the echocardiogram is normal at that time, it should be repeated every 1–2 months until respiratory status improves in those with moderate and severe BPD forms⁴⁴. In addition to a screening echocardiogram at 36 weeks PMA, for any infant thereafter with chronic challenges including persistent oxygen requirement, impaired growth and/or nutritional progress, unclear clinical improvement over time, or other concerns we screen for PH with consideration for repeat screening every 4–6 weeks if the clinical concerns persist. PH may also develop post-NICU discharge, for instance in the setting of a viral respiratory illness or other acute insults, and should be suspected in a patient with escalating respiratory support or worsening hypoxemia, in addition to subtle findings of poor weight gain and feeding difficulties; screening for PH in these settings should be dictated by the clinical condition and course⁴¹.

Echocardiogram

Transthoracic echocardiogram is an important modality for both screening and monitoring response to pharmacologic and non-pharmacologic interventions. While echocardiography is non-invasive and easily accessible, it does come with limitations and cardiac catheterization remains the gold standard for diagnosis of PH. Echocardiogram evaluation should identify anatomic differences with characterization of shunts and pulmonary veins, as pulmonary vein stenosis in the setting of BPD-PH impacts management, with careful balancing of pre- and post-capillary disease³⁹. Echocardiogram should also assess interventricular septal position during systole and diastole, as well as biventricular size, degree of hypertrophy, and any ventricular dysfunction⁴¹. One of the most utilized tools is using the tricuspid regurgitant jet (TRJV) doppler measurement to estimate the right ventricular pressure (RVp). This can then be compared to the systemic blood pressure, which should be included in the echocardiogram report. Unfortunately, the TRJV is not always reproducible and can be difficult to detect based on other influences, such as lung hyperinflation. Estimated pulmonary artery pressure by echocardiogram has been shown to poorly correlate with mPAP determined by cardiac catheterization⁴⁵. Echocardiography is sensitive for detection of PH but is not as accurate as cardiac catheterization in classifying disease severity⁴¹. However, trending multiple findings, such as non-invasive markers of severity (TRJV, septal position, RV systolic time intervals), degree of RV performance (morphology and function), and shunt physiology can be useful in monitoring disease progression⁴⁶. If PH is identified on echocardiogram, follow-up studies should be considered at frequent intervals, as in every 1–2 weeks initially, until the patient has stabilized.

Laboratory Evaluation

Serum brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are helpful biomarkers for monitoring right ventricular strain, as they are released from the cardiac myocardium during wall stress, either from pressure or volume overload states^{34, 40}. Studies have associated BNP and NT-pro-BNP with pulmonary vascular resistance, mPAP, and disease outcomes^47–50. There is limited data on the use of these markers in patients with BPD-PH^51–53. However, clinically they are used in trending cardiac performance in conjunction with echocardiography and aiding in the diagnosis of PH⁵⁴. These markers should not be used to rule out PH or replace formal diagnostic modalities of echocardiogram and cardiac catheterization.

Cardiac Catheterization

Cardiac catheterization is typically recommended prior to initiation of PH-specific drug therapy. However, consideration of cardiac catheterization should carefully balance need for hemodynamic measurements and potential risk from anesthesia and the procedure⁴¹. At our Center, most infants for whom we feel confident about the diagnosis of BPD-PH without substantial confounding factors (for example, intracardiac shunt) will be initiated on a PDE5i (specifically, sildenafil, which in the ICU setting for particularly ill children we will often dose every 6 hours rather than the TID dosing we use at discharge) prior to cardiac catheterization; however, unless medically contraindicated, a cardiac catheterization will be pursued prior to the addition of a second chronic PH-specific therapy (an exception to this approach may be the transient use of inhaled nitric oxide or inhaled epoprostenol). Cardiac catheterization should be performed by an experienced team that is skilled in handling PH emergencies, given risk of sedation in these infants^55–57. Cardiac catheterization not only verifies the diagnosis of PH but provides a thorough hemodynamic profile with assessment of RV function, mPAP, PVR, cardiac output, and pulmonary capillary wedge pressure⁴⁶. Catheterization can more reliably assess shunt lesions, pulmonary vein stenosis, parenchymal lung disease, and aortopulmonary collaterals. Evaluation of shunt contribution is critical in patients born prematurely and meticulous hemodynamic evaluation is necessary prior to consideration of shunt closure⁴¹. Cardiac catheterization is recommended prior to initiation of combination therapy, most importantly if starting chronic prostacyclin therapy. Catheterization can also be helpful in evaluation when the clinical course is out of proportion to what is visualized on echocardiogram or in the setting of worsening PH⁴¹. Catheterization should also be considered if there is an unexpected response from therapy, such as pulmonary edema, as this could indicate left-sided disease or post-capillary pulmonary hypertension, in which PH-specific therapies are not recommended.

Other

In addition to the above studies to further assess PH, care should be taken to evaluate for comorbidities that could aggravate PVD⁴¹. These may include any insults to the developing pulmonary vasculature, such as gastroesophageal reflux, aspiration, hypoventilation, and intermittent hypoxemia. Airway obstruction from laryngomalacia, tracheomalacia, and bronchomalacia may contribute to hypoxemia, hypercarbia, and result in worsening PH. Airway malacia can be evaluated in select patients by dynamic, flexible bronchoscopy and/or imaging⁵⁸, which can also evaluate for any airway stenosis or granulomas. Rigid bronchoscopy should also be considered for evaluation of subglottic stenosis in suspected patients. Other studies may include an upper gastrointestinal series, impedance probe for evaluation of pathologic reflux, and a formal swallow study to assess for dysphagia with aspiration. Another important consideration is prevention of viral illness with administration of palivizumab when appropriate.

High resolution chest CT (HRCT) or CT angiography (CTA) may be indicated based on the clinical situation. In our experience, HRCT should be considered in patients with severe BPD or in those who have parenchymal disease that is inconsistent with gestational age, in order to assess for other etiologies, such as developmental lung diseases^{41, 59}; in addition, unless clinical instability does not allow, we pursue not only echocardiogram but also CTA and BNP in concert prior to the initiation of any non-inhalational PH-specific therapy. Further evaluation of vascular structures can be accomplished with CTA, which may provide additional information in patients with larger vascular irregularities as well as venous problems such as pulmonary vein stenosis.

Management

Supportive measures

Initial management of BPD-PH should focus on optimizing supportive measures for underlying lung disease and treatment of comorbidities that could worsen PVD, as described above. Optimizing gas exchange is critical, as even mild ongoing desaturations can chronically elevate pulmonary artery pressure^{41, 60–65}. Supplemental oxygen therapy should be used to avoid episodic desaturations, and this is often the first line of treatment for infants, especially those with mild PH. Oxygen saturations should be targeted between 92%−95%⁴¹, with weaning of supplemental oxygen as needed to achieve this saturation goal. Prior to PH-specific pharmacotherapy, supplemental oxygen therapy was the mainstay of treatment in BPD-PH, as supplemental oxygen can also have a vasodilatory effect, particularly in those with pulmonary vascular disease³⁹. In some cases, chronic supplemental oxygen use with close outpatient monitoring has been associated with resolution of PH, as well as improved weight gain⁴¹. Typically, supplemental oxygen therapy is continued in patients even as PH-specific therapy is weaned or discontinued⁴¹.

Alveolarization with capillary growth occurs as infants grow and mature. Therefore, survivors typically have improvement in both lung disease and PH with time³⁹. Nutritional support is imperative for these infants to achieve adequate weight gain and lung growth⁴⁴.

Other considerations should include adequate respiratory support for chronic respiratory failure, treatment of gastroesophageal reflux disease, and feeding tube placement in infants with dysphagia. Choice of feeding method, such as gastric versus post-pyloric or use of fundoplication, can be dictated by clinical response to feeds and degree of gastroesophageal reflux and/or aspiration. Diuretics may be clinically indicated but cardiac preload must be maintained in those with PH¹⁰.

These infants require highly specialized, multidisciplinary care both while in the inpatient setting and for outpatient care⁶⁶. PH specialists should be involved in the diagnosis and management of infants with BPD-PH, particularly more challenging cases³⁶. Infants with BPD-PH should be monitored closely in the outpatient setting following NICU discharge, with echocardiograms obtained every 3–4 months until stable^{5, 41, 44, 59}.

Pharmacotherapy

PH-specific therapy focuses on inducing vasodilation of the pulmonary vasculature by targeting three molecular pathways: nitric oxide, endothelin, and prostacyclin³⁴. The overall purpose of PH-specific therapy, in addition to reducing mPAP and PVR, is to improve symptoms, clinical outcomes, and quality of life³⁴. Due to an expansion of PH-specific pharmaceuticals available (most of which are only regulatory-approved for adults), there are now PH-specific drugs available for children. However, there is very limited evidence on safety and efficacy in BPD-PH, especially regarding randomized controlled trials^{7, 67–70}. There is also increasing use of combined pharmacotherapy. Combined pharmacotherapy has been thought to augment treatment response and enhance the likelihood of improvement and/or recovery⁷¹. As above, strong consideration for the involvement of a PH specialist in the development of treatment plans is recommended.

Nitric oxide is an endogenous substance produced by endothelial cells with several biologic effects⁷². Whether produced naturally or given by inhalation, this molecule diffuses into smooth muscle cells, increases intracellular cyclic guanosine monophosphate (cGMP), relaxes vascular smooth muscle, and results in pulmonary vasodilation. Inhaled nitric oxide (iNO) at present is only available on an inpatient basis. Unlike systemic therapies (enteral and parenteral) described below, which can cause ventilation perfusion mismatch with dose escalation, iNO causes selective pulmonary vasodilation to the ventilated areas of the lung which receive the agent. iNO has been shown to improve oxygenation in patients with established BPD regardless of PH status^{60, 73, 74}. iNO is recommended for use during an acute PH crisis, with weaning of iNO after the patient stabilizes and/or chronic PH-specific therapy can be initiated⁴¹. A dose of 10–20 ppm is recommended⁶⁰ and weaning is typically performed in increments of 3–5 ppm although close observation for clinical condition is recommended. Clinically, patients often have difficulty with weaning from 1 ppm to off, as low-dose iNO may improve ventilation-perfusion matching⁴¹ and oxygenation. Of note, while ppm is the dosing increment in the United States, some countries have smaller concentrations available (e.g., parts per billion, ppb). Higher doses are often needed to improve hemodynamics⁴¹.

Phosphodiesterase-5 (PDE5) inhibitors (e.g., sildenafil and tadalafil), act on the nitric oxide (NO) pathway and are most commonly taken by enteral delivery. PDE5 inhibitors can be used to supplement iNO therapy and to provide stability during iNO weaning, by prolonging cyclic guanosine monophosphate (cGMP) levels⁷⁵. Phosphodiesterases inactivate cGMP and cyclic adenosine monophosphate (cAMP), which regulate vasoconstriction and intracellular calcium concentrations³⁶. By increasing intracellular cGMP levels, these medications may also promote alveolar growth and vasculogenesis³⁹. Sildenafil use in neonatal animal models resulted in decreased lung inflammation, decreased right ventricular hypertrophy, and improved mortality⁷⁶. Sildenafil is regarded as safe and efficacious by PH experts and remains a key component of treatment guidelines^{34, 41}. Sildenafil at standard dosing (2–3 mg/kg/day, divided into 3 or 4 doses in a 24-hour period) should be considered in children with BPD-PH.

The next class of medications is endothelin receptor antagonists (ERAs). Endothelin-1 (ET-1) is produced by endothelial cells in response to hypoxia and is a potent vasoconstrictor³⁶. ET-1 promotes remodeling and smooth muscle proliferation, in addition to causing inflammation and fibrosis⁷⁷. Bosentan is approved by the FDA for treatment of pulmonary arterial hypertension (PAH) in children 3 years and older, and often used off label for BPD-PH. Bosentan is a non-selective ETA and ETB receptor antagonist and has shown favorable outcomes in pediatric PAH⁷⁸. Some institutions use bosentan as initial therapy for BPD-PH, with a steady increase to goal dosing of 2 mg/kg twice daily⁴¹. Bosentan is associated with a risk for liver irritation, especially in the setting of concomitant viral infection. Given this, hepatic enzymes levels must be followed closely. Other endothelin receptor antagonists include macitentan and ambrisentan, which have less commonly been used in the BPD-PH population. Macitentan and ambrisentan have the advantage of a more favorable safety profile with less liver irritation and macitentan has no known associated teratogenicity³⁴. Overall, there is a paucity of knowledge regarding use of endothelin receptor antagonists in children, especially in the BPD-PH population.

Lastly, there are medications that modify the prostacyclin pathway, including prostacyclin (PGI2) and its derivatives (prostanoids). PGI2 is produced by the vascular endothelium and upon binding to its receptor, stimulates cAMP production. By activating the PGI2 receptor, there is subsequent vasodilation and inhibition of smooth muscle proliferation³⁴. Several different preparations are currently available, including intravenous, subcutaneous, inhaled, and now oral prostanoids⁴⁰. Epoprostenol was one of the earliest available medications for treatment of PAH. This medication is typically given IV and the short half-life requires continuous infusion. Epoprostenol can also be used inhaled but there is less published evidence regarding use in subjects with BPD-PH. Treprostinil is a longer acting medication that is a prostacyclin analogue (prostanoid)⁷⁹. This can also be administered by inhalation or by subcutaneous route⁷⁹. While clinical conditions will dictate the precise approach to every child, a general guideline for consideration is presented in Figure 1⁸⁰. Following the initial screen, if there are features suggestive of PH, infants should be evaluated at least monthly by echocardiogram, or sooner if clinically indicated. For example, those children with any degree of right ventricular dysfunction may deserve more frequent reassessments by echocardiogram as well as BNP/NTproBNP and vigilance to reduce concurrent insults or features of worsening. Features of worsening are varied, but include recurrent cardiopulmonary exacerbations with or without hypoxemia, inability to reduce respiratory support settings, failure of growth, escalating BNP and/or NTpro-BNP value over time, or other features of clinical decline and/or stagnation. Evaluation by echocardiogram and initiation of therapy never occur in isolation, as additional clinical, imaging, and other assessments and attempts to reduce and/or eliminate concurrent co-morbid conditions should be pursued. Notably, providers should continually consider target for oxygen saturation ≥ 93%, as well as the utility of additional chest Imaging (e.g., chest CT with angiographic imaging), laboratory assessments including but perhaps not limited to BNP/NTproBNP, work to reduce concurrent co-morbidities, and as appropriate consider the use of severe BPD respiratory support strategies. Of note, Figure 1 may not apply to children with intracardiac, and perhaps extracardiac, forms of shunt for whom careful consideration for the direction and extent of shunt, timing of potential approaches for closure in the context of a fragile pulmonary hypertensive child, and other factors demand careful consideration and often consultative discussions among pulmonary hypertension specialists, cardiologists, interventional cardiologists, and intensivists.

Figure 1.

An example approach to care that includes pharmacotherapy for a child with BPD-PH (adapted from reference 78) without significant contribution from intracardiac or extracardiac shunt. We suggest a screening echocardiogram for all infants born less than 32 weeks when they reach 36 weeks PMA (or at the time of NICU discharge), regardless of BPD determination. Following the initial screen, if there are features suggestive of PH, infants should be evaluated at least monthly by echocardiogram, or sooner if clinically indicated. For example, those children with any degree of right ventricular dysfunction may deserve more frequent reassessments by echocardiogram as well as BNP/NTproBNP and vigilance to reduce concurrent insults or features of worsening. Features of worsening are varied, but include recurrent cardiopulmonary exacerbations with or without hypoxemia, inability to reduce respiratory support settings, failure of growth, escalating BNP and/or NTpro-BNP value over time, or other features of clinical decline and/or stagnation. Interval for reassessment by clinical re-evaluation, echocardiogram, labs, and other metrics require flexibility depending on clinical severity and degree of impairment, if any, of ventricular function. * For infants with severe BPD who require positive pressure support for oxygenation and/or ventilation, strategies to best support these children should be pursued, as recently described43. ** PH-specific Rx refers to chronic pulmonary vasodilator therapy, such as a PDE5i.

Conclusion

BPD-PH continues to associate with significant morbidity and mortality, despite advancements in neonatal care. It is important to screen for PH in the BPD patient population to quickly identify exacerbating factors, optimize supportive care, and consider PH-specific treatment. In spite of growing evidence on the pathophysiology and risk factors associated with BPD-PH, there is much to learn, and clinical and translational studies are still urgently needed, especially examining PH-specific therapies and novel biomarkers specifically in this patient population. These children require a multidisciplinary approach from both clinical and research standpoints to further advance the field and outcomes for patients and families.