Pulmonary Hypertension in Bronchopulmonary Dysplasia Namasivayam Ambalavanan*1 and Peter Mourani2
Pulmonary hypertension is common in bronchopulmonary dysplasia and is associated with increased mortality and morbidity. This pulmonary hypertension is due to abnormal microvascular development and pulmonary vascular remodeling resulting in reduced cross-sectional area of pulmonary vasculature. The epidemiology, etiology, clinical features, diagnosis, suggested management, and outcomes of pulmonary hypertension in the setting of bronchopulmonary dysplasia are reviewed. In summary, pulmonary hypertension is noted in a fifth of extremely low birth weight infants, primarily those with moderate or severe bronchopulmonary dysplasia, and persists to discharge in many infants. Diagnosis is generally by echocardiography, and some infants require cardiac catheterization to identify associated anatomic cardiac lesions or systemic-pulmonary collaterals, pulmonary venous obstruction or myocardial dysfunction. Serial echocardiography and B-type
natriuretic peptide measurement may be useful for following the course of pulmonary hypertension. Currently, there is not much evidence to indicate optimal management approaches, but many clinicians maintain oxygen saturation in the range of 91 to 95%, avoiding hypoxia and hyperoxia, and often provide inhaled nitric oxide, sometimes combined with sildenafil, prostacyclin, or its analogs, and occasionally endothelin-receptor antagonists. Birth Defects Research (Part A) 100:240–246, 2014. C 2014 Wiley Periodicals, Inc. V
Key words: infant; premature; bronchopulmonary dysplasia; chronic lung disease; respiratory distress syndrome; pulmonary hypertension
Introduction
Epidemiology
Bronchopulmonary dysplasia (BPD) is characterized by inhibition of lung alveolar septation and varying degrees of lung fibrosis and inflammation (Coalson, 2003, 2006). Major abnormalities in lung microvascular development, often observed in BPD, may either contribute to inhibition of alveolar septation, or result from such inhibition. In addition, pulmonary vascular remodeling is seen in BPD, with thicker-walled pulmonary arteries and more distal extension of muscular arteries (Bhatt et al., 2001; Coalson, 2003, 2006). Therefore, it is not surprising that infants with BPD not only demonstrate abnormal lung structure and function (decreased compliance, increased airway and tissue resistance) but also have elevations of pulmonary vascular resistance and pulmonary arterial pressures that sometimes result in cor pulmonale. In this review, the epidemiology, etiology, clinical features, diagnosis, suggested management, and outcomes of pulmonary hypertension in the setting of bronchopulmonary dysplasia are described, with the caveat that many of our recommendations are based on clinical experience and biologic plausibility as there is limited evidence from clinical trials or even strong epidemiologic data.
Approximately a decade after the first description of BPD by Northway et al. in 1967 (Northway et al., 1967), Bonikos et al. described symptoms or signs of cardiac atrial or ventricular stress, including cor pulmonale in 6 of 21 patients who died of BPD (Bonikos et al., 1976). Since then, there has been increasing recognition of pulmonary hypertension and resulting right cor pulmonale in BPD using echocardiographic, cardiac catheterization, or autopsy (gross and histologic) data. However, most studies to date have been based on case reports, case series or retrospective studies that may be biased toward identification of pulmonary hypertension in more severe BPD, and there have been few large prospective studies. In addition, the phenotype of BPD has changed over the past four decades with increasing survival of smaller more immature infants. A recent single-center study by Bhat et al. evaluated 145 extremely low birth weight infants by screening echocardiography at 4 weeks of age and subsequently if signs of cardiac failure or severe lung disease were present (Bhat et al., 2012). Overall, 18% were diagnosed with pulmonary hypertension, with 6% diagnosed at the initial screening (median age of 31 days; interquartile range [IQR] 29–41), and 12% subsequently (median age of 112 days; IQR 93–122), indicating that pulmonary hypertension can be a late finding even with previously negative echocardiograms. Of the infants with severe BPD (oxygen requirement at 36 weeks), 50% had pulmonary hypertension (Bhat et al., 2012). Infants with pulmonary hypertension were more likely to have lower birth weight for a given gestational age than infants without pulmonary hypertension, and were more likely to receive higher oxygen supplementation or ventilator support on day 28. Mortality and length of stay were increased in infants with pulmonary hypertension, after adjusting for other variables. Pulmonary hypertension persisted to discharge in many infants (5 of 9 with early pulmonary hypertension,
1 Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 2 Section of Critical Care, Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado
Dr. Ambalavanan has been funded by the NIH (R01 HL092906 and R01 HD 067126). *Correspondence to: Namasivayam Ambalavanan, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, 176F Suite 9380, Women and Infants Center, 619 South 19th Street, Birmingham, AL 35249-7335. E-mail: [email protected] Published online 10 March 2014 in Wiley Online Library (wileyonlinelibrary. com). Doi: 10.1002/bdra.23241
C 2014 Wiley Periodicals, Inc. V
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and 10 of 17 with late pulmonary hypertension) (Bhat et al., 2012). Marked variation in rates of BPD are known, even after adjustment for patient characteristics (Ambalavanan et al., 2011), and it is likely that rates of pulmonary hypertension secondary to BPD are no exception to center variation. It is also very likely that there is center variation in the criteria for screening preterm infants with BPD for pulmonary hypertension, as well as in criteria used for the diagnosis of pulmonary hypertension, leading to differences in the rates of pulmonary hypertension associated with BPD across centers. A retrospective study from Korea (An et al., 2010) identified pulmonary hypertension in 25% of infants with BPD, at a median age of 65 days (range, 7–232 days). The pulmonary hypertension improved in three-fourths of the patients after a median of 85 days (range, 20–765 days), although 14% of these patients died. Another study from Denmark found that 23% of infants with BPD were diagnosed with pulmonary hypertension (Ali et al., 2013). Other retrospective studies have also identified pulmonary hypertension as an independent variable associated with mortality (Khemani et al., 2007; Slaughter et al., 2011). The higher rate (approximately 1 in 4) of pulmonary hypertension in BPD in these retrospective studies rather than the approximately 1 in 6 in the prospective study (Bhat et al., 2012) may be due to selection of infants with more severe BPD for evaluation, rather than a screening of all extremely preterm infants, and to differences in the methods for evaluation. It is possible that many, if not most, of infants with BPD have some degree of elevated pulmonary vascular resistance as compared to preterm infants without BPD even if not meeting diagnostic criteria for pulmonary hypertension. Similarly, as it is possible that many extremely preterm infants have some degree of inhibition of lung development even if not diagnosed with BPD, it is likely that these preterm infants may have elevated pulmonary vascular resistance and are at higher risk for pulmonary hypertension as compared to term infants, particularly if exposed to adverse stimuli (hypoxia, high altitude, respiratory infections, etc.).
Etiology Pulmonary hypertension in the setting of BPD is often multifactorial. A reduction in cross-sectional area of the pulmonary vasculature due to inhibition of lung development combined with vascular remodeling is considered to be the underlying pathology of pulmonary hypertension. It is not clear whether differences in the timing of detection of pulmonary hypertension (early vs. late; An et al., 2010; Bhat et al., 2012) represents a spectrum of impaired pulmonary vascular development, or whether some cases of early pulmonary hypertension represent a different pathology of disease, perhaps with more acute vasoconstriction related to respiratory illness or acute hypoxia, whereas infants with the later onset possibly have more vascular remodeling and
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relative inhibition of vascular development. Further research regarding these questions is clearly indicated. While the lung pathology has many common elements (e.g., fibrosis, inflammation, inhibition of lung development, vascular remodeling) in infants diagnosed with BPD, not all these infants are diagnosed with pulmonary hypertension. Some infants may have a more severe form of BPD that is more often associated with pulmonary hypertension (Khemani et al., 2007). The index of suspicion for pulmonary hypertension is probably higher in infants with severe BPD who may be screened more often for this condition. Infants with associated conditions such as large persistent ductus arteriosus, aorto-pulmonary collaterals, or pulmonary vein stenosis may also be at higher risk of pulmonary hypertension. Infants who have frequent hypoxic episodes or have lower baseline oxygen saturations may also be more prone to develop pulmonary vascular remodeling due to persistent or recurrent hypoxia and episodes of pulmonary vasoconstriction. It is possible that the seeds for pulmonary hypertension in BPD are planted even before birth. Intrauterine growth restriction is a risk factor for BPD, and pulmonary hypertension in infants with BPD (Check et al., 2013), probably due to inhibition of lung development. Other adverse influences on lung development and growth of lung vasculature may include chorioamnionitis that is commonly associated with spontaneous preterm birth (Hartling et al., 2012), or postnatal lung infections. Finally, a strong genetic predisposition is known to be present for BPD (Bhandari et al., 2006), and it is possible that pulmonary hypertension in BPD also has a genetic predisposition.
Clinical Features Pulmonary hypertension in the setting of BPD may either be asymptomatic, or may present with deterioration of respiratory status, failure to wean off respiratory support, and/or impaired somatic growth. Asymptomatic infants may be detected during incidental or screening echocardiography of infants with BPD. Infants who present with deterioration of respiratory status may have either gradual deterioration (e.g., gradual increase in ventilator settings or oxygen requirement) or a more rapid and intermittent onset signs attributable to reduced pulmonary blood flow (increased oxygen requirement, hypoxemia) and right heart dysfunction (hepatomegaly). In some infants with BPD, episodes of pulmonary hypertension are precipitated by infection (e.g., respiratory infections, urinary tract infections, septicemia), aspiration events, or changes in lung pathology (atelectasis, mucus plugging, etc.). In some infants, no obvious precipitating factors can be determined for the sudden onset of a pulmonary hypertensive episode.
Diagnosis It is essential to have a high index of suspicion to avoid missing the diagnosis of pulmonary hypertension in BPD.
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In early pulmonary hypertension, clinical features such as hypoxemia and poor growth may overlap and be indistinguishable from that of the underlying BPD. Clinical features such as a loud second heart sound in the pulmonary area (P2) with narrowing of the split or overlapping of both components (A2 and P2), presence of tricuspid regurgitation, hepatomegaly, and congestion of systemic veins may be present in pulmonary hypertension and right heart failure. Even in the absence of these features, any infant with BPD who has persistent or increasing oxygen requirement or deterioration in respiratory status not easily explained may benefit from evaluation. It is not clear at the current time if early screening of extremely preterm infants for pulmonary hypertension, as done by Bhat et al. (2012) improves management and outcomes, and if so, what is the optimal schedule for initial screening or subsequent screening. Echocardiography is commonly used as the initial method of evaluating infants with BPD for pulmonary hypertension. The advantage of echocardiography is that it can be done at the bedside without sedation and can be repeated at frequent time intervals. The usual features sought in echocardiography are: (1) right ventricular hypertrophy, (2) flattening of interventricular septum, (3) presence of tricuspid regurgitation in the absence of pulmonary stenosis, and (4) elevated right ventricular pressures as estimated by Doppler studies of tricuspid regurgitation jet. While echocardiographic estimates of pulmonary artery pressure done at the same time as cardiac catheterization show very good agreement, results may not always agree if they are done at different times (Skinner et al., 1993). Mourani et al. (2008) did a retrospective review of data from 25 infants who underwent echocardiography and subsequent cardiac catheterization for the evaluation of pulmonary hypertension. Although systolic pulmonary arterial pressure could be estimated in 61% of studies, there was poor correlation between measurements from echocardiography and cardiac catheterization. Compared with cardiac catheterization, echocardiography had 79% sensitivity for the presence of pulmonary hypertension, but determined the severity in only 47%. Importantly, echocardiography failed to diagnose pulmonary hypertension in 11% of infants later found to have pulmonary hypertension on cardiac catheterization (false negative), and diagnosed pulmonary hypertension in 11% of infants who did not have it by cardiac catheterization (false positive). Qualitative echocardiographic findings in the absence of estimated systolic pressures had a worse predictive value (Mourani et al., 2008). It is important to note that measurements of pulmonary vascular resistance and pressures during echocardiography and cardiac catheterization are often not done under the same conditions (sedation, ventilation status, etc.) and hence may not be fully comparable. Pulmonary hypertension is often defined as an estimated systolic pulmonary arterial pressures of 35 or 40 mmHg by echocardiography
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or a mean pulmonary arterial pressure of >25 mmHg by cardiac catheterization. Pulmonary hypertension is generally defined as a ratio of pulmonary to systemic pressures (systolic pressures for echocardiography; mean pressures for cardiac catheterization) of less than 2/3rd for mild/moderate, and at least 2/3rd or greater for severe pulmonary hypertension (Mourani et al., 2008). Newer echocardiographic techniques such as tricuspid annular plane systolic excursion, right ventricular speckle-tracking, or right ventricular index of myocardial performance (Czernik et al., 2012) may provide additional information. Cardiac catheterization enables accurate and precise measurements of right ventricular and pulmonary arterial pressures. Cardiac catheterization also enables detection of lesions such as pulmonary vein stenosis and collaterals that may occur in BPD but are not easy to diagnose or evaluate using echocardiography. In many institutions, cardiac catheterization is performed in infants with BPD and pulmonary hypertension who fail to respond to oxygen or inhaled nitric oxide and in those in whom there is suspicion of associated anatomic cardiac lesions or systemicpulmonary collaterals, pulmonary venous obstruction or myocardial dysfunction. In general, it is probably appropriate to do cardiac catheterization before initiation of a third-line agent (as described in management) if there is insufficient improvement or worsening with first and second-line therapy or if an infant with severe BPD does not improve or deteriorates over time despite adequate therapy and echocardiography is not helpful. However, the risks of cardiac catheterization are not insignificant, especially in a sick preterm infant on high ventilator settings. High resolution computed tomography scanning may be helpful as an adjunct investigation in some infants, to evaluate both the lung parenchyma and the vasculature. Del Cerro et al. (2014) evaluated 29 patients with pulmonary hypertension and BPD without major congenital heart disease, in whom computed tomography scanning was done in 21 and cardiac catheterization in 14 patients. The diagnosis of pulmonary hypertension was made at a median age of 4.5 months (IQR, 2.4–7.8). Cardiovascular anomalies were noted in approximately 2/3rd of patients: aortopulmonary collaterals (n 5 9), pulmonary vein stenosis (n 5 7), atrial septal defect (n 5 4), and persistent ductus arteriosus (n 5 9). The use of B-type natriuretic peptide (BNP) or NT-proBNP for evaluation of pulmonary hypertension in BPD is becoming increasingly common (Kim, 2010). However, there are occasionally infants with elevations of BNP in whom echocardiography does not suggest significant elevations of right ventricular pressure and other infants in whom BNP is low despite echocardiography suggesting pulmonary hypertension. It is important to remember that BNP is a marker of cardiac ventricular strain that is not specific to the right ventricle. Infants with systemic hypertension (frequently seen in BPD, especially during corticosteroid
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therapy), persistent ductus arteriosus (Sanjeev et al., 2005; Kim and Shim, 2012), or left ventricular dysfunction for other reasons may also have elevations of BNP.
Management There is much controversy about the optimal management of pulmonary hypertension in the setting of BPD, mainly because of a paucity of data from large randomized controlled trials. Despite the lack of evidence, many therapeutic agents are currently in use for the management of pulmonary hypertension in BPD, and this review describes such therapies without endorsing any specific treatment regimen or approach. The pulmonary hypertension in BPD consists of a fixed component, secondary to a reduction of cross-sectional area of the pulmonary vasculature due to impaired lung development and nonresponsive remodeling of pulmonary arteries, and a responsive component presumably due to pulmonary vascular smooth muscle that is capable of relaxation in response to vasodilatory stimuli. The goals of management are, therefore, to (a) promote normal lung development, (b) prevent or attenuate the abnormal remodeling, and (c) induce vasorelaxation of constricted pulmonary arteries and improve ventilationperfusion matching. The therapeutic agents used are generally vasodilators (e.g., oxygen, inhaled nitric oxide, sildenafil, prostacyclin analogs) or inhibitors of vasoconstrictors (e.g., endothelin-receptor antagonists). Berman et al. (1982) initially described a variable response of pulmonary vascular resistance to oxygen in nine patients with BPD, and it was considered that oxygen supplementation may not be very effective. However, of seven infants with elevated pulmonary pressure, four were noted to improve with oxygen supplementation (Berman et al., 1982). Abman et al. (1985) demonstrated in 1985 using cardiac catheterization that the pulmonary vascular resistance in infants with BPD was responsive to oxygen, with a greater than 10 mmHg reduction in mean pulmonary artery pressure on exposure to high concentrations of oxygen (FiO2 > 0.8). Most of the reduction in pulmonary artery pressure could be achieved by oxygen supplementation using a nasal cannula at lower flow rates. However, it is important to note that although there was a significant reduction in pulmonary arterial pressure from a mean of 48 mmHg to 25 mmHg with high oxygen concentrations (Abman et al., 1985), this pressure is still above the normal range. In a patient followed up to 45 months of age, a reduction in pulmonary arterial pressure was noted, suggesting that pulmonary vascular resistance may reduce over time associated with lung growth (Abman et al., 1985). Further studies have shown that even mild hypoxia can cause marked elevations in pulmonary artery pressure, including infants with established BPD and only modest basal levels of pulmonary hypertension (Mourani et al., 2004). Exaggerated pulmonary vascular constriction
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in response to hypoxia was even demonstrated in the absence of baseline pulmonary hypertension, and can persist late into childhood. Although these were limited studies, many performed in infants born more than 3 decades ago and studied by cardiac catheterization at a relatively late time point (generally at >1 year), the lessons of these studies still resonate in clinical practice today, as oxygen supplementation is the initial management of pulmonary hypertension in BPD. However, while maintenance of adequate oxygenation is important, it is important to avoid hyperoxia, which may induce further inhibition of alveolar and lung vascular development. Within the neonatal intensive care unit, the usual clinical practice for infants with BPD diagnosed with pulmonary hypertension generally consists initially of maintenance of oxygen saturation in the target range of 91 to 95% (avoiding dips in saturation to 85% or below as well as hyperoxia with saturations of 97% or above) which may reduce hypoxic pulmonary vasoconstriction, combined with inhaled nitric oxide (iNO) at 5 to 20 ppm. Identification and treatment of factors contributing to poor oxygenation (e.g., tracheobronchomalacia, anatomic airway obstruction, aspiration, bronchial reactivity, etc.) are also important to optimizing gas exchange. Other supportive therapy for BPD, such as diuretics, bronchodilators, corticosteroids, and fluid/electrolyte/nutrition management are also optimized, although the evidence for these therapies is limited and they may not directly impact the course of pulmonary hypertension. It is unclear at the current time to what extent ancillary therapies such as management of gastroesophageal reflux, evaluation of the airway, polysomnographic evaluation, or other specialized investigations are necessary in the evaluation of pulmonary hypertension in BPD. Clinical improvement (or lack thereof) may be followed using serial echocardiography that may be combined with BNP measurements. Currently, there are no published reports of the utility of serial BNP measurements in neonatal pulmonary hypertension, but we have found that BNP elevation and magnitude of pulmonary hypertension are positively correlated (unpublished data). The frequency of these repeat measurements generally depends upon the severity of the pulmonary hypertension and underlying clinical illness. In general, we obtain echocardiograms and/or BNP twice a week for unstable infants with an acute pulmonary hypertensive crisis or those undergoing weaning of pulmonary hypertension therapies such as iNO and once or twice a month for infants who are more stable. Upon resolution of the pulmonary hypertension, the iNO is gradually weaned off over days to weeks, with careful clinical monitoring, evaluation of oxygen requirement, and sometimes BNP measurements following every wean of iNO. If the pulmonary hypertension is attenuated by iNO therapy but not eliminated, or there is no response to iNO, a second-line agent such as sildenafil (0.5–1 mg/kg/dose every 8 hr; generally
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started at the lower dose and increased slowly as needed) may be added, and iNO weaned if tolerated. As recently reviewed by Wardle et al. (2013), sildenafil may possibly both safe and effective in infants with pulmonary hypertension in BPD, and may improve survival if continued until resolution of pulmonary hypertension. However, sildenafil did not improve short-term respiratory outcomes in a pilot trial of extremely preterm infants as an attempt to prevent BPD (Konig et al., 2014), suggesting earlier use may not be beneficial. Mourani et al. (2009) did a retrospective review of 25 infants with BPD and pulmonary hypertension who received sildenafil, initiated at a median of 171 days (range, 14–673 days) for a median duration of 241 days (range, 28–940 days). Twenty-two of the 25 (88%) improved hemodynamically (defined as a 20% decrease in ratio of pulmonary to systemic arterial pressures or improvement of ventricular septal flattening on serial echocardiographic evaluations), suggesting that chronic sildenafil therapy may be reasonably effective. On the other hand, Nyp et al. (2012) reported in a retrospective review of 21 infants with BPD-associated pulmonary hypertension that although sildenafil reduced estimated right ventricular systolic pressures, it did not improve oxygenation in the short term (the first 48 hr). In fact, sildenafil may rarely worsen ventilation/perfusion mismatch and oxygenation, and cause systemic hypotension. It is important to remember that safety cannot be established from smaller retrospective studies and that effectiveness will need to include evaluation of long-term benefit on pulmonary arterial pressures as well as on gas exchange parameters. It must be noted that the U.S. Food and Drug Administration has issued a warning against use of sildenafil in children between 1 and 17 years of age, as the STARTS-2 study noted higher mortality in older children taking a higher dose (>3 mg/kg/day) as compared to those taking a lower dose (Barst et al., 2012). Infants on sildenafil, therefore, need close monitoring. In addition, sildenafil pharmacokinetics are currently under investigation (ClinicalTrials.gov # NCT01670136), as it is likely that pharmacokinetics of sildenafil in preterm infants are different from those of older children or adults, and it is possible that the optimal dosing is different from what is currently used in infants. Infants who do not respond to BPD management and iNO/sildenafil are usually started on a third-line agent. This third-line agent may be either a prostacyclin analog (e.g., epoprostenol [Flolan] by continuous intravenous infusion, iloprost [Ventavis] by inhalation, or treprostinil [Remodulin] by subcutaneous or intravenous infusion) or an endothelin-receptor antagonist (e.g., a nonselective endothelin receptor antagonist such as bosentan, or a selective ET-A receptor antagonist such as ambrisentan). There are limited data on the effectiveness and safety of these third-line agents in infants with BPD and pulmonary hypertension, and these agents should be used cautiously with careful monitoring for efficacy and toxicity.
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Epoprostenol has been shown in case reports to reduce pulmonary hypertension in the setting of BPD (Zaidi et al., 2005) as well as in younger neonates with persistent pulmonary hypertension of the newborn (Eronen et al., 1997). Other prostacyclin analogs may be expected to have a similar effect, and there are case reports and case series of use of inhaled iloprost for pulmonary hypertension in BPD (Hwang et al., 2009; Gurakan et al., 2011; Piastra et al., 2012). However, it is important to carefully evaluate for side effects such as hypotension, increased airway reactivity, pulmonary edema, and increased cyanosis due to potential for augmentation of intrapulmonary shunt. Bosentan has clinical and hemodynamic efficacy in retrospective cohort studies of children with pulmonary arterial hypertension (idiopathic, associated with congenital heart, or connective tissue disease) (Rosenzweig et al., 2005; Ivy et al., 2010; Hislop et al., 2011). A small randomized controlled trial showed that bosentan improves outcomes (improved oxygenation and reduction in pulmonary arterial pressure without toxicity) in neonates with persistent pulmonary hypertension of the newborn (Mohamed and Ismail, 2012) but its efficacy in younger infants with BPD needs to be determined as there are only case reports (Rugolotto et al., 2006) or small case series (Krishnan et al., 2008) demonstrating its use in BPD, usually in combination with either prostacyclin analogs or sildenafil. Also, bosentan may potentially increase liver toxicity in patients with BPD who also have total perenteral nutrition-induced cholestasis and liver dysfunction. Currently, there is limited evidence on how long these therapies need to be continued. Often, many infants are discharged from the neonatal intensive care unit on these medications and followed-up by pediatric pulmonologists or centers focusing on pulmonary hypertension. If pulmonary hypertension gradually resolves with lung growth as expected, the medications may be either gradually tapered off, or the infant allowed to outgrow the dose before discontinuation of the drugs one by one (usually the most “invasive” or least effective medication first to go).
Outcomes Multiple studies have documented that the presence of pulmonary hypertension in BPD is associated with higher mortality (Khemani et al., 2007; Slaughter et al., 2011; Kim et al., 2012). In addition, these infants have a greater morbidity, with higher usage of health care resources, with prolonged respiratory support and longer initial hospitalizations (Check et al., 2013; Stuart et al., 2013). It is, therefore, conventional wisdom that pulmonary hypertension in BPD contributes to mortality and morbidity. While it is certain that the presence of pulmonary hypertension is associated with worse outcomes (i.e., pulmonary hypertension is a biomarker), it is not clear how much the
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presence of pulmonary hypertension, as opposed to the underlying parenchymal and airway lung disease, contributes to poor outcome. There are no randomized trials to date evaluating if treatment of pulmonary hypertension improves outcome in BPD, as it is generally assumed that pulmonary hypertension if left untreated would lead to worse oxygenation, deterioration of right heart failure and subsequent mortality. The long-term (adolescence/adult) effects of pulmonary hypertension in BPD are essentially unknown. It is possible that these individuals remain at life-long increased risk of pulmonary hypertension following hypoxia or other stimuli, or may be at greater risk of pulmonary hypertension and chronic obstructive pulmonary disease during age-related declines in pulmonary function in middle age.
Future Directions Additional research is needed to fill several knowledge gaps in our understanding of BPD and associated pulmonary hypertension. A better understanding of normal alveolar and lung vascular development, including biomarkers of lung development and how these are disturbed in BPD is essential for the development of novel therapeutic strategies and for the optimization of existing therapies. In addition, careful clinical phenotyping of BPD, with specific focus on the magnitude of airway, parenchymal, and vascular involvement at different time points during the postnatal course is required to target therapies specifically at phenotype. Evaluation of long-term pulmonary and pulmonary vascular outcomes in extremely preterm infants is needed, as infants who have BPD and pulmonary hypertension may possibly be at higher risk of adult-onset chronic obstructive pulmonary disease and cor pulmonale, although data are lacking at present (Filippone et al., 2010; Shi and Warburton, 2010).
Acknowledgment There are no conflicts of interest to disclose.
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Khemani E, McElhinney DB, Rhein L, et al. 2007. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics 120:1260–1269. Kim DH, Kim HS, Choi CW, et al. 2012. Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia. Neonatology 101:40–46. Kim GB. 2010. Pulmonary hypertension in infants with bronchopulmonary dysplasia. Korean J Pediatr 53:688–693. Kim JS, Shim EJ. 2012. B-type natriuretic Peptide assay for the diagnosis and prognosis of patent ductus arteriosus in preterm infants. Korean Circ J 42:192–196. Konig K, Barfield CP, Guy KJ, et al. 2014. The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study. J Matern Fetal Neonatal Med 27:439–444. Krishnan U, Krishnan S, Gewitz M. 2008. Treatment of pulmonary hypertension in children with chronic lung disease with newer oral therapies. Pediatr Cardiol 29:1082–1086. Mohamed WA, Ismail M. 2012. A randomized, double-blind, placebo-controlled, prospective study of bosentan for the treatment of persistent pulmonary hypertension of the newborn. J Perinatol 32:608–613. Mourani PM, Ivy DD, Gao D, Abman SH. 2004. Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulmonary dysplasia. Am J Respir Crit Care Med 170:1006–1013.
Piastra M, De Luca D, De Carolis MP, et al. 2012. Nebulized iloprost and noninvasive respiratory support for impending hypoxaemic respiratory failure in formerly preterm infants: a case series. Pediatr Pulmonol 47:757–762. Rosenzweig EB, Ivy DD, Widlitz A, et al. 2005. Effects of longterm bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 46:697–704. Rugolotto S, Errico G, Beghini R, et al. 2006. Weaning of epoprostenol in a small infant receiving concomitant bosentan for severe pulmonary arterial hypertension secondary to bronchopulmonary dysplasia. Minerva Pediatr 58:491–494. Sanjeev S, Pettersen M, Lua J, et al. 2005. Role of plasma B-type natriuretic peptide in screening for hemodynamically significant patent ductus arteriosus in preterm neonates. J Perinatol 25: 709–713. Shi W, Warburton D. 2010. Is COPD in adulthood really so far removed from early development? Eur Respir J 35:12–13. Skinner JR, Stuart AG, O’Sullivan J, et al. 1993. Right heart pressure determination by Doppler in infants with tricuspid regurgitation. Arch Dis Child 69:216–220. Slaughter JL, Pakrashi T, Jones DE, et al. 2011. Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation. J Perinatol 31:635–640. Stuart BD, Sekar P, Coulson JD, et al. 2013. Health-care utilization and respiratory morbidities in preterm infants with pulmonary hypertension. J Perinatol 33:543–547.
Mourani PM, Sontag MK, Ivy DD, Abman SH. 2009. Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease. J Pediatr 154:379–384, 384 e371–e372.
Wardle AJ, Wardle R, Luyt K, Tulloh R. 2013. The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia. Arch Dis Child 98:613–617.
Mourani PM, Sontag MK, Younoszai A, et al. 2008. Clinical utility of echocardiography for the diagnosis and management of pulmonary vascular disease in young children with chronic lung disease. Pediatrics 121:317–325.
Zaidi AN, Dettorre MD, Ceneviva GD, Thomas NJ. 2005. Epoprostenol and home mechanical ventilation for pulmonary hypertension associated with chronic lung disease. Pediatr Pulmonol 40: 265–269.
Pulmonary hypertension is common in bronchopulmonary dysplasia and is associated with increased mortality and morbidity. This pulmonary hypertension is due to abnormal microvascular development and pulmonary vascular remodeling resulting in reduced cross-sectional area of pulmonary vasculature. The epidemiology, etiology, clinical features, diagnosis, suggested management, and outcomes of pulmonary hypertension in the setting of bronchopulmonary dysplasia are reviewed. In summary, pulmonary hypertension is noted in a fifth of extremely low birth weight infants, primarily those with moderate or severe bronchopulmonary dysplasia, and persists to discharge in many infants. Diagnosis is generally by echocardiography, and some infants require cardiac catheterization to identify associated anatomic cardiac lesions or systemic-pulmonary collaterals, pulmonary venous obstruction or myocardial dysfunction. Serial echocardiography and B-type
natriuretic peptide measurement may be useful for following the course of pulmonary hypertension. Currently, there is not much evidence to indicate optimal management approaches, but many clinicians maintain oxygen saturation in the range of 91 to 95%, avoiding hypoxia and hyperoxia, and often provide inhaled nitric oxide, sometimes combined with sildenafil, prostacyclin, or its analogs, and occasionally endothelin-receptor antagonists. Birth Defects Research (Part A) 100:240–246, 2014. C 2014 Wiley Periodicals, Inc. V
Key words: infant; premature; bronchopulmonary dysplasia; chronic lung disease; respiratory distress syndrome; pulmonary hypertension
Introduction
Epidemiology
Bronchopulmonary dysplasia (BPD) is characterized by inhibition of lung alveolar septation and varying degrees of lung fibrosis and inflammation (Coalson, 2003, 2006). Major abnormalities in lung microvascular development, often observed in BPD, may either contribute to inhibition of alveolar septation, or result from such inhibition. In addition, pulmonary vascular remodeling is seen in BPD, with thicker-walled pulmonary arteries and more distal extension of muscular arteries (Bhatt et al., 2001; Coalson, 2003, 2006). Therefore, it is not surprising that infants with BPD not only demonstrate abnormal lung structure and function (decreased compliance, increased airway and tissue resistance) but also have elevations of pulmonary vascular resistance and pulmonary arterial pressures that sometimes result in cor pulmonale. In this review, the epidemiology, etiology, clinical features, diagnosis, suggested management, and outcomes of pulmonary hypertension in the setting of bronchopulmonary dysplasia are described, with the caveat that many of our recommendations are based on clinical experience and biologic plausibility as there is limited evidence from clinical trials or even strong epidemiologic data.
Approximately a decade after the first description of BPD by Northway et al. in 1967 (Northway et al., 1967), Bonikos et al. described symptoms or signs of cardiac atrial or ventricular stress, including cor pulmonale in 6 of 21 patients who died of BPD (Bonikos et al., 1976). Since then, there has been increasing recognition of pulmonary hypertension and resulting right cor pulmonale in BPD using echocardiographic, cardiac catheterization, or autopsy (gross and histologic) data. However, most studies to date have been based on case reports, case series or retrospective studies that may be biased toward identification of pulmonary hypertension in more severe BPD, and there have been few large prospective studies. In addition, the phenotype of BPD has changed over the past four decades with increasing survival of smaller more immature infants. A recent single-center study by Bhat et al. evaluated 145 extremely low birth weight infants by screening echocardiography at 4 weeks of age and subsequently if signs of cardiac failure or severe lung disease were present (Bhat et al., 2012). Overall, 18% were diagnosed with pulmonary hypertension, with 6% diagnosed at the initial screening (median age of 31 days; interquartile range [IQR] 29–41), and 12% subsequently (median age of 112 days; IQR 93–122), indicating that pulmonary hypertension can be a late finding even with previously negative echocardiograms. Of the infants with severe BPD (oxygen requirement at 36 weeks), 50% had pulmonary hypertension (Bhat et al., 2012). Infants with pulmonary hypertension were more likely to have lower birth weight for a given gestational age than infants without pulmonary hypertension, and were more likely to receive higher oxygen supplementation or ventilator support on day 28. Mortality and length of stay were increased in infants with pulmonary hypertension, after adjusting for other variables. Pulmonary hypertension persisted to discharge in many infants (5 of 9 with early pulmonary hypertension,
1 Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 2 Section of Critical Care, Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado, School of Medicine, Aurora, Colorado
Dr. Ambalavanan has been funded by the NIH (R01 HL092906 and R01 HD 067126). *Correspondence to: Namasivayam Ambalavanan, Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, 176F Suite 9380, Women and Infants Center, 619 South 19th Street, Birmingham, AL 35249-7335. E-mail: [email protected] Published online 10 March 2014 in Wiley Online Library (wileyonlinelibrary. com). Doi: 10.1002/bdra.23241
C 2014 Wiley Periodicals, Inc. V
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and 10 of 17 with late pulmonary hypertension) (Bhat et al., 2012). Marked variation in rates of BPD are known, even after adjustment for patient characteristics (Ambalavanan et al., 2011), and it is likely that rates of pulmonary hypertension secondary to BPD are no exception to center variation. It is also very likely that there is center variation in the criteria for screening preterm infants with BPD for pulmonary hypertension, as well as in criteria used for the diagnosis of pulmonary hypertension, leading to differences in the rates of pulmonary hypertension associated with BPD across centers. A retrospective study from Korea (An et al., 2010) identified pulmonary hypertension in 25% of infants with BPD, at a median age of 65 days (range, 7–232 days). The pulmonary hypertension improved in three-fourths of the patients after a median of 85 days (range, 20–765 days), although 14% of these patients died. Another study from Denmark found that 23% of infants with BPD were diagnosed with pulmonary hypertension (Ali et al., 2013). Other retrospective studies have also identified pulmonary hypertension as an independent variable associated with mortality (Khemani et al., 2007; Slaughter et al., 2011). The higher rate (approximately 1 in 4) of pulmonary hypertension in BPD in these retrospective studies rather than the approximately 1 in 6 in the prospective study (Bhat et al., 2012) may be due to selection of infants with more severe BPD for evaluation, rather than a screening of all extremely preterm infants, and to differences in the methods for evaluation. It is possible that many, if not most, of infants with BPD have some degree of elevated pulmonary vascular resistance as compared to preterm infants without BPD even if not meeting diagnostic criteria for pulmonary hypertension. Similarly, as it is possible that many extremely preterm infants have some degree of inhibition of lung development even if not diagnosed with BPD, it is likely that these preterm infants may have elevated pulmonary vascular resistance and are at higher risk for pulmonary hypertension as compared to term infants, particularly if exposed to adverse stimuli (hypoxia, high altitude, respiratory infections, etc.).
Etiology Pulmonary hypertension in the setting of BPD is often multifactorial. A reduction in cross-sectional area of the pulmonary vasculature due to inhibition of lung development combined with vascular remodeling is considered to be the underlying pathology of pulmonary hypertension. It is not clear whether differences in the timing of detection of pulmonary hypertension (early vs. late; An et al., 2010; Bhat et al., 2012) represents a spectrum of impaired pulmonary vascular development, or whether some cases of early pulmonary hypertension represent a different pathology of disease, perhaps with more acute vasoconstriction related to respiratory illness or acute hypoxia, whereas infants with the later onset possibly have more vascular remodeling and
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relative inhibition of vascular development. Further research regarding these questions is clearly indicated. While the lung pathology has many common elements (e.g., fibrosis, inflammation, inhibition of lung development, vascular remodeling) in infants diagnosed with BPD, not all these infants are diagnosed with pulmonary hypertension. Some infants may have a more severe form of BPD that is more often associated with pulmonary hypertension (Khemani et al., 2007). The index of suspicion for pulmonary hypertension is probably higher in infants with severe BPD who may be screened more often for this condition. Infants with associated conditions such as large persistent ductus arteriosus, aorto-pulmonary collaterals, or pulmonary vein stenosis may also be at higher risk of pulmonary hypertension. Infants who have frequent hypoxic episodes or have lower baseline oxygen saturations may also be more prone to develop pulmonary vascular remodeling due to persistent or recurrent hypoxia and episodes of pulmonary vasoconstriction. It is possible that the seeds for pulmonary hypertension in BPD are planted even before birth. Intrauterine growth restriction is a risk factor for BPD, and pulmonary hypertension in infants with BPD (Check et al., 2013), probably due to inhibition of lung development. Other adverse influences on lung development and growth of lung vasculature may include chorioamnionitis that is commonly associated with spontaneous preterm birth (Hartling et al., 2012), or postnatal lung infections. Finally, a strong genetic predisposition is known to be present for BPD (Bhandari et al., 2006), and it is possible that pulmonary hypertension in BPD also has a genetic predisposition.
Clinical Features Pulmonary hypertension in the setting of BPD may either be asymptomatic, or may present with deterioration of respiratory status, failure to wean off respiratory support, and/or impaired somatic growth. Asymptomatic infants may be detected during incidental or screening echocardiography of infants with BPD. Infants who present with deterioration of respiratory status may have either gradual deterioration (e.g., gradual increase in ventilator settings or oxygen requirement) or a more rapid and intermittent onset signs attributable to reduced pulmonary blood flow (increased oxygen requirement, hypoxemia) and right heart dysfunction (hepatomegaly). In some infants with BPD, episodes of pulmonary hypertension are precipitated by infection (e.g., respiratory infections, urinary tract infections, septicemia), aspiration events, or changes in lung pathology (atelectasis, mucus plugging, etc.). In some infants, no obvious precipitating factors can be determined for the sudden onset of a pulmonary hypertensive episode.
Diagnosis It is essential to have a high index of suspicion to avoid missing the diagnosis of pulmonary hypertension in BPD.
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In early pulmonary hypertension, clinical features such as hypoxemia and poor growth may overlap and be indistinguishable from that of the underlying BPD. Clinical features such as a loud second heart sound in the pulmonary area (P2) with narrowing of the split or overlapping of both components (A2 and P2), presence of tricuspid regurgitation, hepatomegaly, and congestion of systemic veins may be present in pulmonary hypertension and right heart failure. Even in the absence of these features, any infant with BPD who has persistent or increasing oxygen requirement or deterioration in respiratory status not easily explained may benefit from evaluation. It is not clear at the current time if early screening of extremely preterm infants for pulmonary hypertension, as done by Bhat et al. (2012) improves management and outcomes, and if so, what is the optimal schedule for initial screening or subsequent screening. Echocardiography is commonly used as the initial method of evaluating infants with BPD for pulmonary hypertension. The advantage of echocardiography is that it can be done at the bedside without sedation and can be repeated at frequent time intervals. The usual features sought in echocardiography are: (1) right ventricular hypertrophy, (2) flattening of interventricular septum, (3) presence of tricuspid regurgitation in the absence of pulmonary stenosis, and (4) elevated right ventricular pressures as estimated by Doppler studies of tricuspid regurgitation jet. While echocardiographic estimates of pulmonary artery pressure done at the same time as cardiac catheterization show very good agreement, results may not always agree if they are done at different times (Skinner et al., 1993). Mourani et al. (2008) did a retrospective review of data from 25 infants who underwent echocardiography and subsequent cardiac catheterization for the evaluation of pulmonary hypertension. Although systolic pulmonary arterial pressure could be estimated in 61% of studies, there was poor correlation between measurements from echocardiography and cardiac catheterization. Compared with cardiac catheterization, echocardiography had 79% sensitivity for the presence of pulmonary hypertension, but determined the severity in only 47%. Importantly, echocardiography failed to diagnose pulmonary hypertension in 11% of infants later found to have pulmonary hypertension on cardiac catheterization (false negative), and diagnosed pulmonary hypertension in 11% of infants who did not have it by cardiac catheterization (false positive). Qualitative echocardiographic findings in the absence of estimated systolic pressures had a worse predictive value (Mourani et al., 2008). It is important to note that measurements of pulmonary vascular resistance and pressures during echocardiography and cardiac catheterization are often not done under the same conditions (sedation, ventilation status, etc.) and hence may not be fully comparable. Pulmonary hypertension is often defined as an estimated systolic pulmonary arterial pressures of 35 or 40 mmHg by echocardiography
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or a mean pulmonary arterial pressure of >25 mmHg by cardiac catheterization. Pulmonary hypertension is generally defined as a ratio of pulmonary to systemic pressures (systolic pressures for echocardiography; mean pressures for cardiac catheterization) of less than 2/3rd for mild/moderate, and at least 2/3rd or greater for severe pulmonary hypertension (Mourani et al., 2008). Newer echocardiographic techniques such as tricuspid annular plane systolic excursion, right ventricular speckle-tracking, or right ventricular index of myocardial performance (Czernik et al., 2012) may provide additional information. Cardiac catheterization enables accurate and precise measurements of right ventricular and pulmonary arterial pressures. Cardiac catheterization also enables detection of lesions such as pulmonary vein stenosis and collaterals that may occur in BPD but are not easy to diagnose or evaluate using echocardiography. In many institutions, cardiac catheterization is performed in infants with BPD and pulmonary hypertension who fail to respond to oxygen or inhaled nitric oxide and in those in whom there is suspicion of associated anatomic cardiac lesions or systemicpulmonary collaterals, pulmonary venous obstruction or myocardial dysfunction. In general, it is probably appropriate to do cardiac catheterization before initiation of a third-line agent (as described in management) if there is insufficient improvement or worsening with first and second-line therapy or if an infant with severe BPD does not improve or deteriorates over time despite adequate therapy and echocardiography is not helpful. However, the risks of cardiac catheterization are not insignificant, especially in a sick preterm infant on high ventilator settings. High resolution computed tomography scanning may be helpful as an adjunct investigation in some infants, to evaluate both the lung parenchyma and the vasculature. Del Cerro et al. (2014) evaluated 29 patients with pulmonary hypertension and BPD without major congenital heart disease, in whom computed tomography scanning was done in 21 and cardiac catheterization in 14 patients. The diagnosis of pulmonary hypertension was made at a median age of 4.5 months (IQR, 2.4–7.8). Cardiovascular anomalies were noted in approximately 2/3rd of patients: aortopulmonary collaterals (n 5 9), pulmonary vein stenosis (n 5 7), atrial septal defect (n 5 4), and persistent ductus arteriosus (n 5 9). The use of B-type natriuretic peptide (BNP) or NT-proBNP for evaluation of pulmonary hypertension in BPD is becoming increasingly common (Kim, 2010). However, there are occasionally infants with elevations of BNP in whom echocardiography does not suggest significant elevations of right ventricular pressure and other infants in whom BNP is low despite echocardiography suggesting pulmonary hypertension. It is important to remember that BNP is a marker of cardiac ventricular strain that is not specific to the right ventricle. Infants with systemic hypertension (frequently seen in BPD, especially during corticosteroid
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therapy), persistent ductus arteriosus (Sanjeev et al., 2005; Kim and Shim, 2012), or left ventricular dysfunction for other reasons may also have elevations of BNP.
Management There is much controversy about the optimal management of pulmonary hypertension in the setting of BPD, mainly because of a paucity of data from large randomized controlled trials. Despite the lack of evidence, many therapeutic agents are currently in use for the management of pulmonary hypertension in BPD, and this review describes such therapies without endorsing any specific treatment regimen or approach. The pulmonary hypertension in BPD consists of a fixed component, secondary to a reduction of cross-sectional area of the pulmonary vasculature due to impaired lung development and nonresponsive remodeling of pulmonary arteries, and a responsive component presumably due to pulmonary vascular smooth muscle that is capable of relaxation in response to vasodilatory stimuli. The goals of management are, therefore, to (a) promote normal lung development, (b) prevent or attenuate the abnormal remodeling, and (c) induce vasorelaxation of constricted pulmonary arteries and improve ventilationperfusion matching. The therapeutic agents used are generally vasodilators (e.g., oxygen, inhaled nitric oxide, sildenafil, prostacyclin analogs) or inhibitors of vasoconstrictors (e.g., endothelin-receptor antagonists). Berman et al. (1982) initially described a variable response of pulmonary vascular resistance to oxygen in nine patients with BPD, and it was considered that oxygen supplementation may not be very effective. However, of seven infants with elevated pulmonary pressure, four were noted to improve with oxygen supplementation (Berman et al., 1982). Abman et al. (1985) demonstrated in 1985 using cardiac catheterization that the pulmonary vascular resistance in infants with BPD was responsive to oxygen, with a greater than 10 mmHg reduction in mean pulmonary artery pressure on exposure to high concentrations of oxygen (FiO2 > 0.8). Most of the reduction in pulmonary artery pressure could be achieved by oxygen supplementation using a nasal cannula at lower flow rates. However, it is important to note that although there was a significant reduction in pulmonary arterial pressure from a mean of 48 mmHg to 25 mmHg with high oxygen concentrations (Abman et al., 1985), this pressure is still above the normal range. In a patient followed up to 45 months of age, a reduction in pulmonary arterial pressure was noted, suggesting that pulmonary vascular resistance may reduce over time associated with lung growth (Abman et al., 1985). Further studies have shown that even mild hypoxia can cause marked elevations in pulmonary artery pressure, including infants with established BPD and only modest basal levels of pulmonary hypertension (Mourani et al., 2004). Exaggerated pulmonary vascular constriction
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in response to hypoxia was even demonstrated in the absence of baseline pulmonary hypertension, and can persist late into childhood. Although these were limited studies, many performed in infants born more than 3 decades ago and studied by cardiac catheterization at a relatively late time point (generally at >1 year), the lessons of these studies still resonate in clinical practice today, as oxygen supplementation is the initial management of pulmonary hypertension in BPD. However, while maintenance of adequate oxygenation is important, it is important to avoid hyperoxia, which may induce further inhibition of alveolar and lung vascular development. Within the neonatal intensive care unit, the usual clinical practice for infants with BPD diagnosed with pulmonary hypertension generally consists initially of maintenance of oxygen saturation in the target range of 91 to 95% (avoiding dips in saturation to 85% or below as well as hyperoxia with saturations of 97% or above) which may reduce hypoxic pulmonary vasoconstriction, combined with inhaled nitric oxide (iNO) at 5 to 20 ppm. Identification and treatment of factors contributing to poor oxygenation (e.g., tracheobronchomalacia, anatomic airway obstruction, aspiration, bronchial reactivity, etc.) are also important to optimizing gas exchange. Other supportive therapy for BPD, such as diuretics, bronchodilators, corticosteroids, and fluid/electrolyte/nutrition management are also optimized, although the evidence for these therapies is limited and they may not directly impact the course of pulmonary hypertension. It is unclear at the current time to what extent ancillary therapies such as management of gastroesophageal reflux, evaluation of the airway, polysomnographic evaluation, or other specialized investigations are necessary in the evaluation of pulmonary hypertension in BPD. Clinical improvement (or lack thereof) may be followed using serial echocardiography that may be combined with BNP measurements. Currently, there are no published reports of the utility of serial BNP measurements in neonatal pulmonary hypertension, but we have found that BNP elevation and magnitude of pulmonary hypertension are positively correlated (unpublished data). The frequency of these repeat measurements generally depends upon the severity of the pulmonary hypertension and underlying clinical illness. In general, we obtain echocardiograms and/or BNP twice a week for unstable infants with an acute pulmonary hypertensive crisis or those undergoing weaning of pulmonary hypertension therapies such as iNO and once or twice a month for infants who are more stable. Upon resolution of the pulmonary hypertension, the iNO is gradually weaned off over days to weeks, with careful clinical monitoring, evaluation of oxygen requirement, and sometimes BNP measurements following every wean of iNO. If the pulmonary hypertension is attenuated by iNO therapy but not eliminated, or there is no response to iNO, a second-line agent such as sildenafil (0.5–1 mg/kg/dose every 8 hr; generally
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started at the lower dose and increased slowly as needed) may be added, and iNO weaned if tolerated. As recently reviewed by Wardle et al. (2013), sildenafil may possibly both safe and effective in infants with pulmonary hypertension in BPD, and may improve survival if continued until resolution of pulmonary hypertension. However, sildenafil did not improve short-term respiratory outcomes in a pilot trial of extremely preterm infants as an attempt to prevent BPD (Konig et al., 2014), suggesting earlier use may not be beneficial. Mourani et al. (2009) did a retrospective review of 25 infants with BPD and pulmonary hypertension who received sildenafil, initiated at a median of 171 days (range, 14–673 days) for a median duration of 241 days (range, 28–940 days). Twenty-two of the 25 (88%) improved hemodynamically (defined as a 20% decrease in ratio of pulmonary to systemic arterial pressures or improvement of ventricular septal flattening on serial echocardiographic evaluations), suggesting that chronic sildenafil therapy may be reasonably effective. On the other hand, Nyp et al. (2012) reported in a retrospective review of 21 infants with BPD-associated pulmonary hypertension that although sildenafil reduced estimated right ventricular systolic pressures, it did not improve oxygenation in the short term (the first 48 hr). In fact, sildenafil may rarely worsen ventilation/perfusion mismatch and oxygenation, and cause systemic hypotension. It is important to remember that safety cannot be established from smaller retrospective studies and that effectiveness will need to include evaluation of long-term benefit on pulmonary arterial pressures as well as on gas exchange parameters. It must be noted that the U.S. Food and Drug Administration has issued a warning against use of sildenafil in children between 1 and 17 years of age, as the STARTS-2 study noted higher mortality in older children taking a higher dose (>3 mg/kg/day) as compared to those taking a lower dose (Barst et al., 2012). Infants on sildenafil, therefore, need close monitoring. In addition, sildenafil pharmacokinetics are currently under investigation (ClinicalTrials.gov # NCT01670136), as it is likely that pharmacokinetics of sildenafil in preterm infants are different from those of older children or adults, and it is possible that the optimal dosing is different from what is currently used in infants. Infants who do not respond to BPD management and iNO/sildenafil are usually started on a third-line agent. This third-line agent may be either a prostacyclin analog (e.g., epoprostenol [Flolan] by continuous intravenous infusion, iloprost [Ventavis] by inhalation, or treprostinil [Remodulin] by subcutaneous or intravenous infusion) or an endothelin-receptor antagonist (e.g., a nonselective endothelin receptor antagonist such as bosentan, or a selective ET-A receptor antagonist such as ambrisentan). There are limited data on the effectiveness and safety of these third-line agents in infants with BPD and pulmonary hypertension, and these agents should be used cautiously with careful monitoring for efficacy and toxicity.
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Epoprostenol has been shown in case reports to reduce pulmonary hypertension in the setting of BPD (Zaidi et al., 2005) as well as in younger neonates with persistent pulmonary hypertension of the newborn (Eronen et al., 1997). Other prostacyclin analogs may be expected to have a similar effect, and there are case reports and case series of use of inhaled iloprost for pulmonary hypertension in BPD (Hwang et al., 2009; Gurakan et al., 2011; Piastra et al., 2012). However, it is important to carefully evaluate for side effects such as hypotension, increased airway reactivity, pulmonary edema, and increased cyanosis due to potential for augmentation of intrapulmonary shunt. Bosentan has clinical and hemodynamic efficacy in retrospective cohort studies of children with pulmonary arterial hypertension (idiopathic, associated with congenital heart, or connective tissue disease) (Rosenzweig et al., 2005; Ivy et al., 2010; Hislop et al., 2011). A small randomized controlled trial showed that bosentan improves outcomes (improved oxygenation and reduction in pulmonary arterial pressure without toxicity) in neonates with persistent pulmonary hypertension of the newborn (Mohamed and Ismail, 2012) but its efficacy in younger infants with BPD needs to be determined as there are only case reports (Rugolotto et al., 2006) or small case series (Krishnan et al., 2008) demonstrating its use in BPD, usually in combination with either prostacyclin analogs or sildenafil. Also, bosentan may potentially increase liver toxicity in patients with BPD who also have total perenteral nutrition-induced cholestasis and liver dysfunction. Currently, there is limited evidence on how long these therapies need to be continued. Often, many infants are discharged from the neonatal intensive care unit on these medications and followed-up by pediatric pulmonologists or centers focusing on pulmonary hypertension. If pulmonary hypertension gradually resolves with lung growth as expected, the medications may be either gradually tapered off, or the infant allowed to outgrow the dose before discontinuation of the drugs one by one (usually the most “invasive” or least effective medication first to go).
Outcomes Multiple studies have documented that the presence of pulmonary hypertension in BPD is associated with higher mortality (Khemani et al., 2007; Slaughter et al., 2011; Kim et al., 2012). In addition, these infants have a greater morbidity, with higher usage of health care resources, with prolonged respiratory support and longer initial hospitalizations (Check et al., 2013; Stuart et al., 2013). It is, therefore, conventional wisdom that pulmonary hypertension in BPD contributes to mortality and morbidity. While it is certain that the presence of pulmonary hypertension is associated with worse outcomes (i.e., pulmonary hypertension is a biomarker), it is not clear how much the
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presence of pulmonary hypertension, as opposed to the underlying parenchymal and airway lung disease, contributes to poor outcome. There are no randomized trials to date evaluating if treatment of pulmonary hypertension improves outcome in BPD, as it is generally assumed that pulmonary hypertension if left untreated would lead to worse oxygenation, deterioration of right heart failure and subsequent mortality. The long-term (adolescence/adult) effects of pulmonary hypertension in BPD are essentially unknown. It is possible that these individuals remain at life-long increased risk of pulmonary hypertension following hypoxia or other stimuli, or may be at greater risk of pulmonary hypertension and chronic obstructive pulmonary disease during age-related declines in pulmonary function in middle age.
Future Directions Additional research is needed to fill several knowledge gaps in our understanding of BPD and associated pulmonary hypertension. A better understanding of normal alveolar and lung vascular development, including biomarkers of lung development and how these are disturbed in BPD is essential for the development of novel therapeutic strategies and for the optimization of existing therapies. In addition, careful clinical phenotyping of BPD, with specific focus on the magnitude of airway, parenchymal, and vascular involvement at different time points during the postnatal course is required to target therapies specifically at phenotype. Evaluation of long-term pulmonary and pulmonary vascular outcomes in extremely preterm infants is needed, as infants who have BPD and pulmonary hypertension may possibly be at higher risk of adult-onset chronic obstructive pulmonary disease and cor pulmonale, although data are lacking at present (Filippone et al., 2010; Shi and Warburton, 2010).
Acknowledgment There are no conflicts of interest to disclose.
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