Vasodilator drugs for pulmonary hypertension in bronchopulmonary dysplasia

Introduction

Infants born extremely prematurely are at risk for bronchopulmonary dysplasia (BPD), or chronic lung disease of prematurity. Based on recommendations from a 2001 National Institutes of Health workshop, BPD is defined by the presence and type of respiratory support required at 36 weeks postmenstrual age in infants born at less than 32 weeks gestation. The lung parenchymal features of BPD have changed since the introduction of surfactant therapy, with “new” BPD characterized primarily by immature alveolar development and significantly less pulmonary fibrosis compared to “old” BPD, first described in 1967. ^, Nonetheless, the incidence of BPD has remained essentially unchanged, with approximately 40% of extremely premature infants developing BPD. With nearly one in 10 infants born prematurely in the United States, BPD results in a significant healthcare burden. ^,

The development of pulmonary hypertension (PH) is an important potential consequence of BPD. PH is defined as an elevated mean pulmonary arterial pressure greater than 20 mmHg, with precapillary PH further defined by a pulmonary vascular resistance of at least 3 Wood units, indexed for body surface area (WU·m ² ). ^, Approximately 20% of infants with BPD develop PH, the frequency of which increases with BPD severity. Importantly, PH imparts significant risk for mortality; a recent meta-analysis reported 16% mortality prior to discharge and 40% mortality within the first 2 years of life. ^{, ,} Despite this early mortality, most survivors have resolution of PH and are able to discontinue PH therapies by 2 years of age. ^, PH in infants with BPD is associated with impaired somatic growth and neurodevelopment. Although treating the underlying respiratory disease and promoting lung growth are key strategies in the management of BPD-associated PH (BPD-PH), targeted PH therapy is often employed for infants with persistent or severe PH. This chapter focuses on the use of pulmonary vasodilators in infants with BPD-PH.

Pathophysiology and risk factors

BPD-PH pathophysiology is complex and related to a combination of both pre- and postnatal factors. Central to the development of both BPD and PH is the immature alveolar and pulmonary vascular development associated with premature birth. Preterm birth during the late canalicular to saccular stage of lung development results in a reduced number of alveoli that appear architecturally simplified and are accompanied by fewer blood vessels than fully developed lungs. ^{, ,} Postnatal vascular injury from periods of hypoxia or hyperoxia, inflammation secondary to sepsis or aspiration, and/or hemodynamic influence of cardiac shunt lesions may promote pulmonary vasoconstriction and muscularization of the pulmonary arteries. ^, Ultimately, these factors together confer a risk of BPD-PH due to a significantly decreased vascular surface area, elevated pulmonary vascular tone, and pathologic vascular changes ( Table 16.1 ).

There are a number of recognized risk factors that affect the development of BPD and BPD-PH, the most significant being lung disease severity. Generally, the risk for BPD-PH increases with more severe BPD. However, infants with no or mild BPD may develop PH, whereas some with severe BPD never develop PH, highlighting additional pre- and postnatal contributors. Prenatal factors affecting lung development, including fetal growth restriction and oligohydramnios, impart increased risk for BPD and BPD-PH. ^{, ,} Early evidence of PH at 7 days of age is associated with the development of late PH at 36 weeks postmenstrual age and may reflect a reduced pulmonary vascular bed. Other postnatal factors associated with BPD-PH include indices of impaired development, lung disease severity and systemic inflammation, lower gestational age, duration of mechanical ventilation, duration of hospitalization, sepsis, necrotizing enterocolitis, and retinopathy of prematurity. ^,

Diagnosis

Establishing the correct diagnosis is imperative in the appropriate treatment of BPD-PH. Clinical signs of PH may be vague and overlap considerably with BPD. Because PH may be triggered by worsening respiratory status, symptoms may include tachypnea, respiratory distress, and hypoxia. On cardiac exam, infants with PH may have a loud second heart sound, palpable right ventricular impulse, and a systolic murmur related to tricuspid valve insufficiency. Some infants may present with signs of right ventricular failure related to BPD-PH, including tachycardia, hepatomegaly, peripheral edema, and poor growth. Hypoxia may be present in infants with right-to-left shunts from elevated pulmonary vascular resistance, manifested as either systemic hypoxia (in the case of an intracardiac shunt) or a pre- and postductal saturation differential (in the case of a patent ductus arteriosus). Conversely, BPD-PH may be present with no overt clinical signs. Therefore, multiple expert panels recommend echocardiographic screening for BPD-PH in at-risk infants at 36 weeks postmenstrual age ( Figure 16.1 ). ^{, ,} However, criteria to define those most “at-risk” for BPD-PH and the most appropriate screening protocols remain controversial. Serum brain natriuretic peptide is often used in combination with echocardiography as a biomarker of pulmonary hypertension and/or right heart failure in BPD-PH.

Transthoracic echocardiogram is the most commonly used modality to screen for PH and identify shunt lesions. In addition to characterizing cardiac anatomy, echocardiography may estimate the right ventricular (RV) systolic pressure by Doppler assessment of a tricuspid regurgitation jet. Similarly, Doppler interrogation of patent ductus arteriosus flow may estimate systolic pulmonary artery pressure. When flattening of the interventricular septum at end systole is observed, it suggests that the RV pressure is at least half the systemic systolic pressure. Pulmonary vein stenosis is increasingly recognized in premature infants, which may cause postcapillary PH, and should be included in PH assessment. Finally, RV hypertrophy, dilation, and systolic function reflect both PH severity and duration and are important factors when selecting pulmonary vasodilator therapy.

When PH is suggested by echocardiogram, additional imaging modalities are often used to determine if there are potential structural contributors to PH. Chest computed tomography angiography can assess for pulmonary vascular anomalies, such as pulmonary vein stenosis or peripheral pulmonary arterial stenoses, which may contribute to RV hypertension yet not be apparent by echocardiogram. Chest computed tomography angiography also effectively characterizes the airways and lung parenchyma, highlighting airway malacia, atelectasis, or other structural abnormalities that alter clinical management. ^{, ,} Cardiac magnetic resonance imaging may have specific indications in this population (e.g., defining degree of cardiac shunt or cardiac and pulmonary vascular anatomy). However, it is less commonly used to assess lung parenchyma, and the need for anesthesia limits its clinical utility in most centers. ^,

Cardiac catheterization is the gold standard for the diagnosis of PH, as it provides direct hemodynamic measurements, angiographic assessment of the pulmonary vasculature, and calculation of the pulmonary vascular resistance. Catheterization also provides a means to diagnose and potentially intervene if anatomic abnormalities, such as cardiac shunts and pulmonary vein stenosis, are observed. Catheterization should be undertaken with caution and by providers experienced in the care of infants with BPD-PH, given the small patient size, potential clinical instability, and known risk for periprocedural adverse events in those with PH. ^, Depending on diagnostic certainty by echocardiogram, PH-targeted therapy may be initiated without catheterization if the perceived risk of the procedure outweighs the clinical benefit. Catheterization, however, should be undertaken in cases of diagnostic uncertainty, when additional anatomic and hemodynamic information may alter therapeutic decisions, when infants have an unexpected response to pulmonary vasodilator therapy, and for assessment of disease severity when considering combination PH-targeted therapies. ^,

Management