Diagnostic Approach to Pulmonary Hypertension in Premature Neonates

Abstract

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease in premature infants following respiratory distress at birth. With increasing survival of extremely low birth weight infants, alveolar simplification is the defining lung characteristic of infants with BPD, and along with pulmonary hypertension, increasingly contributes to both respiratory morbidity and mortality in these infants. Growth restricted infants, infants born to mothers with oligohydramnios or following prolonged preterm rupture of membranes are at particular risk for early onset pulmonary hypertension. Altered vascular and alveolar growth particularly in canalicular and early saccular stages of lung development following mechanical ventilation and oxygen therapy, results in developmental lung arrest leading to BPD with pulmonary hypertension (PH). Early recognition of PH in infants with risk factors is important for optimal management of these infants. Screening tools for early diagnosis of PH are evolving; however, echocardiography is the mainstay for non-invasive diagnosis of PH in infants. Cardiac computed tomography (CT) and magnetic resonance are being used as imaging modalities, however their role in improving outcomes in these patients is uncertain. Follow-up of infants at risk for PH will help not only in early diagnosis, but also in appropriate management of these infants. Aggressive management of lung disease, avoidance of hypoxemic episodes, and optimal nutrition determine the progression of PH, as epigenetic factors may have significant effects, particularly in growth-restricted infants. Infants with diagnosis of PH are managed with pulmonary vasodilators and those resistant to therapy need to be worked up for the presence of cardio-vascular anomalies. The management of infants and toddlers with PH, especially following premature birth is an emerging field. Nonetheless, combination therapies in a multi-disciplinary setting improves outcomes for these infants.

Keywords: bronchopulmonary dysplasia; nitric oxide; premature newborns; pulmonary hypertension; sildenafil.

Figure 1

Lung development and bronchopulmonary dysplasia (BPD). Perinatal and postnatal factors play an important role in the development of BPD. The figure illustrates stages of lung development in mice: (A) canalicular stage; (B) saccular stage; (C) alveolar stage; (D) lung histology in adult mice; (E) new BPD with simplified alveoli and fewer secondary septae in mice exposed to 85% O₂ from day 3 (P3) to day 14 (P14); (F) lung similar to chronic obstructive pulmonary disease (COPD) in adult mice at 9 months following neonatal oxygen exposure. IUGR: intrauterine growth retardation; O₂: oxygen. (Slide magnification—100×; Inset slides—400×; See text for details).

Figure 2

Bronchopulmonary dysplasia and pulmonary hypertension (PH). (A–C) Altered angiogenesis during lung development in the presence of perinatal and postnatal factors leads to pulmonary hypertension in BPD; (D) smooth muscle actin (SMA) staining demonstrating increasing thickness of the pulmonary arterioles following neonatal O₂ exposure (arrows—Figure 2D); (E) high power magnification (400×) illustrating smooth muscle thickness of the pulmonary vessel wall. SGA: small for gestational age. ROM: rupture of membranes.

Figure 3

Diagnostic approach to PH in premature neonates. pPROM: preterm prolonged rupture of membranes; Echo: echocardiography; BNP: B-type natriuretic peptide; PMA: post menstrual age; GERD: gastro-esophageal reflux disease; ASD: atrial septal defect; PDA: patent ductus arteriosus; SPC: systemic to pulmonary collaterals; PVS: pulmonary vein stenosis; RV: right ventricle; LV: left ventricle; CMR: cardiac magnetic resonance imaging; PVT: pulmonary vasodilator therapy.

Figure 4

Management of pulmonary hypertension in premature neonates. Dotted lines indicate negative feedback loop on development of PH. RAD: reactive airway disease; UGI: upper gastro-intestinal series; OI: oxygenation index; * second line drugs are not well studied in neonates and infants with PH.

Figure 5

Schematic diagram of vascular mediators of the lung, their mechanism of action, interaction between the endothelial cell and the smooth muscle cell in the pulmonary vasculature, and its relationship to drugs used in the management of PH in BPD. The three predominant signaling pathways illustrated include: (i) nitric oxide—cGMP system; (ii) PGI₂-cAMP system; and (iii) endothelin-1 system. NO: nitric oxide; PGI₂: prostacyclin; NOS: nitric oxide synthase; EC: endothelial cell; ET-1: endothelin-1; ECE: endothelin converting enzyme; SES: subendothelial space; SMC: smooth muscle cell; PDE5: phosphodiesterase type 5; PDE3: phosphodiesterase type 3; ET_A: endothelin receptor type A; ET_B: endothelin receptor type B; AC: adenylate cyclase; sGC: soluble guanylyl cyclase; cGMP: cyclin GMP; COX1: cyclo-oxygenase type 1; PGIS: Prostaglandin synthase

Figure 6

Fetal programing, preterm birth and pulmonary hypertension. Extremely Low Birth Weight (ELBW) infants born between 23 and 28 weeks (grey zone) are at risk for BPD and PH, as determined by lung development, fetal growth, and epigenetics. The degree of altered angiogenesis and alveologenesis determine the severity of BPD and/or PH. (A) Cross-section of pulmonary arteriole at birth in premature infant; (B) alveoli exposed to high PO₂, hence higher arterial PO₂; (C) BPD in mice exposed to O₂ from P3–P14; (D) lungs similar to COPD/emphysema in adult mice; (E) airways with smooth muscle hypertrophy on SMA staining (arrow) in 3-month adult mice. Premature infants with BPD are at increased risk for RAD, bronchial hyper-responsiveness and asthma; (F/G) pulmonary arterioles with thickened walls on SMA staining suggesting smooth muscle proliferation (adult mice aged 3 to 9 months). The risks of preterm birth associated with late onset pulmonary hypertension in children and adults is not known in humans.