Embracing the challenges of neonatal and paediatric pulmonary hypertension

Abstract

Paediatric pulmonary arterial hypertension (PAH) shares common features with adult disease, but is associated with several additional disorders and challenges that require unique approaches. This article discusses recent advances, ongoing challenges and distinct approaches for caring for infants and children with PAH, as presented by the paediatric task force of the 7th World Symposium on Pulmonary Hypertension. We provide updates on diagnosing, classifying, risk-stratifying and treating paediatric pulmonary hypertension (PH) and identify critical knowledge gaps. An updated risk stratification tool and treatment algorithm is provided, now also including strategies for patients with associated cardiopulmonary conditions. Treatment of paediatric PH continues to be hindered by the lack of randomised controlled clinical trials. The challenging management of children failing targeted PAH therapy is discussed, including balloon atrial septostomy, lung transplantation and pulmonary-to-systemic shunt (Potts). A novel strategy using a multimodal approach for the management of PAH associated with congenital heart diseases with borderline pulmonary vascular resistance is included. Advances in diagnosing neonatal PH, especially signs and interpretation of PH by echocardiography, are highlighted. A team approach to the rapidly changing physiology of neonatal PH is emphasised. Challenges in drug approval are discussed, particularly the challenges of designing accurate paediatric clinical trials with age-appropriate end-points and adequate enrolment.

FIGURE 1

Treatment strategy for paediatric patients in pulmonary arterial hypertension (PAH). a) Treatment for children with idiopathic PAH (IPAH)/hereditary PAH (HPAH)/drug- and toxin-induced PAH (DT-PAH) and positive acute vasoreactivity testing. b) Treatment for children with IPAH/HPAH/DT-PAH and negative acute vasoreactivity testing and for children with PAH and associated cardiopulmonary conditions. HC: heart catheterisation; CCB: calcium channel blocker; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase-5 inhibitor; PPA: prostacyclin pathway agent; sGC: soluble guanylate cyclase; CHD: congenital heart disease; L: left; R: right. ^#: inadequate long-term response to CCB (see text); ^¶: suggest early consultation for lung transplant/Potts shunt; ⁺: according to clinical classification of PAH associated with CHD: group A, Eisenmenger syndrome (A); group B, PAH associated with prevalent systemic-to-pulmonary shunts: correctable (B1); noncorrectable (B2); group C, PAH with small/coincidental defects (C); group D, PAH after defect correction (D); group E, PAH associated with CHD without (prolonged) initial shunt; ^§: developmental lung disorders: the underlying lung disease should be aggressively treated and respiratory support optimised before considering PAH therapy (includes bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia, neonatal chronic lung disease); ^ƒ: patients with developmental lung disorders, especially BPD, may normalise pulmonary pressure over time and might be weaned from PAH-targeted therapy with close monitoring.

FIGURE 2

Failure of postnatal adaptation in pulmonary hypertension of the newborn. PAP: pulmonary arterial pressure; PPHN: persistent pulmonary hypertension of the newborn; RDS: respiratory distress syndrome; AVM: arteriovenous malformation; BPD: bronchopulmonary dysplasia; CDH: congenital diaphragmatic hernia; ACD: alveolar capillary dysplasia; MPV: misalignment of pulmonary veins; TBX4: T-box transcription factor 4 variants; TTF: thyroid transcription factor; NKX: NK2 homeobox.

FIGURE 3

Physiology of neonatal pulmonary hypertension (PH) (increased pulmonary arterial pressure). Q_p: pulmonary blood flow; PVR pulmonary vascular resistance; LAP: left atrial pressure; PVS: pulmonary vein stenosis; MS: mitral stenosis; LVDD: left ventricular diastolic dysfunction; PDA: patent ductus arteriosus; VSD: ventricular septal defect; AVM: arteriovenous malformation; TGA: transposition of the great arteries; CDH congenital diaphragmatic hernia; TBX4: T-box transcription factor 4 variants; FOXF1: forkhead box protein F1 variants; NKX2.1: NK2 homeobox 1 variants; BPD: bronchopulmonary dysplasia.