Diagnosis, Evaluation and Treatment of Pulmonary Arterial Hypertension in Children

Abstract

Pulmonary Hypertension (PH), the syndrome of elevated pressure in the pulmonary arteries, is associated with significant morbidity and mortality for affected children. PH is associated with a wide variety of potential underlying causes, including cardiac, pulmonary, hematologic and rheumatologic abnormalities. Regardless of the cause, for many patients the natural history of PH involves progressive elevation in pulmonary arterial resistance and pressure, right ventricular dysfunction, and eventually heart failure. In recent years, a number of pulmonary arterial hypertension (PAH)-targeted therapies have become available to reduce pulmonary artery pressure and improve outcome. A growing body of evidence in both the adult and pediatric literature demonstrates enhanced quality of life, functional status, and survival among treated patients. This review provides a description of select etiologies of PH seen in pediatrics and an update on the most recent data pertaining to evaluation and management of children with PH/PAH. The available evidence for specific classes of PAH-targeted therapies in pediatrics is additionally discussed.

Keywords: pediatrics; pulmonary arterial hypertension; pulmonary hypertension; review.

Figure 1

Kaplan–Meier curves showing the survival pediatric pulmonary arterial hypertension (PAH) patients compiled at 3 pulmonary hypertension (PH) centers (Denver, New York, Netherlands): 1-, 3-, 5- and 7-year transplantation-free survival rates were 96%, 89%, 81% and 79%, respectively [4].

Figure 2

Updated classification of pulmonary hypertension based on recommendations from the 5th World Symposium on Pulmonary Hypertension in Nice, France, 2013. Adapted from [12].

Figure 3

Annual incidence rates for pediatric pulmonary hypertension. PH indicates pulmonary hypertension; PAH, pulmonary arterial hypertension; PAH-CHD, PAH associated with congenital heart defects; and IPAH, idiopathic PAH [14].

Figure 4

Survival curves for the subgroups within the associated pulmonary arterial hypertension (APAH) group from the UK pulmonary hypertension service. The number in each group (brackets) and the predicted survival out of a possible 5 years is depicted. Note the worse survival for children with post-operative congenital heart disease [18].

Figure 5

Normal values for tricuspid annular plane systolic excursion (TAPSE) by age [61].

Figure 6

(A) Parasternal short axis view of the right and left ventricles (RV/LV) at the level of the papillary muscles. The RV/LV ratio is derived from RV diameter and LV diameter at end-systole. RV/LV end-systolic ratio is predictive of outcome; (B) Estimated survival curves for four possible RV/LV ratios estimated from the Cox varying coefficients regression corresponding to a hazard ratio of 2.49 for RV/LV ratio [66].

Figure 7

The systolic (S) to diastolic (D) time ratio from tricuspid regurgitation velocity can be measured as an indicator of right ventricular function. (A) Measurement of the S/D ratio from a continuous wave Doppler spectrogram; (B) An increase in the S/D ratio predicts worse outcome in children with PAH. [68].

Figure 8

(A) A tissue Doppler spectrogram of the right ventricle at the lateral annulus of the tricuspid valve demonstrates the myocardial systolic wave (S’, reflecting the systolic longitudinal movement of the RV) and two diastolic waves (early diastolic (E’) and late diastolic (A’), which reflect the diastolic function of the ventricle); (B) E’ velocity less than 8 cm/s is predictive of poor outcome in pediatric IPAH [72].

Figure 9

Kaplan–Meier survival curves for children with IPAH and PAH associated with CHD. Survival curves are shown for all patients (left) and for the subgroup of IPAH patients (right) categorized with either brain natriuretic peptide (BNP) > 180 pg/mL or < 180 pg/mL [85].

Figure 10

The number of acute pulmonary vasodilator responders according to the three criteria in use, in children vs. adults with idiopathic pulmonary arterial hypertension (IPAH)/hereditary pulmonary arterial hypertension (HPAH), IPAH/HPAH vs. pulmonary arterial hypertension associated with congenital heart disease, and patients without vs. with post-tricuspid shunt, respectively. Data presented as percentage of patient group (%) and patient numbers (indicated in bars). Comparison between groups performed using Fisher’s exact test. Note the few % of patients with PAH-CHD responding to acute vasodilator challenge [114].

Figure 11

Adapted treatment algorithm proposed in the management of pediatric patients with idiopathic or heritable pulmonary arterial hypertension. This may be translatable to other patients with pulmonary hypertension. CCB, calcium channel blocker; ERA, endothelin receptor antagonist; PDE-5i, phosphodiesterase 5 inhibitor [3].

Figure 12

Risk factors that should be considered when planning therapeutic management options in pulmonary hypertension. CI—cardiac index; mPAp—mean pulmonary artery pressure; mSAp—mean systemic aortic pressure; NT-proBNP—N-terminal–pro-brain natriuretic peptide; PVRI—indexed pulmonary vascular resistance; RAP—right atrial pressure; RV—right ventricle; SBNP—serum brain natriuretic peptide [3].

Figure 13

Kaplan–Meier estimated survival from start of sildenafil treatment in Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1) and STARTS-2. Patients were censored at the last date they were known to be alive; if a patient received a transplant, he or she was censored the day before transplant. Patients at risk are those who are ongoing in the study or known to be alive at the specified time (i.e., not dead, not lost to follow-up, or not in study long enough to reach time point) [172].

Figure 14

Change from baseline in 6-min walking distance (6MWD) in the subgroup of patients with pulmonary arterial hypertension associated with congenital heart disease in Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 (PATENT-1; (A) and PATENT-2 (B)). Data are observed values (mean ± SEM) [175].

Figure 15

Survival according to extent of pulmonary hypertension therapy in 275 recently diagnosed consecutive pediatric PAH patients at 3 referral centers between 2000 and 2010. Survival improves on combination therapy for pulmonary hypertension over monotherapy. CCB, calcium channel blocker [4].

Figure 16

Echocardiogram of the Potts shunt in a patient with severe IPAH by 2D imaging (left) and with color Doppler (right). LPA, left pulmonary artery.