BACKGROUND Pediatric patients with severe pulmonary arterial hypertension (PAH) are treated with intravenous epoprostenol or intravenous or subcutaneous treprostinil. Little is known about longitudinal hemodynamics and outcomes of epoprostenol, treprostinil, and transitions from epoprostenol to treprostinil. METHODS This was retrospective study of 77 pediatric patients (47 idiopathic PAH, 24 congenital heart disease-PAH) receiving epoprostenol or treprostinil from 1992 to 2010 at 2 centers. Outcomes were defined as living vs dead/transplant. RESULTS Mean age at baseline was 7.7 ± 5.2 years, with follow-up of 4.3 ± 3.4 years. Thirty-seven patients were treated with epoprostenol, 20 with treprostinil, and 20 were transitioned from epoprostenol to treprostinil. Mean pulmonary-to-systemic vascular resistance ratio (Rp/Rs) for epoprostenol was 1.0 ± 0.4, 0.8 ± 0.4, 0.8 ± 0.4, 1.0 ± 0.4, and 1.2 ± 0.4, respectively, at baseline, 1, 2, 3, and 4 years. For treprostinil, Rp/Rs was 0.9 ± 0.3, 0.7 ± 0.3, 0.5 ± 0.2, (p < 0.01 vs baseline), and 1.1 ± 0.2, respectively, at baseline, 1, 2, and 3 to 4 years, respectively. There were similar changes in mean pulmonary artery pressure and pulmonary vascular resistance index. The Rp/Rs 1 year after epoprostenol to treprostinil transition increased from 0.6 to 0.8 (n = 7). Changes not statistically significant unless noted. Eight patients died or received a transplant within 2 years of baseline; compared with the rest of the cohort, mean baseline Rp/Rs, right atrial pressure, and pulmonary vascular resistance index were significantly worse in this group. Thirty-nine patients remain on prostanoids, 17 are off, 16 died, and 5 received heart-lung transplant. Kaplan-Meier 5-year transplant-free survival was 70% (95% confidence interval, 56%-80%). CONCLUSION There was improvement in Rp/Rs on both therapies at 1 to 2 years that was not sustained. The 5-year transplant-free survival was better than in similar adult studies.

This prospective pilot study of phenylephrine, arginine vasopressin, and epinephrine in pediatric patients with pulmonary hypertensive showed an increase in aortic pressure with all drugs although only vasopressin resulted in a consistent decrease in the ratio of pulmonary-to-systemic vascular resistance. Studies with more subjects are warranted to define optimal dosing strategies of these medications in an acute pulmonary hypertensive crisis.

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR). Optimizing treatment strategies and timing for transplant remains challenging. Thus, a quantitative measure to predict disease progression would be greatly beneficial in treatment planning. We devised a novel method to assess right ventricular (RV) stroke work (RVSW) as a potential biomarker of the failing heart that correlates with clinical worsening. Pediatric patients with idiopathic PAH or PAH secondary to congenital heart disease who had serial, temporally matched cardiac catheterization and magnetic resonance imaging (MRI) data were included. RV and PA hemodynamics were numerically determined by using a lumped parameter (circuit analogy) model to create pressure-volume (P-V) loops. The model was tuned using optimization techniques to match MRI and catheterization derived RV volumes and pressures for each time point. RVSW was calculated from the corresponding P-V loop and indexed by ejection fraction and body surface area (RVSW) to compare across patients. Seventeen patients (8 boys; median age = 9.4 years; age range = 4.4-16.3 years) were enrolled. Nine were clinically stable; the others had clinical worsening between the time of their initial matched studies and their most recent follow-up (mean time = 3.9 years; range = 1.1-8.0 years). RVSW and the ratio of pulmonary to systemic resistance (Rp:Rs) values were found to have more significant associations with clinical worsening within one, two, and five years following the measurements, when compared with PVR index (PVRI). A receiver operating characteristic analysis showed RVSW outperforms PVRI, Rp:Rs and ejection fraction for predicting clinical worsening. RVSW correlates with clinical worsening in pediatric PAH, shows promising results towards predicting adverse outcomes, and may serve as an indicator of future clinical worsening.

Because most medications for pediatric pulmonary hypertension (PH) are used off label and based on adult trials, little information is available on pediatric-specific adverse events (AEs). Although drug manufacturers are required to submit postmarket AE reports to the Food and Drug Administration (FDA), this information is rarely transmitted to practitioners. In the setting of a recent FDA warning for sildenafil, the authors sought to give a better description of the AEs associated with current therapies in pediatric PH. In January 2010, a written request was made to the Food and Drug Administration for AE records of commonly used PH medications. Reports were screened for pediatric patients, analyzed in terms of AEs, and compared with the medical literature. Arbitrarily, AEs that could be attributed to concomitant medications were not attributed to the PH medication in question. Adverse events occurring in more than 5 % of events for each drug were assumed to be associated with the targeted PH medication. Between November 1997 and December 2009, 588 pediatric AE reports (death in 257 cases) were reported for the three most commonly used therapies: bosentan, epoprostenol, and sildenafil. Many of the AEs were similar to those reported previously. However, 27 AEs not previously reported in the literature (e.g., pulmonary hemorrhage, hemoptysis, and pneumonia) were found. The FDA postmarket records for PH medications in pediatric patients show a significant number of AEs. The discovery of AEs not previously reported will better inform those caring for these complex and critically ill children, and the large number of deaths suggest they may be underreported in current literature.

Background: Sildenafil, a phosphodiestase type 5 inhibitor, was approved in 2005 for the treatment of pulmonary arterial hypertension (PAH) in adults and is commonly used off-label for pediatric patients. Little is known, however, about sildenafil’s side effects in this population.Methods: Single institution, longitudinal survey-based study performed in an outpatient pediatric cardiology clinic. Pediatric patients on sildenafil [alone or in combination with other pulmonary hypertension (PH) therapies] completed questionnaires regarding frequency of vascular, gastrointestinal, neurologic, and hematologic side effects.Results: Between January 2011 and May 2014, 66 pediatric patients with PH on sildenafil filled out 214 surveys, 32 patients (96 surveys) on monotherapy, and 43 patients (118 surveys) on sildenafil plus an endothelin receptor antagonist (ERA) (bosentan or ambrisentan) and/or a prostacyclin (epoprostenol or treprostinil). Overall, 30% of respondents identified at least one side effect. For all patients on sildenafil, incidence of side effects by system was 37% gastrointestinal, 35% vascular, and 22% neurologic. For patients on sildenafil monotherapy, incidence of side effects by system was 24% gastrointestinal, 21% vascular, and 18% neurologic compared to patients on combination therapy who reported an incidence of 48% gastrointestinal, 45% vascular, and 25% neurologic.Conclusion: Incidence of vascular, gastrointestinal, and neurologic side effect in pediatric patients on sildenafil therapy for PAH was 30%. Side effects were more common in patients on combination therapy with an ERA and/or prostacyclin than in patients on sildenafil monotherapy.