Subcutaneous and Intravenous Treprostinil Pharmacokinetics in Children With Pulmonary Vascular Disease.

This study evaluated the pharmacokinetics of intravenous (IV) and subcutaneous (SC) treprostinil in pediatric patients with pulmonary vascular disease, and compared them with existing adult data from a similar cohort. Blood samples were collected from pediatric patients receiving steady-state IV or SC treprostinil and were assessed for plasma treprostinil concentration using liquid chromatography and tandem mass spectrometry. Forty participants, 15 receiving IV and 25 receiving SC treprostinil, were included in the analysis. Age ranged from 0.1 to 15.6 years. The median dose of treprostinil was 45.5 ng·kg·min with a range of 8-146 ng·kg·min. There was a linear relationship between treprostinil dose and plasma concentration with an R of 0.57. On average, there were higher blood concentrations per given dose of IV treprostinil compared with those per given dose of SC, but the difference was not significant. Compared with adult data, the slope of the pediatric data was similar, but the y-intercept was significantly lower. Additionally, the concentration per dose ratio was significantly higher in adults compared with children. Pediatric patients have significantly lower average blood concentrations of treprostinil per given dose compared with adults, and higher, but not significantly so, blood concentrations when treprostinil is administered IV as compared with SC administration.

Pulmonary lung Doppler signals: normative data in a pediatric population compared with adults.

Lung Doppler signals (LDS) acquired via transthoracic echocardiography is a novel technology previously reported in adults for use in detecting pulmonary hypertension. The aim of this study was to characterize LDS in healthy children to establish normative pediatric LDS data, and compare the pediatric data to the previously published healthy adult LDS. In this prospective, two-center study, LDS were acquired in children without cardiopulmonary disease using a 2 MHz transthoracic pulsed Doppler transducer. The data were processed to obtain Doppler velocity patterns corresponding to phases of the cardiac cycle. Signals were analyzed using a parametric Doppler signal-processing package and performance evaluation of the trained classifiers was performed using cross validation method. Pediatric signals were then compared to a retrospective cohort of healthy adults. Eighty-six healthy pediatric subjects (mean age 9.1 ± 5.1 years) and 79 healthy adult controls (mean age 59.7 ± 10.7 years) were included. The normative LDS velocity profiles were defined for pediatric subjects and then compared to adults; the highest discriminating LDS parameters between healthy children and adults were acceleration of atrial (A) signal contraction (46 ± 18 vs. 90 ± 34; p < 0.001), peak systolic (S) signal velocity (10.0 ± 3.5 vs. 11.7 ± 3.5; p < 0.001), and ratio of peak diastolic (D)-to-atrial (A) signal velocity (1.4 ± 0.5 vs. 0.4 ± 0.3; p < 0.001). The sensitivity and specificity of this LDS based method to discern between healthy children and adult subjects was 98.6% and 97.4%, respectively. Subgroup analyses between younger (2-8 years) and older (9-18 years) pediatric LDS yielded significant differences between atrial (A) acceleration (43.7 ± 33.9 vs. 47.7 ± 42.1; p = 0.04) and diastolic (D)-to-atrial (A) signal velocity (1.2 ± 0.5 vs. 1.5 ± 0.5; p = 0.01) but not systolic (S) signals (0.14 ± 0.05 vs. 0.14 ± 0.05; p = 0.97). In this study, we defined the normal LDS profile for healthy children and have demonstrated differences in LDS between children and adults. Specifically, healthy children had lower atrial contraction power, differences in ventricular compliance and increased chronotropic response. Further studies are warranted to investigate the application of this technology, for example as a tool to aid in the detection of pulmonary hypertension in children.

Right ventricular stroke work correlates with outcomes in pediatric pulmonary arterial hypertension.

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 (RVSWEF) 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). RVSWEF 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 RVSWEF outperforms PVRI, Rp:Rs and ejection fraction for predicting clinical worsening. RVSWEF correlates with clinical worsening in pediatric PAH, shows promising results towards predicting adverse outcomes, and may serve as an indicator of future clinical worsening.