The introduction of prostanoid therapy has revolutionized the treatment of pulmonary arterial hypertension (PAH). However, continuous intravenous prostacyclin infusion poses significant risks and challenges, particularly in children. Inhaled treprostinil has been shown to be safe and efficacious in adults. This study describes the safety and efficacy of inhaled treprostinil in children with PAH. A retrospective analysis of 29 children treated with inhaled treprostinil for ≥6 weeks was performed. Effects of inhaled treprostinil on exercise capacity, functional class, and echocardiographic and hemodynamic data were evaluated. Adverse events were documented. Patients received 3 to 9 breaths (6 μg/breath) of inhaled treprostinil 4 times/day. All were receiving background PAH therapy; 12 had previously received parenteral prostanoid. Inhaled treprostinil was discontinued in 4 patients because of symptoms including cough and bronchospasm (n = 3) and progression of PAH (n = 1). Mild side effects including cough (n = 9) and sore throat (n = 6) did not require discontinuation of therapy. World Health Organization functional class improved in 19 and was unchanged in 10; exercise capacity significantly improved with the 6-minute walk distance, improving on follow-up from 455.7 ± 71.5 to 498 ± 70 m (p = 0.01) and peak oxygen consumption increasing from 25.5 ± 10.2 to 27.4 ± 10 (p = 0.04). In conclusion, inhaled treprostinil was associated with improvement in exercise capacity and World Health Organization functional class when added to background targeted PAH therapy in children and had an acceptable safety profile. Based on these early data, further study of inhaled treprostinil appears warranted in pediatric patients with PAH.
Outcomes for children with pulmonary arterial hypertension (PAH) have improved over the previous decade since the introduction of advanced PAH therapies. Parenteral prostanoids have increased long-term survival and improved quality of life in PAH. However, intravenous and subcutaneous prostanoid therapies have significant complications related to the delivery system. Therefore, research has been intensely concentrated on finding other therapeutic targets including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and inhaled prostanoids with more favorable risk–benefit profiles. Although the use of inhaled iloprost has been reported in children, the delivery system requires dosing 6 to 9 times/day. Inhaled treprostinil, a longer-acting prostanoid, enabling dosing 4 times/day, was approved for use in adults in 2010. In this descriptive report, we present the early safety and efficacy data of adding inhaled treprostinil to background PAH therapy in children.
Methods
To evaluate the safety, efficacy, and tolerability of inhaled treprostinil in children, we retrospectively reviewed the data from all patients with group 1 PAH treated with inhaled treprostinil for ≥6 weeks at 2 large pediatric pulmonary hypertension centers (Columbia University Medical Center and Children’s Hospital Colorado). Indications for initiation of inhaled treprostinil therapy included symptomatic PAH on background therapy or as a strategy to transition select patients off parenteral prostanoids. Before initiation of inhaled treprostinil, all children were trained on a proper nebulizer technique with the Opti-Neb device (a hand-held, ultrasonic, single-breath nebulizer; Metropolitan Medical, Inc., Winchester, Virginia), and therapy was started at 3 breaths (6 μg/breath) 4 times/day. Specialty home nursing was used to train the subjects on the technique and monitor therapy. In general, the dose was uptitrated weekly as tolerated as determined by weekly telephone calls to a maximum of 9 breaths (54 μg/treatment) 4 times/day ( Table 1 ). Some younger patients were intentionally held at 4 to 6 breaths/treatment. Some patients with cough or known asthma were treated with a bronchodilator before treatment. Baseline data collected before initiation of inhaled treprostinil included demographics, functional class, serum brain natriuretic peptide (BNP) levels, echocardiographic parameters, 6-minute walk distance (6MWD), cardiopulmonary exercise testing, and cardiac catheterization with vasoreactivity testing. Pulmonary function test (PFT) data included forced expiratory volume in 1 second, forced vital capacity, ratio of forced expiratory volume in 1 second to forced vital capacity, and mid volume forced expiratory flow (FEF 25 to 75%).
| Variable | Initiation | 6 Months | 12 Months |
|---|---|---|---|
| (n = 29) | (n = 23) | (n = 19) | |
| Dose in breaths per treatment (1 breath = 6 μg) | 1–3 | 8 ± 1.73 | 7.8 ± 1.9 |
| Time to maximum dose (weeks) | 5.7 ± 4.2 | ||
| Breaths, median (range) | 8 (3–9) | 9 (3–9) | 9 (3–9) |
| Frequency (treatments/day) | 4 | 4 | 4 |
| Total daily dose (μg), mean ± SD | 24–72 | 192 ± 41.6 | 187.2 ± 45.6 |
Echocardiographic parameters included baseline diagnostic study, tricuspid regurgitation gradient to estimate right ventricular systolic pressure (millimeters of mercury), pulmonary regurgitation gradient (millimeters of mercury), and right ventricular function. Hemodynamic parameters recorded at cardiac catheterization on room air, 100% oxygen, and inducible nitric oxide (40 to 80 ppm) included mean right atrial pressures, mean pulmonary arterial pressure, pulmonary capillary wedge pressure, and mean arterial pressure. Oxymetry included mixed venous, pulmonary artery, pulmonary vein (when available), and systemic arterial saturations. Parameters calculated were systemic and pulmonary blood flows (Qs and Qp; liters per minute), and indexed resistances (pulmonary and systemic resistances in Wood units per meter squared). The 6MWD test was performed in children ≥6 years old. Borg dyspnea scores were recorded. Heart rate and systemic arterial saturation were measured at rest and at 6 minutes and the distance walked was recorded in meters. World Health Organization (WHO) functional class obtained from the history was included for analysis. BNP (picograms per milliliter) was recorded when available. Cardiopulmonary exercise testing measurements included peak workload (watts), peak oxygen consumption (milliliters per kilogram per minute), Ventilatiory equivalent ratio for Carbondioxide – Pulmonary ventilation/Carbondioxide production (VE/VCO2), and end-tidal carbon dioxide.
Patients were followed at 3- to 6-month intervals and data collected included functional class, echocardiogram, BNP levels, 6MWD, cardiopulmonary exercise testing, PFTs, and hemodynamics when available. Adverse events and need to stop or alter the inhaled treprostinil dose were documented.
We compared 6MWD, WHO class, BNP, cardiopulmonary exercise testing, and hemodynamics at baseline and follow-up. Because this was a retrospective descriptive analysis, the study was not powered to detect a specific effect. Summary statistics were prepared for numeric results. All values are given as median with range or mean ± SD. Paired 2-tailed Student’s t tests were used to compare key variables at baseline and on latest follow-up; a p value <0.05 was considered statistically significant.
The study was approved by the Columbia University institutional review board (IRB-AAAF3463). All children from the University of Colorado were enrolled and consented to this study as part of Prospective Evaluation of Children with Pulmonary Hypertension (PEACH) protocol (COMIRB 05-0551).
Results
Twenty-nine consecutive pediatric patients with Group 1 PAH who received inhaled treprostinil for ≥6 weeks were included. Baseline demographic data are listed in Table 2 . There were 14 male and 15 female subjects (mean age 11.3 ± 4.5 years, median 12, range 3.2 to 19) with idiopathic PAH (n = 19) or associated PAH (n = 10). Average treatment duration was 15.7 ± 8.2 months (median 17, range 1.5 to 27.5). All patients were on background therapy. Four patients were on calcium channel blockers, 26 were on phosphodiesterase-5 inhibitors, 22 were on endothelin receptor antagonists, and 18 were on dual therapy. Twelve patients had previously been on parenteral prostanoids for 4.7 ± 3.3 years. Six of these patients were on inhaled iloprost in the interim period from intravenous/subcutaneous prostanoid to inhaled treprostinil. Twenty patients reached the target dose of 9 breaths/treatment 4 times/day, and 9 were held at 4 to 8 breaths because of young age or side effects.
| Patient | Age (years)/Sex | Type of PAH | Diagnosis | PDE5 | ERA | PGI2 | Previous PGI2 (years) | iTre Follow-Up (months) |
|---|---|---|---|---|---|---|---|---|
| 1 | 3.2/F | APAH | CHD | S | B | 11 | ||
| 2 | 4.6/M | APAH | CDH | S | B | 19.5 | ||
| 3 | 6.7/M | APAH | CHD | B | 23.6 | |||
| 4 | 10.5/F | APAH | CHD | S | A | 1.5 | ||
| 5 | 11.8/F | APAH | CHD | C | B | 19.1 | ||
| 6 | 14.2/M | APAH | HIV | B | E, I | 4 | 27.3 | |
| 7 | 15/F | APAH | CHD | C | E, T | 3 | 24.8 | |
| 8 | 15.3/M | APAH | Down CHD | C | E, T | 11 | 26.1 | |
| 9 | 17.9/F | APAH | CHD | C | A | E, T, I | 7 | 19.9 |
| 10 | 19.2/M | APAH | CHD | C | E, T, I | 2 | 17 | |
| 11 | 5.2/F | IPAH | C | 5.3 | ||||
| 12 | 5.6/M | IPAH | S | A | 24 | |||
| 13 | 6.2/F | IPAH | S | A | 19.9 | |||
| 14 | 6.3/M | IPAH | C | A | 3 | |||
| 15 | 7.1/F | IPAH | S | A | 7 | |||
| 16 | 7.1/F | IPAH | S | A | 7.2 | |||
| 17 | 9.3/M | IPAH | S | B | 13.1 | |||
| 18 | 9.8/F | IPAH | S | E, T | 2 | 1.9 | ||
| 19 | 9.9/F | IPAH | S | B | 5 | |||
| 20 | 10.5/F | IPAH | C | B | E | 8 | 26.5 | |
| 21 | 11.3/M | IPAH | S | B | 26.2 | |||
| 22 | 12.1/F | IPAH | C | B | E, I | 9 | 17.3 | |
| 23 | 12.3/F | IPAH | S | 21 | ||||
| 24 | 12.4/F | IPAH | S | A | 17 | |||
| 25 | 14/M | IPAH | S | A | 9.9 | |||
| 26 | 14.2/M | IPAH | C | B | E | 6 | 10.3 | |
| 27 | 14.8/M | IPAH | C | B | E | 4 | 16.3 | |
| 28 | 15.3/M | IPAH | C | A | E, T, I | 5 | 2.3 | |
| 29 | 16.6/M | IPAH | S | B | E, I | 9 | 13.9 |
Four patients discontinued inhaled treprostinil after 4.33 ± 4 months because of desaturation (n = 1), dyspnea and chest tightness with bronchospasm demonstrated on PFTs (n = 2), and progression of PAH requiring intravenous prostanoids (n = 1). Children with bronchospasm reported chest tightness after each inhalation. Two patients had their dosage downtitrated because of nausea (n = 1) and hypotension (n = 1). Hypotension was suspected because the child developed dizziness and fatigue after each treatment. At follow-up catheterization, inhaled treprostinil caused a 15% decrease in arterial pressure and was downtitrated from 54 to 36 μg/treatment. Of the remaining, the most common self-limited and mild side effects were cough (n = 9), sore throat (n = 6), and headache and nausea (n = 4). Two patients died. These patients had tolerated therapy and titrated up to 54 μg, 4 times/day without side effects. One patient, a 10-year-old girl with unoperated hemitruncus and previous recurrent hemoptysis, died suddenly after a bout of severe hemoptysis after 6 weeks of therapy. The other patient, an 11-year-old severely depressed child who initially showed an improved functional class with inhaled treprostinil, stopped all medications and died shortly after.
Twelve patients had received prostanoids previously. In 3 patients, intravenous prostanoids were weaned to 15 ± 5 ng/kg/min and inhaled treprostinil was initiated during the last 3 weeks of weaning before discontinuation of intravenous therapy. Six were switched from iloprost to inhaled treprostinil for ease of administration, 1 of whom preferred iloprost and switched back. Three other patients had intravenous prostanoids weaned off to oral medications 4.6 ± 2.5 years before adding inhaled treprostinil to optimize vasodilator therapy. The baseline profiles of patients who were prostanoid naive and those who were on previous prostanoids are presented in Table 3 . Patients who were previously on prostanoids had better hemodynamics as evidenced by lower pulmonary and systemic resistance values, suggesting that they had improved enough on the previous intravenous prostanoids to have been considered optimal candidates to be weaned off parenteral prostanoids.
| Previous prostanoid | Age | APAH/IPAH | F/M | iTre Dose ‡ | 6MWD | Rp § | Rp/Rs ∥ |
|---|---|---|---|---|---|---|---|
| Naive (n = 17) ⁎ | 10.2 ± 4.6 | 6/11 | 9/8 | 6.6 ± 3.2 | 477 ± 149 | 14.5 ± 6 | 1 ± 0.5 |
| Transitioned (n = 12) † | 13.8 ± 3.2 | 5/7 | 6/6 | 7 ± 3.5 | 491 ± 128 | 9.6 ± 4.6 | 0.6 ± 0.3 |
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