ABSTRACT
Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4-44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.
Subject(s)
Hypertension, Pulmonary/drug therapy , Phenylpropionates/pharmacokinetics , Phenylpropionates/therapeutic use , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Adolescent , Antihypertensive Agents/therapeutic use , Bosentan , Child , Child, Preschool , Cohort Studies , Familial Primary Pulmonary Hypertension , Female , Humans , Male , Phenylpropionates/adverse effects , Pyridazines/adverse effects , Retrospective Studies , Sulfonamides/therapeutic useABSTRACT
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.
Subject(s)
Antihypertensive Agents/administration & dosage , Epoprostenol/analogs & derivatives , Hypertension, Pulmonary/drug therapy , Pulmonary Wedge Pressure/drug effects , Administration, Inhalation , Adolescent , Child , Child, Preschool , Dose-Response Relationship, Drug , Epoprostenol/administration & dosage , Exercise Tolerance , Familial Primary Pulmonary Hypertension , Female , Follow-Up Studies , Humans , Hypertension, Pulmonary/physiopathology , Male , Nebulizers and Vaporizers , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
This study aimed to investigate the safety, tolerability, and effects of tadalafil on children with pulmonary arterial hypertension (PAH) after transition from sildenafil or after tadalafil received as initial therapy. A total of 33 pediatric patients with PAH were retrospectively evaluated. Of the 33 patients, 29 were switched from sildenafil to tadalafil. The main reason for the change from sildenafil was once-daily dosing. The average dose of sildenafil was 3.4 ± 1.1 mg/kg/day, and that of tadalafil was 1.0 ± 0.4 mg/kg/day. For 14 of the 29 patients undergoing repeat catheterization, statistically significant improvements were observed after transition from sildenafil to tadalafil in terms of mean pulmonary arterial pressure (53.2 ± 18.3 vs. 47.4 ± 13.7 mmHg; p < 0.05) and pulmonary vascular resistance index (12.2 ± 7.0 vs 10.6 ± 7.2 Units/m(2); p < 0.05). Clinical improvement was noted for four patients treated with tadalafil as initial therapy. The side effect profiles were similar for the patients who had transitioned from sildenafil to tadalafil including headache, nausea, myalgia, nasal congestion, flushing, and allergic reaction. Two patients discontinued tadalafil due to migraine or allergic reaction. One patient receiving sildenafil had no breakthrough syncope after transition to tadalafil. Tadalafil can be safely used for pediatric patients with PAH and may prevent disease progression.
Subject(s)
Carbolines/therapeutic use , Hypertension, Pulmonary/drug therapy , Phosphodiesterase 5 Inhibitors/therapeutic use , Adolescent , Carbolines/administration & dosage , Carbolines/adverse effects , Cardiac Output , Child , Child, Preschool , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Phosphodiesterase 5 Inhibitors/administration & dosage , Phosphodiesterase 5 Inhibitors/adverse effects , Piperazines/therapeutic use , Purines/therapeutic use , Retrospective Studies , Sildenafil Citrate , Statistics, Nonparametric , Sulfones/therapeutic use , Tadalafil , Treatment Outcome , Vascular Resistance/drug effectsABSTRACT
Our case series describes three children who were initially diagnosed as having severe pulmonary arterial hypertension (PAH) and subsequently found to be positive for specific autoantibodies suggestive of an underlying autoimmune process. The signs and symptoms of PAH are subtle and may be part of the initial presentation of childhood connective tissue disease (CTD). Evaluation for connective tissue disease in the newly diagnosed pulmonary hypertension (PH) patient is important because early diagnosis of PH as well as CTD is crucial in the successful management of these complex patients. Ongoing monitoring for CTD in patients with severe PAH is warranted.
Subject(s)
Connective Tissue Diseases/diagnosis , Hypertension, Pulmonary/etiology , Adolescent , Child , Connective Tissue Diseases/complications , Connective Tissue Diseases/physiopathology , Diagnosis, Differential , Echocardiography, Doppler , Familial Primary Pulmonary Hypertension , Female , Follow-Up Studies , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/physiopathology , Male , Pulmonary Wedge Pressure , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: Intravenous prostanoids (epoprostenol and treprostinil) are effective therapies for pulmonary arterial hypertension but carry a risk of catheter-related bloodstream infection (CR-BSI). Prevention of CR-BSI during long-term use of indwelling central venous catheters is important. OBJECTIVE: To evaluate whether using a closed-hub system and waterproofing catheter hub connections reduces the rate of CR-BSI per 1,000 catheter-days. DESIGN: Single-center open observational study (January 2003-December 2008). PATIENTS: Pediatric patients with pulmonary arterial hypertension who received intravenous prostanoids. METHODS: In July 2007, CR-BSI preventive measures were implemented, including the use of a closed-hub system and the waterproofing of catheter hub connections during showering. Rates of CR-BSI before and after implementing preventive measures were compared with respect to medication administered and type of bacterial infection. RESULTS: Fifty patients received intravenous prostanoid therapy for a total of 41,840 catheter-days. The rate of CR-BSI during the study period was 0.51 infections per 1,000 catheter-days for epoprostenol and 1.38 infections per 1,000 catheter-days for treprostinil, which differed significantly (P < .01). CR-BSIs caused by gram-negative pathogens occurred more frequently with treprostinil than with epoprostenol (0.91 infections per 1,000 catheter-days vs 0.08 infections per 1,000 catheter-days; P < .01). Patients treated with treprostinil after the implemented changes had a significant decrease in CR-BSI rate (1.95 infections per 1,000 catheter-days vs 0.19 infections per 1,000 catheter-days; P < .01). CONCLUSION: The closed-hub system and the maintenance of dry catheter hub connections significantly reduced the incidence of CR-BSI (particularly infections caused by gram-negative pathogens) in patients receiving intravenous treprostinil.
