Therapies for Pulmonary Arterial Hypertension in Children
Therapies for Pulmonary Arterial Hypertension in Children
Inhaled iloprost has been used in children with PAH for nearly ten years, primarily as a means of testing pulmonary vascular reactivity and providing initial treatment after diagnosis. Two recent articles evaluate its potential as long-term therapy. Alehan and colleagues conducted a retrospective study of 20 children treated over a period of 7 years. The patients ranged from 4 months to 19 years of age (median 3.8 years). Eight children had hereditary or idiopathic PAH, and 12 had PAH associated with congenital heart disease (CHD). Fifteen were receiving combination therapy. The median time of follow-up was 18 months, with a range of 6 to 74 months. Inhaled iloprost was initiated at a delivered dose of 7.5 mcg/day for patients < 10 kg, 12.5 mcg/day for patients 10–20 kg, 17.5 mcg/day for patients 20–30 kg, 22.5 mcg/day for patients 30–40 kg, and 30 mcg/day for those > 40 kg. The frequency of administration was initially 6 times per day, but was increased up to 9 times per day as needed.
The median 6-min walk test for the group increased from 420 to 490 meters after starting iloprost (p = 0.028). Other measurements of response, however, showed little change. World Health Organization (WHO) functional class, evaluated in 18 patients at baseline and 6 months, improved in seven patients, remained unchanged in ten and worsened in one. Six patients died during follow-up, including five with underlying cardiac defects. None of the indices measured in the six children who underwent a second cardiac catheterization (mean pulmonary arterial pressure, aortic pressure, pulmonary vascular resistance, and pulmonary/vascular resistance) demonstrated significant change from baseline after the addition of iloprost. Brain natriuretic peptide levels declined from a median of 125 pg/mL to 80 pg/mL, but the difference failed to reach statistical significance (p = 0.349). Therapy was generally well tolerated. One patient developed a perioral rash associated with the mask used to deliver his iloprost doses and one had headaches requiring dose reduction. None of the children discontinued therapy.
A systematic review of pediatric iloprost studies was published last year by Mulligan and Beghetti in Pediatric Critical Care Medicine. The authors reviewed 28 papers, including seven prospective studies, four retrospective studies, four case series and 13 case studies. A total of 195 infants and children were treated. The dose of iloprost ranged from 1 to 20 mcg/kg/day, given six to nine times daily. The average dose delivered was difficult to estimate because of differences in the duration of nebulization, the equipment used, or the need to administer the drug during mechanical ventilation. Most papers included a mix of patient types: children undergoing acute pulmonary vasoreactivity testing, patients with CHD and PAH after cardiac surgery, and neonates with persistent pulmonary hypertension. While the majority reported positive results, variation in methodology makes summarizing their findings difficult. Moreover, response during pulmonary vasoreactivity testing during catheterization has not been found to provide a reliable prediction of improved cardiac index or long-term survival. While inhaled iloprost offers an alternative to continuous infusion of prostanoids, variation in the amount of drug delivered and the requirement for administration 6 or more times per day make this therapy less than ideal.
Treprostinil, a prostanoid developed for parenteral administration, was approved by the FDA for administration by inhalation in adults in 2010. The primary advantage of inhaled treprostinil is the longer duration of effect, allowing dosing four times per day versus the six to nine times per day schedule for inhaled iloprost. Two recent papers describe its use in children with PAH. Earlier this year, Takatsuki and colleagues published a prospective study of 13 children (ages 4–17 years) given inhaled treprostinil during cardiac catheterization for acute pulmonary vasodilator testing. All of the children initially received inhaled nitric oxide and were then allowed to return to baseline status. Once at baseline, they received treprostinil at a median dose of 1.53 mcg/kg (range 0.71–2.89 mcg/kg) over 6–9 breaths. Eight (62%) of the children were acute responders. Treprostinil produced results similar to nitric oxide, with a significant drop in mean pulmonary artery pressure (31 mmHg compared to 33 mmHg at baseline, p < 0.05) and pulmonary vascular resistance index (4.8 units/m versus 6.7 units/m at baseline, p < 0.05). There were no significant changes in cardiac index, pulmonary/systemic vascular resistance index, right arterial pressure, pulmonary capillary wedge pressure, systemic blood pressure, or arterial pressure of carbon dioxide. All patients tolerated treprostinil without clinical worsening, although one child with asthma developed a cough and two experienced hypotension.
Krishnan, Takatsuki, and colleagues reported their experience with inhaled treprostinil as add-on therapy in 29 children (ages 3.2 to 19 years) with PAH at two children's hospitals, Columbia University and Children's Hospital Colorado. Therapy was initiated at a dose of 3 breaths (6 mcg/breath) four times per day. The dose was titrated weekly as needed to a maximum of 9 breaths per treatment. Follow-up ranged from 1.9 to 26.5 months. Three children were weaned off intravenous prostanoids after starting inhaled treprostinil and six were transitioned from inhaled iloprost. Nineteen patients demonstrated improvement in WHO functional class and ten remained in the same class. Results of the 6-min walk test, assessed in 13 children, improved from 456 + 72 to 498 + 70 meters (p = 0.017). Brain natriuretic peptide levels fell from 93 + 77 to 58 + 62 pg/mL (p = 0.003). Exercise capacity and peak oxygen consumption were also significantly improved. Treprostinil was discontinued in one patient because of worsening disease and in three patients because of desaturations, dyspnea, or bronchospasm. Other adverse effects included cough in nine patients, sore throat in six, and headache and nausea in four. Two children died during follow-up.
Prostanoid Analogs
Inhaled iloprost has been used in children with PAH for nearly ten years, primarily as a means of testing pulmonary vascular reactivity and providing initial treatment after diagnosis. Two recent articles evaluate its potential as long-term therapy. Alehan and colleagues conducted a retrospective study of 20 children treated over a period of 7 years. The patients ranged from 4 months to 19 years of age (median 3.8 years). Eight children had hereditary or idiopathic PAH, and 12 had PAH associated with congenital heart disease (CHD). Fifteen were receiving combination therapy. The median time of follow-up was 18 months, with a range of 6 to 74 months. Inhaled iloprost was initiated at a delivered dose of 7.5 mcg/day for patients < 10 kg, 12.5 mcg/day for patients 10–20 kg, 17.5 mcg/day for patients 20–30 kg, 22.5 mcg/day for patients 30–40 kg, and 30 mcg/day for those > 40 kg. The frequency of administration was initially 6 times per day, but was increased up to 9 times per day as needed.
The median 6-min walk test for the group increased from 420 to 490 meters after starting iloprost (p = 0.028). Other measurements of response, however, showed little change. World Health Organization (WHO) functional class, evaluated in 18 patients at baseline and 6 months, improved in seven patients, remained unchanged in ten and worsened in one. Six patients died during follow-up, including five with underlying cardiac defects. None of the indices measured in the six children who underwent a second cardiac catheterization (mean pulmonary arterial pressure, aortic pressure, pulmonary vascular resistance, and pulmonary/vascular resistance) demonstrated significant change from baseline after the addition of iloprost. Brain natriuretic peptide levels declined from a median of 125 pg/mL to 80 pg/mL, but the difference failed to reach statistical significance (p = 0.349). Therapy was generally well tolerated. One patient developed a perioral rash associated with the mask used to deliver his iloprost doses and one had headaches requiring dose reduction. None of the children discontinued therapy.
A systematic review of pediatric iloprost studies was published last year by Mulligan and Beghetti in Pediatric Critical Care Medicine. The authors reviewed 28 papers, including seven prospective studies, four retrospective studies, four case series and 13 case studies. A total of 195 infants and children were treated. The dose of iloprost ranged from 1 to 20 mcg/kg/day, given six to nine times daily. The average dose delivered was difficult to estimate because of differences in the duration of nebulization, the equipment used, or the need to administer the drug during mechanical ventilation. Most papers included a mix of patient types: children undergoing acute pulmonary vasoreactivity testing, patients with CHD and PAH after cardiac surgery, and neonates with persistent pulmonary hypertension. While the majority reported positive results, variation in methodology makes summarizing their findings difficult. Moreover, response during pulmonary vasoreactivity testing during catheterization has not been found to provide a reliable prediction of improved cardiac index or long-term survival. While inhaled iloprost offers an alternative to continuous infusion of prostanoids, variation in the amount of drug delivered and the requirement for administration 6 or more times per day make this therapy less than ideal.
Treprostinil, a prostanoid developed for parenteral administration, was approved by the FDA for administration by inhalation in adults in 2010. The primary advantage of inhaled treprostinil is the longer duration of effect, allowing dosing four times per day versus the six to nine times per day schedule for inhaled iloprost. Two recent papers describe its use in children with PAH. Earlier this year, Takatsuki and colleagues published a prospective study of 13 children (ages 4–17 years) given inhaled treprostinil during cardiac catheterization for acute pulmonary vasodilator testing. All of the children initially received inhaled nitric oxide and were then allowed to return to baseline status. Once at baseline, they received treprostinil at a median dose of 1.53 mcg/kg (range 0.71–2.89 mcg/kg) over 6–9 breaths. Eight (62%) of the children were acute responders. Treprostinil produced results similar to nitric oxide, with a significant drop in mean pulmonary artery pressure (31 mmHg compared to 33 mmHg at baseline, p < 0.05) and pulmonary vascular resistance index (4.8 units/m versus 6.7 units/m at baseline, p < 0.05). There were no significant changes in cardiac index, pulmonary/systemic vascular resistance index, right arterial pressure, pulmonary capillary wedge pressure, systemic blood pressure, or arterial pressure of carbon dioxide. All patients tolerated treprostinil without clinical worsening, although one child with asthma developed a cough and two experienced hypotension.
Krishnan, Takatsuki, and colleagues reported their experience with inhaled treprostinil as add-on therapy in 29 children (ages 3.2 to 19 years) with PAH at two children's hospitals, Columbia University and Children's Hospital Colorado. Therapy was initiated at a dose of 3 breaths (6 mcg/breath) four times per day. The dose was titrated weekly as needed to a maximum of 9 breaths per treatment. Follow-up ranged from 1.9 to 26.5 months. Three children were weaned off intravenous prostanoids after starting inhaled treprostinil and six were transitioned from inhaled iloprost. Nineteen patients demonstrated improvement in WHO functional class and ten remained in the same class. Results of the 6-min walk test, assessed in 13 children, improved from 456 + 72 to 498 + 70 meters (p = 0.017). Brain natriuretic peptide levels fell from 93 + 77 to 58 + 62 pg/mL (p = 0.003). Exercise capacity and peak oxygen consumption were also significantly improved. Treprostinil was discontinued in one patient because of worsening disease and in three patients because of desaturations, dyspnea, or bronchospasm. Other adverse effects included cough in nine patients, sore throat in six, and headache and nausea in four. Two children died during follow-up.