We studied the effects of inhaled iloprost in 22 pediatric PAH patients (12 male, 10 female), with a median age of 11.5 years (range 4.5 to 17.7 years) and median body weight of 35.6 kg (range 15 to 73 kg) (). Pulmonary arterial hypertension was idiopathic or familial in 12 patients and associated with congenital heart disease in 10 patients, which included the following diagnoses: unrepaired heart disease in 1 (atrial septal defect) and surgically repaired disease in 9 patients (atrial septal defect; ventricular septal defect; ventricular septal defect with patent ductus arteriosus; ventricular septal defect with coarctation of the aorta; D-transposition of the great arteries repaired by the arterial switch procedure; patent ductus arteriosus with left pulmonary artery stenosis and congenital diaphragmatic hernia; patent ductus arteriosus; partial atrioventricular canal; and double-outlet right ventricle with patent ductus arteriosus and coarctation of the aorta).
Because a recent publication reported that anatomical airway obstruction might be present in as many as 25% of children with PAH (31
), previous chest tomographies were reviewed, if available. Of 17 patients, 1 showed evidence of upper airway obstruction caused by tonsillar hypertrophy (tonsillectomy performed) and another showed compression of left main bronchus by the aorta. Fifty-three percent showed pulmonary artery enlargement and 18% had ground glass appearance.
At the time of iloprost initiation, 19 patients were treated with at least 1 other PAH therapy (). Concomitant therapies included IV treprostinil (n = 5), IV epoprostenol (n = 3), subcutaneous treprostinil (n = 1), sildenafil (n = 16), bosentan (n = 11), and calcium channel blockers (n = 3) (). Seven patients had concomitant PAH therapies added for inadequate response to therapy (Patients #2, #4, #9, #12, #17, #21, and #22) at a median time of 2.4 months after the initiation of iloprost. Bosentan doses were consistent with those recommended in the pediatric pharmacokinetic trial (32
). The median sildenafil dose was 40 mg three times a day (3.5 mg/kg/dose) and did not change significantly during the study period. In 2 patients (Patients #3 and #21), concomitant PAH therapy at initiation was discontinued after iloprost initiation at a median time of 3 months.
Acute hemodynamic and pulmonary effects of inhaled iloprost
Cardiac catheterization was performed in all patients before the initiation of iloprost (n = 22) (). Baseline hemodynamic status demonstrated significant PAH (i.e., mean PAP 64 ± 15 mm Hg [mean ± SD; median 68 mm Hg, range 28 to 84 mm Hg]) and a pulmonary to systemic vascular resistance index ratio of 1.1 ± 0.6. Of these 22 patients, 8 (Patients #2, #5, #6, #7, #11, #13, #19, and #21) had acute pulmonary vasoreactivity testing with inhaled NO and iloprost (). Reduction in the mean PAP by inhaled NO and iloprost were similar (). Inhaled NO (40 ppm) reduced mean PAP from 66 ± 13 mm Hg at baseline to 58 ± 18 mm Hg (p < 0.05 vs. baseline), representing a reduction of 12% for the entire study group. The reduction in mean PAP after acute inhalation of iloprost (57 ± 19 mm Hg; p < 0.05 vs. baseline) was similar to the level achieved with inhaled NO therapy. Neither inhaled NO nor inhaled iloprost significantly lowered PVR. The PVR/ SVR ratio fell from 1.0 ± 0.5 at baseline to 0.8 ± 0.4 (p < 0.05) after iloprost inhalation. There were no significant changes from baseline values for cardiac index, pulmonary capillary wedge pressure, or right atrial pressure, during the acute treatment with either NO or iloprost. Two patients (Patients #6 and #7) had a decrease in mean PAP of at least 20% in response to inhaled NO and inhaled iloprost.
Acute Hemodynamic Effects of Inhaled Iloprost
Acute Inhalation of Iloprost Lowered Mean PAP Equivalent to the Response to 40 ppm Inhaled NO
The acute effects of inhaled iloprost were also assessed by pulmonary function tests before the initiation of chronic iloprost therapy in 13 patients. Baseline FEV1 (expressed as % predicted) was 84 ± 16% (range 56% to 119%), which decreased to 79 ± 15% after a single inhalation of iloprost (p = 0.02) (). At baseline, mean FEF25–75 was 82% of predicted (range 32% to 119%). After iloprost inhalation, mean FEF25–75 decreased to 72 ± 29% (p = 0.03) (). In 5 of 13 (38%) patients, FEF25–75 decreased by more than 15% (range −53% to −17%). Two of these patients did not receive chronic iloprost therapy, owing to symptomatic lower airway obstruction.
The Acute Effects of Inhaled Iloprost Were Assessed by Pulmonary Function Tests in 13 Patients
Acute Effects of Inhaled Iloprost Were Assessed by Pulmonary Function Tests in 13 Patients
Physiologic effects of chronic iloprost therapy
The median duration of iloprost therapy was 0.9 years (range 0.1 to 7.9 years). At initiation (n = 22) the median dose of iloprost was 5 μg (range 0.63 to 10 μg), with a frequency of 6 times daily (range 4 to 9) and total daily dose of 30 μg/day (range 3.75 to 50 μg/day) (). At 6 months, 18 patients continued on iloprost therapy; the median dose was 5 μg (range 2.5 to 10 μg), with a median frequency of 6 times daily and a total daily dose of 30 μg/day (range 13.75 to 50 μg/day). Twelve patients remained on therapy for 12 months or longer. At one year, the median dose was 5 μg (range 5 to 10 μg), with a median frequency of 6 times daily and total daily dose of 30 μg/day (range 25 to 50 μg/day).
Follow-up cardiac catheterizations were performed in 12 patients (Patients #1, #2, #3, #4, #5, #6, #8, #9, #12, #16, #18, and #21) to assess the response to long-term iloprost therapy at trough before iloprost inhalation at a mean follow-up period of 10 months (range 3 to 24 months) (). In comparison with baseline hemodynamic status, there were no differences in mean PAP, cardiac index, PVR index, or PVR/SVR ratio. In a subgroup of patients (n = 7) receiving inhaled NO during the initial and follow-up cardiac catheterizations, the acute response to inhaled NO did not change, despite chronic iloprost therapy.
Chronic Hemodynamic Effects of Inhaled Iloprost
The 6MW tests were obtained for 13 of 22 patients at baseline and after 6 months (). Overall, there was no change in 6MW distance from baseline (n = 13; 397 m) to 6 months (n = 13; 428 m); however, 6MW distance did increase by >10% in 5, was unchanged in 7, and decreased by >10% in 1 child. By comparison, the mean 6MW distance was 355 m with an average improvement of 30 m in 12 weeks in the adult trial of iloprost as an add on therapy to bosentan (25
6MW Tests Were Obtained for 13 of 22 Patients at Baseline and After 6 Months
The median WHO functional class of the 22 patients at baseline was class III. Among the 20 patients that remained on therapy at 6 months, WHO class improved in 7 patients, remained unchanged in 10 patients, and worsened in 3 patients (). Of these 20 patients, 13 were receiving iloprost therapy for 12 months or longer. During the second 6-month period, the functional class improved in 2 patients, declined in 3 patients, and remained unchanged in 8 patients.
Of 22 Patients, 20 Remained on Therapy at 6 Months
Safety and tolerability
The most common side effects reported were headache (36%), cough (23%), and dizziness (14%), which generally improved within several days of initiation. Two patients experienced syncope during the study period, which could have been related to noncompli-ance with recommended frequency. Although 5 patients (23%) were initiated at 7 to 9 treatments daily, within 9 months, all patients remaining on iloprost reported 5 to 6 treatments daily, owing to the time required for treatments.
Of the 22 patients, 6 (27%) had marked deterioration during the study period (). Two deaths occurred, and 4 patients were transitioned to IV prostanoid therapy. Two patients (Patients #15 and #22) died 2 and 6 months, respectively, after initiation of inhaled therapy and refused IV prostanoid therapy. Four patients were transitioned to IV prostanoid therapy from inhaled iloprost for clinical deterioration (Patients #2, #3, #5, and #21).
Of the 22 Patients Treated With Iloprost, 9 Were Transitioned From IV Prostanoids With 8 Tolerating the Transition
In 9 patients on chronic IV prostanoids, 8 tolerated the transition from IV prostanoids to inhaled iloprost therapy (). One patient had a moderate fall in systemic arterial oxygen saturations through an unrepaired atrial septal defect but elected to remain on inhaled iloprost, owing to recurrent and severe central venous line infections. Among the transition patients, 1 death occurred 7 months after the transition (owing to worsening PAH).
Two patients without a prior history of lung disease discontinued initial therapy, owing to persistent cough and dyspnea (). In Patient #11, inhaled iloprost was discontinued after a single dose of 2.5 μg. In this patient, predicted FEV1 decreased by 18% and FEF25–75 decreased by 53%. A repeat trial of 2.5 μg during cardiac catheterization produced audible wheezing, respiratory distress, and a decrease in room air oxygen saturation from 95% to 88%. In Patient #19, iloprost was discontinued after 48 h (dose, 2.5 μg 6 times daily), owing to complaints of tingling in the chest and shortness of breath, accompanied by a decrease in room air oxygen saturation from 100% to 89% after iloprost inhalation. Pre-treatment spirometry showed a decrease in predicted FEV1 of 12% and a decrease in FEF25–75 of 20% after inhalation of iloprost.
Two patients became symptomatic with signs of lower airways obstruction several months after initiation of iloprost. One patient (Patient #20) had congenital scoliosis and a history of wheezing. Both patients were initiated on chronic inhaled corticosteroids and beta-agonist agents and subsequently tolerated chronic iloprost therapy.