Pediatric Pulmonology
Use of Inhaled Iloprost in Children With Pulmonary Hypertension s de Mir Messa, Antonio Moreno-Galdo , MD, PhD,1 Alba Torrent-Vernetta, MD,1* Ine ~ a, MD,2 Silvia Gartner, MD,1 Sandra Rovira Amigo, MD,1 Ferran Gran Pin and Dimpna Albert Brotons, MD, PhD2
MD, PhD,
1
Summary. Pulmonary hypertension (PH) in children is a serious disorder, for which the major goal of treatment is to prevent progressive vascular remodeling, and improve clinical status and survival. Iloprost is approved for the treatment of PH in adults; however, few studies have evaluated its effects in children. The objective of this study is to analyze the long-term effects of inhaled iloprost treatment in children with PH. A retrospective study was conducted in patients treated with iloprost between 2000 and 2012. Patients with left–right cardiac shunt and persistent PH of the newborn were excluded. The cohort comprised 22 patients (15 females) with a median age of 2.6 years. Twelve patients had pulmonary arterial hypertension including idiopathic (n ¼ 6), hereditary (n ¼ 2) and associated (congenital heart disease [n ¼ 3], and schistosomiasis [n ¼ 1]). One patient had pulmonary veno-occlusive disease, six patients had PH secondary to lung disease and three had multifactorial PH. Median mean pulmonary arterial pressure was 55 mmHg and median pulmonary vascular resistance was 15.5 Wood units. Good tolerability was observed, with the exception of one case of recurring abdominal pain. PH resolved in two patients, with functional capacity improvement in 10 patients and stabilization in three patients. The clinical condition of six patients deteriorated; two died, and two received lung transplants. In conclusion, the results of this uncontrolled study showed that iloprost was effective and well tolerated in children. However, further research is needed to support this study, as PH is a serious condition that can require organ transplantation or result in death. Pediatr Pulmonol. ß 2014 Wiley Periodicals, Inc.
Key words: pediatric; prostacyclin; safety; tolerability.
INTRODUCTION
Pulmonary hypertension (PH) in children is a rare, progressive disorder for which the prognosis is poor if the disease is not diagnosed and treated at an early stage. Data from several European countries estimate the incidence of
idiopathic pulmonary arterial hypertension (IPAH) in children at 0.5–0.7 cases/million/year1,2 and the prevalence at 2.1–4.4 cases/million.1,3 There is currently no cure for PH, although in the last 20 years there has been major progress in our understanding of the pathophysiology of this condition, which has led to the development of
1 Unidad de Neumologı´a Pedia´trica y Fibrosis Quı´stica, Hospital Universitari Vall d’Hebron, Universitat Auto`noma de Barcelona, Barcelona, Spain.
board member for Vertex and Gilead, has been funded to attend medical meetings by Praxis pharmaceutical, and received a fee for speaking engagements from Novartis Laboratories.
2 Seccio´n de Cardiologı´a Pedia´trica, Hospital Universitari Vall d’Hebron, Universitat Auto`noma de Barcelona, Barcelona, Spain.
Antonio Moreno-Galdo´ and Alba Torrent-Vernetta contributed equally to this work.
Antonio Moreno-Galdo´ has been an advisory board member for Abbott Laboratories, and has received research funding from Abbott Laboratories. He has been funded to travel to conferences by Actelion, Novartis, Gilead, Bayer Pharma AG, and Ferrer Laboratories, and received a fee for speaking engagements from Merck Sharp & Dohme. Alba Torrent Vernetta has been funded to attend medical meetings by Gilead, Bayer Pharma AG, Ferrer and Novartis Laboratories. Ines de Mir Messa, Sandra Rovira Amigo, and Ferran Gran Pi~na have been funded to attend medical meetings by Actelion and Novartis Laboratories. Dimpna Albert Brotons has received research funding from Abbvie Laboratories and Actelion and received a fee for speaking engagements from Abbvie. Silvia Gartner has been an advisory
ß 2014 Wiley Periodicals, Inc.
Correspondence to: Alba Torrent Vernetta, MD, Unidad de Neumologı´a Pedia´trica y Fibrosis Quı´stica, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119–129, Barcelona 08025, Spain. E-mail: [email protected] Received 6 November 2013; Accepted 6 March 2014. DOI 10.1002/ppul.23044 Published online in Wiley Online Library (wileyonlinelibrary.com).
2
Moreno-Galdo et al.
effective new treatments, helping to achieve radical changes in the prognosis for patients with PH.3–6 The guidelines on clinical practice produced jointly by the European Society of Cardiology, the European Respiratory Society, and the International Society of Heart and Lung Transplantation advise the same therapeutic approach for adults and children, although they acknowledge that the level of evidence is lower for pediatric use, and based mainly on expert opinion.7 Due to the ethical considerations relating to studies in children, it has been necessary to extrapolate results from studies conducted in adults with PH to the condition in children.8,9 In fact, only one placebo-controlled trial has been conducted in children with PH, in a study of sildenafil monotherapy.10 The prostanoid epoprostenol was the first pulmonary vasodilator used in children. However, epoprostenol must be administered intravenously, as a continuous infusion via a permanent catheter. Iloprost (Ventavis1, Bayer Pharma AG), another prostanoid, can be delivered directly to the lungs with a nebulizer. Clinical trials have shown that inhaled iloprost improved the functional class, exercise capacity, and pulmonary hemodynamics of adult patients with pulmonary arterial hypertension (PAH).11–13 In patients with PAH who remained symptomatic while on bosentan, addition of iloprost resulted in a significant improvement in functional class, distance achieved in the 6-min walk test and time to clinical worsening.14,15 In a combination study of iloprost and sildenafil, a marked and persistent improvement in exercise capacity was observed.16 Iloprost is approved as a treatment for PH in adults in World Health Organization (WHO) functional class III, and is also used on a compassionate basis in pediatric patients.17–19 Many studies have been published on iloprost treatment for PH in adults, whereas few studies have analyzed its effects in children;20–22 with long-term results assessed in only two observational studies.21,22 The objective of this study was to evaluate the long-term effects of inhaled iloprost in the treatment of children with PH, based on survival and change in functional class status. We report data collated retrospectively over a 12year period for a cohort of pediatric patients with PH, treated with iloprost as monotherapy and in combination with other drugs, and assess the course of their condition and survival rates.
MATERIALS AND METHODS Study Participants
This was a retrospective study, and data were analyzed from consecutive pediatric patients with PH who were treated with nebulized iloprost at our pediatric PH unit. Clinical characteristics and etiology, as well as hemodyPediatric Pulmonology
namic and echocardiographic data were determined. The patients were classified according to the Dana Point Classification of PH.23 Patients with left–right cardiac shunt or persistent PH of the newborn were excluded. Transthoracic echocardiography was performed in all patients. In some patients, the diagnosis was confirmed by right-heart catheterization under a general anesthetic, including a vasodilation test with inhaled nitric oxide (up to 80 ppm) and/or intravenous epoprostenol (2–12 ng/kg/ min). Where catheterization could not be performed, the diagnosis was based solely on echocardiographic data. Patients were stratified on the basis of a modification of the New York Heart Association (NYHA) classification of functional status, amended for PH by assessment of clinical status and a 6-min walk test where possible.7 Patients were classified according to their clinical status as functional class I (asymptomatic), functional class II (slight limitation of physical activity or problems with feeding), functional class III (marked limitation of physical activity, compromised growth or presenting with syncope), or functional class IV (signs of right heart failure or required mechanical ventilation due to hypoxic crisis). All patients were examined by a physician to rule out the presence of associated disorders. Treatment Approach and Outcome Measures
In all cases, the treatment strategy was agreed following multidisciplinary discussion between pulmonologists, cardiologists, and intensive care physicians. The following general treatment pattern was followed. Patients in functional class III or patients with severe PH secondary to lung disease began iloprost treatment. Patients with pulmonary arterial hypertension (PAH) functional class II were prescribed oral therapy, while patients in functional class IV were administered epoprostenol. Patients with moderate PH secondary to lung disease were treated with sildenafil. Initially we prescribed inhaled iloprost as monotherapy. However, we found that most patients required additional combined therapies so we changed our practice such that iloprost was initiated as combined treatment for patients in functional class III. These criteria were applied except for two patients in functional class II, diagnosed in 2001. Iloprost therapy was initiated following hospitalization, for initial treatment after diagnosis or after clinical deterioration despite other therapies. The nebulizer system employed was dependent upon patient age and clinical status. For patients in a critical condition with high oxygen requirements or requiring mechanical ventilation, a Jet type nebulizer (Cirrus1, Intersurgical Ltd., Madrid, Spain) connected to an oxygen supply was initially used. From 2005 onwards, a vibrating mesh nebulizer fitted in the respirator circuit (Aeroneb1 Pro,
Inhaled Iloprost in Children With PH
Aerogen, Inc., Galway, Ireland) was used for patients requiring mechanical ventilation. For patients of non-critical status under 7 years of age, a Jet type nebulizer (Freeway Sidestream1, Philips Respironics, Eindhoven, the Netherlands) was used between 2000 and 2005. From 2006, this was replaced with a continuous-flow vibrating mesh nebulizer with a face mask (Omron Micro Air U221, Omron Healthcare Europe B.V., the Netherlands). Patients of non-critical status over 7 years of age initially used a HaloLite1 nebulizer (Philips Respironics), and from 2006 a vibrating mesh nebulizer with an Adaptive Aerosol Delivery system (I-neb1 AAD1, Philips Respironics, Eindhoven, the Netherlands) was used. The frequency of use was five to six times daily for patients of non-critical status, and eight times daily for patients who were hospitalized and whose status was critical. In all cases in which a continuous flow nebulizer was used, a dose of 20 mg was administered per nebulization to compensate for the dose lost when the patient exhaled. To assess tolerability, iloprost was first administered at 5 mg/nebulization and the dose was gradually increased to 20 mg/nebulization over the course of 24–48 hr. In patients using the I-neb1 nebulizer, the dose used was 5 mg per nebulization, starting first with 2.5 mg per nebulization to assess tolerability. In all cases, the consent of the parents or guardians was sought for compassionate use of iloprost, and such use was authorized by the Spanish Ministry of Health. Additional drugs administered during the study were used at the following doses: nifedipine 2 mg/kg/day; sildenafil 0.5–1 mg/kg/8 hr for children 20 kg in weight; bosentan 31.25 mg/ 12 hr for children 10–20 kg in weight, 62.5 mg/12 hr for children 20–40 kg in weight, and 125 mg/12 hr for children >40 kg in weight. Response to treatment and the course of the patients’ condition were subsequently analyzed. Data are presented as an absolute value, percentage or median. Dilatation or hypertrophy of the right ventricle was assessed by echocardiography. The data collated during right-heart catheterization were as follows: systolic pulmonary arterial pressure, diastolic pulmonary arterial pressure, mean pulmonary arterial pressure, invasive systemic arterial pressure, cardiac output, pulmonary vascular resistance, pulmonary capillary pressure, and pulmonary arterial pressure in response to the pulmonary vasodilation test. The pulmonary vasodilation test was considered positive if the reduction in mean pulmonary arterial pressure was 10 mmHg to reach an absolute value of 40 mmHg, with an increased or unchanged cardiac output.7 All data are expressed in international reference units. The Kaplan–Meier method was used to analyze survival.
3
RESULTS
During the period from 2000 to 2012, 22 patients with PH were treated with inhaled iloprost (7 males and 15 females). The categorization of patients according to the Dana Point Classification is shown in Table 1. In total, six patients presented with PH associated with congenital heart disease. Patients 1 and 20 underwent surgery for persistent ductus arteriosus at the ages of 8 years and 8 months, respectively. Patients 7 and 11 had surgery to correct ventricular septal defect at the ages of 1 year and 4 months, respectively. Patient 21 underwent surgery to repair an aortopulmonary window at 1 month of age, and patient 22 underwent valvuloplasty for aortic stenosis after birth and surgery to correct persistent ductus arteriosus at 2 years of age. The median age at diagnosis was 2.6 years (age range: 3.6 months to 12.5 years). Seven patients (31.8%) were diagnosed before they were 1 year of age, and nine (40.9%) between the ages of 1 and 5 years. Two patients had a family history of PH (Table 2). Initial Findings
The majority of patients (15 [68.2%]) presented with minor symptoms, but for five patients (22.7%) the onset of symptoms was sudden, with cardiogenic syncope. Two
TABLE 1— Categorization of Patients With Pulmonary Hypertension According to the Dana Point Classification (N ¼ 22)23
n (%) Group 1. Pulmonary arterial hypertension 1.1. Idiopathic pulmonary hypertension 1.2. Heritable 1.2.1. BMPR2 1.2.2. ALK1 1.4. Associated with 1.4.4. Congenital heart diseases 1.4.5. Schistosomiasis Group 1’. Pulmonary veno-occlusive disease Group 3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.3. Bronchopulmonary dysplasia 3.3. Bronchiolitis obliterans 3.7. Congenital diaphragmatic hernia Mixed etiologies/mechanisms 3.3. and 1.4.4. Bronchopulmonary dysplasia and congenital heart disease 1.4.4. and 2.2. Congenital heart disease and left-sided heart failure
12 (54.6) 6 (50.0) 1 (8.3) 1 (8.3) 3 1 1 6
(25.0) (8.3) (4.6) (27.3)
4 1 1 3 2
(66.7) (16.7) (16.7) (13.6) (66.7)
1 (33.3)
ALK1, activin receptor-like kinase type 1; BMPR2, bone morphogenetic protein receptor type 2.
Pediatric Pulmonology
F
F
F F
M
F
M
M
M
F M
F
F
F
M
F
F
F
F
F
2
3 4
5
6
71
8
91,2
10 11
12
131
14
15
16
17
18
19
20
Gender
1
Patient no.
Pediatric Pulmonology
0.5
3.5
9.8
0.4
0.3
0.6
0.4
7.0
2.7
0.3 3.4
0.3
2.1
3.3
12.5
3.3
7.2 1.7
5.5
8.4
Age at diagnosis (years)
2003
2009
2008
2006
2004
2003
2002
2010
2010
2008 2008
2008
2007
2004
2004
2004
2001 2002
2001
2000
Year of diagnosis
Secondary to BPD Secondary to BPD Secondary to BPD Secondary to bronchiolitis obliterans Secondary to BPD Secondary to congenital diaphragmatic hernia Associated with CHD and BPD
IPAH
PVOD Associated with CHD IPAH
IPAH
Associated with CHD Hereditable
Associated with schistosomiasis
IPAH
Hereditable IPAH
Associated with CHD IPAH
Type of PH
TABLE 2— Patients With Pulmonary Hypertension
I
III
III
III
III
IV
III
III
II
II II
III
III
III
II
II
II IV
I
II
Functional class at diagnosis
III
III
III
III
III
IV
III
III
III
II III
III
III
III
III
III
II IV
II
III
Functional class when iloprost started
43
51
NR
NR
NR
NR
41
56
64
39 77
87
90
54
62
56
52 60
40
57
mPAP (mmHg)
PH resolved PH resolved Death
Iloprost4 (2.1) Iloprost4 (2) Iloprost (2) iloprost4 (2.1) epoprostenol (2.1)
—
Nifedipine4 (0.2), iloprost (0.2) bosentan (1.2)
Nifedipine3
Condition improved
Condition improved
Condition improved
Lost from follow-up
Nifedipine4 (0.7), iloprost (0.7)
Iloprost (0.5)
Condition improved
Condition stabilized
Condition deteriorated Condition improved
Condition deteriorated
Condition improved
Heart-lung transplant (1.6)6 Death Condition improved
Condition stabilized Double-lung transplant (0.16)6 Death
Condition stabilized
Condition improved
Course7
—
Bosentan (0.1)
Iloprost (2.5) bosentan (2.5) treprostinil (2.8) Bosentan (1.5) —
Bosentan (1.1)
Sildenafil & iloprost
Sildenafil
Sildenafil
Iloprost
Iloprost
Sildenafil & iloprost Sildenafil & nifedipine Iloprost Sildenafil & iloprost Sildenafil & iloprost Iloprost & bosentan Nifedipine3
Bosentan
Iloprost
Iloprost Sildenafil & iloprost Iloprost
Iloprost (0.1) sildenafil (1.3)
Nifedipine4 (4) bosentan (4) iloprost (6) Iloprost5 (3) sildenafil (3) bosentan (3) Sildenafil (0.5) bosentan (2) Iloprost4 (0.02) bosentan (0.02) epoprostenol (0.02) Iloprost4 (0.1) epoprostenol (0.1) Bosentan (0.25)
Nifedipine3 Iloprost
Subsequent treatments (years since starting treatment)
Initial treatment
9.1
3.7
4.9
2.1
8.6
9.5
1.3
2.7
2
4.1 4.7
4.5
5.1
8.2
6.4
0.1
11 10
11.7
12.8
Follow-up period (years)
4 Moreno-Galdo et al.
2005 2.41 M 221
BPD, bronchopulmonary dysplasia; CHD, congenital heart disease; F, female; IPAH, idiopathic pulmonary arterial hypertension; M, male; mPAP, mean pulmonary arterial pressure; NR, not recorded; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PVOD, pulmonary veno-occlusive disease. 1 Atrial septostomy performed. 2 Positive result of vasodilation test. 3 Nifedipine was initiated elsewhere and was stopped in our center after a negative result in a vasodilation test. 4 End of treatment. 5 End of treatment due to a side effect (recurrent abdominal pain). 6 Time of the transplantation since starting treatment (years). 7 Condition improved, patient’s functional class improved; condition stabilized, patient’s functional class remained in the same; condition deteriorated, patient’s functional class worsened.
7.7 Bosentan (2) iloprost (3) III
III
40
Sildenafil
Condition improved
9.5 Condition improved Bosentan (1) Iloprost 2.58 21
F
2003
Associated with CHD and BPD Associated with left heart BPD and CHD
III
III
30
Subsequent treatments (years since starting treatment) Gender Patient no.
Age at diagnosis (years)
TABLE 2— (Continued)
Year of diagnosis
Type of PH
Functional class at diagnosis
Functional class when iloprost started
mPAP (mmHg)
Initial treatment
Course7
Follow-up period (years)
Inhaled Iloprost in Children With PH
5
patients were asymptomatic and were diagnosed with PH when being assessed for another reason. The most frequent clinical presentation was dyspnea and restricted physical activity. Nine patients were diagnosed in the early stages of the disease (functional classes I and II), 11 were in functional class III and two were in functional class IV (Table 2). The echocardiographic examination that led to the diagnosis of PH detected dilation of the right ventricle in all patients, with a median systolic pulmonary arterial pressure of 72.5 mmHg (interquartile range 55– 87.5 mmHg). Right-heart catheterization of 18 patients found a median mean pulmonary arterial pressure of 55 mmHg (interquartile range 41–64 mmHg). Median pulmonary vascular resistance was 15.5 Wood Units (WU) (interquartile range 12–21 WU). A positive pulmonary vasodilation test result was obtained in only one patient, with IPAH. Eight patients (median age 4.5 years; interquartile range 3.4–7.0 years) completed the 6min walk test at the start of the study, the remainder being clinically unstable or too young. The median distance traveled was 257 m (interquartile range 237–317 m). Median minimum hemoglobin saturation was 90% (interquartile range 86.8–93.0%). Treatment
Iloprost was administered as the initial treatment for PH in 14 patients (63.6%); in eight cases as monotherapy and in six cases in combination with other drugs (Fig. 1). In the remaining eight patients, iloprost was added during follow-up in combination with the established treatments nifedipine, bosentan, sildenafil, epoprostenol, or treprostinil (Fig. 2). Overall, at the time that iloprost was introduced, three patients (13.6%) were in functional class II, 17 patients (77.3%) in functional class III, and two (9%) in functional class IV. Over the course of the study period, four patients were treated with inhaled iloprost as monotherapy and 18 patients received iloprost in combination with either one (n ¼ 10), two (n ¼ 7), or four (n ¼ 1) drugs. Iloprost was replaced with intravenous epoprostenol in three patients whose condition deteriorated and who required mechanical ventilation. In four cases, an atrial septostomy was performed due to the presence of severe PH with syncope that could not be controlled with pharmacological treatment. Other adjuvant treatments during the course of the condition were anticoagulants or antiplatelet drugs (10 patients), diuretics (11 patients), and digoxin (four patients). Course of the Disease
During the follow-up period, it was reported that inhaled iloprost was well tolerated, except in one case in Pediatric Pulmonology
6
Moreno-Galdo et al. Monotherapy (n = 2) Monotherapy (n = 8) In combination (n = 6)
Iloprost initial treatment (n = 14)
Stop Iloprost + Epoprostenol (n = 1) + Sildenafil + Bosentan (n = 2)
+ Bosentan (n = 3) Iloprost Bosentan (n = 1) In combination (n = 6) Iloprost Sildenafil (n = 5)
+ Bosentan (n = 2)
+ Bosentan (n = 1)
Stop Iloprost + Epoprostenol
= Iloprost = Sildenafil (n = 2) Fig. 1. Use of iloprost in monotherapy and in combination, when used as the initial treatment.
which treatment was discontinued due to recurrent abdominal pain. In patients who used a nebulizer face mask, transient perioral erythema was observed after inhalation, which could be prevented by using a barrier cream. Furthermore, treatment with iloprost was stopped in two patients after improvement in the underlying bronchopulmonary dysplasia that led to resolution of PH. No patients discontinued treatment due to poor adherence. After a median follow-up time of 5.8 years (range 2– 12.8 years), 19 patients (86.4%) had survived (Fig. 3). One patient was lost to follow-up after 1.3 years of treatment. Most patients received a combination of treatments during the study period. Two children, whose PH resolved, were treated with iloprost monotherapy. Since the beginning of iloprost treatment, 10 patients (45.4%) showed an improvement in functional capacity, as evidenced by a reduction in NYHA functional class from III to II, and three patients (13.6%) stabilized (remained in the same functional class), two in functional class II and one in class III. Six patients (27.3%) did not respond to treatment and their condition deteriorated. Of those who deteriorated, two patients died due to episodes of PH that did not respond to treatment (one patient Pediatric Pulmonology
classified as having IPAH and one patient with PH secondary to bronchiolitis obliterans). A double-lung transplant was received by one patient and another had a heart and lung transplant, but died 4 years after the procedure. DISCUSSION
The guidelines for the treatment of PH in children are similar to those for adults, as most research has been conducted in adults and the results extrapolated to the pediatric population. Given that few studies have examined the effect of iloprost in children, our aim was to review a cohort of pediatric patients with PH treated with inhaled iloprost, as a monotherapy and in combination with other drugs, to assess the tolerability and effectiveness of this treatment in children. Some of the endpoints used in adults to evaluate the response to treatment (such as 6-min walk test, echocardiographic parameters, and hemodynamic data), can be difficult to assess in the pediatric population,24 and there are not acceptable surrogates for endpoints such as survival and functional class.25 Furthermore, some consider NYHA functional class to be an unsuitable measure of PH disease
Inhaled Iloprost in Children With PH + Iloprost + Bosentan Nifedipine Stop
Nifedipine1 (n = 2)
Iloprost added in the follow-up (n = 8)
7
Bosentan (n = 1)
+ Iloprost + Sildenafil
Nifedipine1 (n = 1)
+ Iloprost Nifedipine Stop
Sildenafil (n = 1)
+ Iloprost
Sildenafil (n = 1)
+ Iloprost
Sildenafil (n = 1)
+ Iloprost + Bosentan
Sildenafil Nifedipine (n = 1)
+ Iloprost + Bosentan
Stop Iloprost + Epoprostenol
+ Treprostinil
Fig. 2. Use of iloprost in monotherapy, and in combination, when added during follow-up treatment. 1Nifedipine was initiated elsewhere and was stopped at our center after a negative result in a vasodilation test.
100 90 Survival probability (%)
80 70 60 50 40 30 20 10 0
0
1
2
3 4 5 Time (years)
6
7
8
12
11
10
9
10
9
9
8
Number at risk Group: Overall survival 22 21 19 17 16 Group: Transplant-free survival 22 20 17 15 14
Fig. 3. Cumulative overall survival probability and transplantfree survival probability during the period 2000–2012.
status in children.26 Therefore, we have chosen to base the assessment of patient outcomes on the clinical status and survival or transplantation data, and we have used a modified NYHA classification, similar to that published recently by Lammers et al.26 The data obtained in our study suggest a long-term beneficial effect of iloprost (median follow-up of 5.8 years), with clinical improvement (excluding the patient lost to follow-up) in 12 patients (57.1%) and stabilization in three patients (14.3%). Iloprost appears to be an effective and well tolerated drug in children, as both a monotherapy and in combination with other treatments, with few side effects. However, owing to the retrospective nature of this study and the lack of a comparator group, the validity of our findings are limited. As PH is a serious disease, most of the patients monitored in this study received iloprost alongside other therapies. Nevertheless, despite the use of combined therapy, poor responses were observed in six patients; the condition of six patients deteriorated, two died and two required lung or heart– lung transplants. Treatment choice was based on the functional and hemodynamic status of the patient, and evolved in the study period according to the availability of new drugs and new information regarding the treatment of PH. In Pediatric Pulmonology
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Moreno-Galdo et al.
agreement with guidelines, the majority of patients (77.3%) who started inhaled iloprost were in functional class III. However, three patients began iloprost treatment when in functional class II and, due to rapid disease progression, two patients were started on iloprost therapy when in functional class IV. One of the patients in functional class IV (patient 15) was a child with bronchopulmonary dysplasia, who had high oxygen requirements and received mechanical ventilation. Iloprost therapy, rather than intravenous epoprostenol, was preferentially used in this patient, to avoid clinical worsening of hypoxemia due to intrapulmonary shunt, and led to patient improvement. The other patient (patient 4), with IPAH, presented with intermittent episodes of hypoxemia and was quickly switched to intravenous epoprostenol after a week of treatment with iloprost, sildenafil, and bosentan without any improvement. However, after approximately 8 weeks, a lung transplant was required by this patient, following no improvement with epoprostenol treatment. Iloprost therapy was offered to two of the patients (patients 2 and 3) in functional class II as they were diagnosed in 2001, when there was also little experience of using oral medications for children with PH. The third patient (patient 10) in functional class II, who was suffering from pulmonary veno-occlusive disease, was treated with iloprost and assessed to ensure that therapy was well tolerated and did not result in pulmonary edema. In this case, there was clinical improvement of the patient. The introduction of new pulmonary vasodilators over the course of the study led to some changes in the treatment strategy. With the advent of bosentan therapy in 2002 and sildenafil therapy in 2005, therapeutic strategies were developed that combined drugs with different mechanisms of action, with a view to increasing efficacy. During the study period, eight patients were treated initially with inhaled iloprost as monotherapy. The majority (six patients) required combination treatment with further drugs. At present, our treatment strategy is to use iloprost for children in functional class III, and always as a combined treatment. Two of the patients in our study were suffering from severe bronchopulmonary dysplasia and needed mechanical ventilation and 100% oxygen. Iloprost monotherapy resulted in a highly marked clinical improvement that meant that these patients could be weaned off mechanical ventilation, subsequently progressing to resolution of PH. Sildenafil is currently the most commonly prescribed treatment for PH associated with bronchopulmonary dysplasia.27 However, in severe cases or those that do not respond to sildenafil, we suggest that the use of iloprost should be considered as, when administered via nebulization, iloprost has the added advantage of pulmonary selectivity unlike vasodilators such as epoprostenol. Pediatric Pulmonology
The results obtained in our study are similar to those of the two single series published previously, and corroborate the beneficial effect of iloprost treatment.21,22 In the multicentre study by Ivy et al.,21 examining the use of inhaled iloprost where intravenous prostanoid therapy was unsuitable, functional class improved in 35% of children and remained unchanged in 50% after 6 months. Some of the children (27%) deteriorated while receiving inhaled iloprost and were transitioned to epoprostenol therapy, resulting in a global survival of 91%. In the series by Alehan et al.,22 after a 1.5 year median follow-up, 15 out of 20 patients had used iloprost combined with an endothelin receptor antagonist or phosphodiesterase-type 5 inhibitor, with a 70% survival rate. These two published studies differ in regards to the age of the children included. In the Ivy et al. study, children aged 4.5–17.7 years were included, and in the study by Alehan et al., the age range of patients was 4 months to 19 years. Similar to the latter study, our series also included young children (age range 3.6 months to 12.8 years), with seven children under 1 year of age at the time of diagnosis. As iloprost dosing and pharmacokinetic studies have not been conducted in children, the doses used were extrapolated from studies carried out in adults. There is no consistent approach to the extrapolation of the dose of aerosolized agents from adults to children. Some authors recommend prescribing aerosolized drugs in doses adjusted to age or body weight.28 This assumes that a fixed fraction of the prescribed dose of aerosol reaches the lungs irrespective of age, to provide similar drug concentrations in patients of different ages. However, for anatomical and physiological reasons, it is more likely that drug deposition in the lung is age dependent.29 Several studies have found that for nasally administered aerosols, drug deposition in the lung is reduced in infants compared with older children. In the study of Chua et al.,28 the dose of a nasally administered aerosol deposited in the lungs of infants (median age 0.8 years) with cystic fibrosis was approximately half that for older children with cystic fibrosis (median age 10.8 years). In infants, the rate of nebulizer flow may be higher than the speed of inhalation, resulting in deposition of a lower dose in the lung than anticipated.30 In another study, the systemic exposure of budesonide was similar in young children and adults who inhaled a fixed dose, suggesting an increased capacity for drug deposition in the lung with increasing age, and that from a safety perspective, similar doses may be prescribed in young children and adults without a risk of increased exposure.29 In contrast, a study with inhaled salbutamol using a fixed dose found a higher systemic exposure in younger children compared with older children, suggesting the need to adjust the dose for age in this instance.31 There are no similar data for iloprost in the literature. As the literature data regarding
Inhaled Iloprost in Children With PH
age and drug deposition in the lung are contradictory, research into the dosage regimens of iloprost in children is needed to provide evidence for the optimal treatment dose. In our case, the dose of iloprost used in the children over 7 years old was similar to that used in adults and in the Ivy et al. study (5 mg per nebulization, effective dose). In young children, we followed a fixed dosage regimen irrespective of age, and administered a dose of 20 mg in the medication chamber (100–160 mg/day) via a continuous flow nebulizer, as it is generally assumed that approximately one-quarter of the dose reaches the patient when using a continuous flow nebulizer and a mask.22 These doses were higher than those used in the Alehan et al. study, which used a dose based on body weight.22 The doses ranged from 30 mg/day in those weighing
Use of Inhaled Iloprost in Children With Pulmonary Hypertension s de Mir Messa, Antonio Moreno-Galdo , MD, PhD,1 Alba Torrent-Vernetta, MD,1* Ine ~ a, MD,2 Silvia Gartner, MD,1 Sandra Rovira Amigo, MD,1 Ferran Gran Pin and Dimpna Albert Brotons, MD, PhD2
MD, PhD,
1
Summary. Pulmonary hypertension (PH) in children is a serious disorder, for which the major goal of treatment is to prevent progressive vascular remodeling, and improve clinical status and survival. Iloprost is approved for the treatment of PH in adults; however, few studies have evaluated its effects in children. The objective of this study is to analyze the long-term effects of inhaled iloprost treatment in children with PH. A retrospective study was conducted in patients treated with iloprost between 2000 and 2012. Patients with left–right cardiac shunt and persistent PH of the newborn were excluded. The cohort comprised 22 patients (15 females) with a median age of 2.6 years. Twelve patients had pulmonary arterial hypertension including idiopathic (n ¼ 6), hereditary (n ¼ 2) and associated (congenital heart disease [n ¼ 3], and schistosomiasis [n ¼ 1]). One patient had pulmonary veno-occlusive disease, six patients had PH secondary to lung disease and three had multifactorial PH. Median mean pulmonary arterial pressure was 55 mmHg and median pulmonary vascular resistance was 15.5 Wood units. Good tolerability was observed, with the exception of one case of recurring abdominal pain. PH resolved in two patients, with functional capacity improvement in 10 patients and stabilization in three patients. The clinical condition of six patients deteriorated; two died, and two received lung transplants. In conclusion, the results of this uncontrolled study showed that iloprost was effective and well tolerated in children. However, further research is needed to support this study, as PH is a serious condition that can require organ transplantation or result in death. Pediatr Pulmonol. ß 2014 Wiley Periodicals, Inc.
Key words: pediatric; prostacyclin; safety; tolerability.
INTRODUCTION
Pulmonary hypertension (PH) in children is a rare, progressive disorder for which the prognosis is poor if the disease is not diagnosed and treated at an early stage. Data from several European countries estimate the incidence of
idiopathic pulmonary arterial hypertension (IPAH) in children at 0.5–0.7 cases/million/year1,2 and the prevalence at 2.1–4.4 cases/million.1,3 There is currently no cure for PH, although in the last 20 years there has been major progress in our understanding of the pathophysiology of this condition, which has led to the development of
1 Unidad de Neumologı´a Pedia´trica y Fibrosis Quı´stica, Hospital Universitari Vall d’Hebron, Universitat Auto`noma de Barcelona, Barcelona, Spain.
board member for Vertex and Gilead, has been funded to attend medical meetings by Praxis pharmaceutical, and received a fee for speaking engagements from Novartis Laboratories.
2 Seccio´n de Cardiologı´a Pedia´trica, Hospital Universitari Vall d’Hebron, Universitat Auto`noma de Barcelona, Barcelona, Spain.
Antonio Moreno-Galdo´ and Alba Torrent-Vernetta contributed equally to this work.
Antonio Moreno-Galdo´ has been an advisory board member for Abbott Laboratories, and has received research funding from Abbott Laboratories. He has been funded to travel to conferences by Actelion, Novartis, Gilead, Bayer Pharma AG, and Ferrer Laboratories, and received a fee for speaking engagements from Merck Sharp & Dohme. Alba Torrent Vernetta has been funded to attend medical meetings by Gilead, Bayer Pharma AG, Ferrer and Novartis Laboratories. Ines de Mir Messa, Sandra Rovira Amigo, and Ferran Gran Pi~na have been funded to attend medical meetings by Actelion and Novartis Laboratories. Dimpna Albert Brotons has received research funding from Abbvie Laboratories and Actelion and received a fee for speaking engagements from Abbvie. Silvia Gartner has been an advisory
ß 2014 Wiley Periodicals, Inc.
Correspondence to: Alba Torrent Vernetta, MD, Unidad de Neumologı´a Pedia´trica y Fibrosis Quı´stica, Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119–129, Barcelona 08025, Spain. E-mail: [email protected] Received 6 November 2013; Accepted 6 March 2014. DOI 10.1002/ppul.23044 Published online in Wiley Online Library (wileyonlinelibrary.com).
2
Moreno-Galdo et al.
effective new treatments, helping to achieve radical changes in the prognosis for patients with PH.3–6 The guidelines on clinical practice produced jointly by the European Society of Cardiology, the European Respiratory Society, and the International Society of Heart and Lung Transplantation advise the same therapeutic approach for adults and children, although they acknowledge that the level of evidence is lower for pediatric use, and based mainly on expert opinion.7 Due to the ethical considerations relating to studies in children, it has been necessary to extrapolate results from studies conducted in adults with PH to the condition in children.8,9 In fact, only one placebo-controlled trial has been conducted in children with PH, in a study of sildenafil monotherapy.10 The prostanoid epoprostenol was the first pulmonary vasodilator used in children. However, epoprostenol must be administered intravenously, as a continuous infusion via a permanent catheter. Iloprost (Ventavis1, Bayer Pharma AG), another prostanoid, can be delivered directly to the lungs with a nebulizer. Clinical trials have shown that inhaled iloprost improved the functional class, exercise capacity, and pulmonary hemodynamics of adult patients with pulmonary arterial hypertension (PAH).11–13 In patients with PAH who remained symptomatic while on bosentan, addition of iloprost resulted in a significant improvement in functional class, distance achieved in the 6-min walk test and time to clinical worsening.14,15 In a combination study of iloprost and sildenafil, a marked and persistent improvement in exercise capacity was observed.16 Iloprost is approved as a treatment for PH in adults in World Health Organization (WHO) functional class III, and is also used on a compassionate basis in pediatric patients.17–19 Many studies have been published on iloprost treatment for PH in adults, whereas few studies have analyzed its effects in children;20–22 with long-term results assessed in only two observational studies.21,22 The objective of this study was to evaluate the long-term effects of inhaled iloprost in the treatment of children with PH, based on survival and change in functional class status. We report data collated retrospectively over a 12year period for a cohort of pediatric patients with PH, treated with iloprost as monotherapy and in combination with other drugs, and assess the course of their condition and survival rates.
MATERIALS AND METHODS Study Participants
This was a retrospective study, and data were analyzed from consecutive pediatric patients with PH who were treated with nebulized iloprost at our pediatric PH unit. Clinical characteristics and etiology, as well as hemodyPediatric Pulmonology
namic and echocardiographic data were determined. The patients were classified according to the Dana Point Classification of PH.23 Patients with left–right cardiac shunt or persistent PH of the newborn were excluded. Transthoracic echocardiography was performed in all patients. In some patients, the diagnosis was confirmed by right-heart catheterization under a general anesthetic, including a vasodilation test with inhaled nitric oxide (up to 80 ppm) and/or intravenous epoprostenol (2–12 ng/kg/ min). Where catheterization could not be performed, the diagnosis was based solely on echocardiographic data. Patients were stratified on the basis of a modification of the New York Heart Association (NYHA) classification of functional status, amended for PH by assessment of clinical status and a 6-min walk test where possible.7 Patients were classified according to their clinical status as functional class I (asymptomatic), functional class II (slight limitation of physical activity or problems with feeding), functional class III (marked limitation of physical activity, compromised growth or presenting with syncope), or functional class IV (signs of right heart failure or required mechanical ventilation due to hypoxic crisis). All patients were examined by a physician to rule out the presence of associated disorders. Treatment Approach and Outcome Measures
In all cases, the treatment strategy was agreed following multidisciplinary discussion between pulmonologists, cardiologists, and intensive care physicians. The following general treatment pattern was followed. Patients in functional class III or patients with severe PH secondary to lung disease began iloprost treatment. Patients with pulmonary arterial hypertension (PAH) functional class II were prescribed oral therapy, while patients in functional class IV were administered epoprostenol. Patients with moderate PH secondary to lung disease were treated with sildenafil. Initially we prescribed inhaled iloprost as monotherapy. However, we found that most patients required additional combined therapies so we changed our practice such that iloprost was initiated as combined treatment for patients in functional class III. These criteria were applied except for two patients in functional class II, diagnosed in 2001. Iloprost therapy was initiated following hospitalization, for initial treatment after diagnosis or after clinical deterioration despite other therapies. The nebulizer system employed was dependent upon patient age and clinical status. For patients in a critical condition with high oxygen requirements or requiring mechanical ventilation, a Jet type nebulizer (Cirrus1, Intersurgical Ltd., Madrid, Spain) connected to an oxygen supply was initially used. From 2005 onwards, a vibrating mesh nebulizer fitted in the respirator circuit (Aeroneb1 Pro,
Inhaled Iloprost in Children With PH
Aerogen, Inc., Galway, Ireland) was used for patients requiring mechanical ventilation. For patients of non-critical status under 7 years of age, a Jet type nebulizer (Freeway Sidestream1, Philips Respironics, Eindhoven, the Netherlands) was used between 2000 and 2005. From 2006, this was replaced with a continuous-flow vibrating mesh nebulizer with a face mask (Omron Micro Air U221, Omron Healthcare Europe B.V., the Netherlands). Patients of non-critical status over 7 years of age initially used a HaloLite1 nebulizer (Philips Respironics), and from 2006 a vibrating mesh nebulizer with an Adaptive Aerosol Delivery system (I-neb1 AAD1, Philips Respironics, Eindhoven, the Netherlands) was used. The frequency of use was five to six times daily for patients of non-critical status, and eight times daily for patients who were hospitalized and whose status was critical. In all cases in which a continuous flow nebulizer was used, a dose of 20 mg was administered per nebulization to compensate for the dose lost when the patient exhaled. To assess tolerability, iloprost was first administered at 5 mg/nebulization and the dose was gradually increased to 20 mg/nebulization over the course of 24–48 hr. In patients using the I-neb1 nebulizer, the dose used was 5 mg per nebulization, starting first with 2.5 mg per nebulization to assess tolerability. In all cases, the consent of the parents or guardians was sought for compassionate use of iloprost, and such use was authorized by the Spanish Ministry of Health. Additional drugs administered during the study were used at the following doses: nifedipine 2 mg/kg/day; sildenafil 0.5–1 mg/kg/8 hr for children 20 kg in weight; bosentan 31.25 mg/ 12 hr for children 10–20 kg in weight, 62.5 mg/12 hr for children 20–40 kg in weight, and 125 mg/12 hr for children >40 kg in weight. Response to treatment and the course of the patients’ condition were subsequently analyzed. Data are presented as an absolute value, percentage or median. Dilatation or hypertrophy of the right ventricle was assessed by echocardiography. The data collated during right-heart catheterization were as follows: systolic pulmonary arterial pressure, diastolic pulmonary arterial pressure, mean pulmonary arterial pressure, invasive systemic arterial pressure, cardiac output, pulmonary vascular resistance, pulmonary capillary pressure, and pulmonary arterial pressure in response to the pulmonary vasodilation test. The pulmonary vasodilation test was considered positive if the reduction in mean pulmonary arterial pressure was 10 mmHg to reach an absolute value of 40 mmHg, with an increased or unchanged cardiac output.7 All data are expressed in international reference units. The Kaplan–Meier method was used to analyze survival.
3
RESULTS
During the period from 2000 to 2012, 22 patients with PH were treated with inhaled iloprost (7 males and 15 females). The categorization of patients according to the Dana Point Classification is shown in Table 1. In total, six patients presented with PH associated with congenital heart disease. Patients 1 and 20 underwent surgery for persistent ductus arteriosus at the ages of 8 years and 8 months, respectively. Patients 7 and 11 had surgery to correct ventricular septal defect at the ages of 1 year and 4 months, respectively. Patient 21 underwent surgery to repair an aortopulmonary window at 1 month of age, and patient 22 underwent valvuloplasty for aortic stenosis after birth and surgery to correct persistent ductus arteriosus at 2 years of age. The median age at diagnosis was 2.6 years (age range: 3.6 months to 12.5 years). Seven patients (31.8%) were diagnosed before they were 1 year of age, and nine (40.9%) between the ages of 1 and 5 years. Two patients had a family history of PH (Table 2). Initial Findings
The majority of patients (15 [68.2%]) presented with minor symptoms, but for five patients (22.7%) the onset of symptoms was sudden, with cardiogenic syncope. Two
TABLE 1— Categorization of Patients With Pulmonary Hypertension According to the Dana Point Classification (N ¼ 22)23
n (%) Group 1. Pulmonary arterial hypertension 1.1. Idiopathic pulmonary hypertension 1.2. Heritable 1.2.1. BMPR2 1.2.2. ALK1 1.4. Associated with 1.4.4. Congenital heart diseases 1.4.5. Schistosomiasis Group 1’. Pulmonary veno-occlusive disease Group 3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.3. Bronchopulmonary dysplasia 3.3. Bronchiolitis obliterans 3.7. Congenital diaphragmatic hernia Mixed etiologies/mechanisms 3.3. and 1.4.4. Bronchopulmonary dysplasia and congenital heart disease 1.4.4. and 2.2. Congenital heart disease and left-sided heart failure
12 (54.6) 6 (50.0) 1 (8.3) 1 (8.3) 3 1 1 6
(25.0) (8.3) (4.6) (27.3)
4 1 1 3 2
(66.7) (16.7) (16.7) (13.6) (66.7)
1 (33.3)
ALK1, activin receptor-like kinase type 1; BMPR2, bone morphogenetic protein receptor type 2.
Pediatric Pulmonology
F
F
F F
M
F
M
M
M
F M
F
F
F
M
F
F
F
F
F
2
3 4
5
6
71
8
91,2
10 11
12
131
14
15
16
17
18
19
20
Gender
1
Patient no.
Pediatric Pulmonology
0.5
3.5
9.8
0.4
0.3
0.6
0.4
7.0
2.7
0.3 3.4
0.3
2.1
3.3
12.5
3.3
7.2 1.7
5.5
8.4
Age at diagnosis (years)
2003
2009
2008
2006
2004
2003
2002
2010
2010
2008 2008
2008
2007
2004
2004
2004
2001 2002
2001
2000
Year of diagnosis
Secondary to BPD Secondary to BPD Secondary to BPD Secondary to bronchiolitis obliterans Secondary to BPD Secondary to congenital diaphragmatic hernia Associated with CHD and BPD
IPAH
PVOD Associated with CHD IPAH
IPAH
Associated with CHD Hereditable
Associated with schistosomiasis
IPAH
Hereditable IPAH
Associated with CHD IPAH
Type of PH
TABLE 2— Patients With Pulmonary Hypertension
I
III
III
III
III
IV
III
III
II
II II
III
III
III
II
II
II IV
I
II
Functional class at diagnosis
III
III
III
III
III
IV
III
III
III
II III
III
III
III
III
III
II IV
II
III
Functional class when iloprost started
43
51
NR
NR
NR
NR
41
56
64
39 77
87
90
54
62
56
52 60
40
57
mPAP (mmHg)
PH resolved PH resolved Death
Iloprost4 (2.1) Iloprost4 (2) Iloprost (2) iloprost4 (2.1) epoprostenol (2.1)
—
Nifedipine4 (0.2), iloprost (0.2) bosentan (1.2)
Nifedipine3
Condition improved
Condition improved
Condition improved
Lost from follow-up
Nifedipine4 (0.7), iloprost (0.7)
Iloprost (0.5)
Condition improved
Condition stabilized
Condition deteriorated Condition improved
Condition deteriorated
Condition improved
Heart-lung transplant (1.6)6 Death Condition improved
Condition stabilized Double-lung transplant (0.16)6 Death
Condition stabilized
Condition improved
Course7
—
Bosentan (0.1)
Iloprost (2.5) bosentan (2.5) treprostinil (2.8) Bosentan (1.5) —
Bosentan (1.1)
Sildenafil & iloprost
Sildenafil
Sildenafil
Iloprost
Iloprost
Sildenafil & iloprost Sildenafil & nifedipine Iloprost Sildenafil & iloprost Sildenafil & iloprost Iloprost & bosentan Nifedipine3
Bosentan
Iloprost
Iloprost Sildenafil & iloprost Iloprost
Iloprost (0.1) sildenafil (1.3)
Nifedipine4 (4) bosentan (4) iloprost (6) Iloprost5 (3) sildenafil (3) bosentan (3) Sildenafil (0.5) bosentan (2) Iloprost4 (0.02) bosentan (0.02) epoprostenol (0.02) Iloprost4 (0.1) epoprostenol (0.1) Bosentan (0.25)
Nifedipine3 Iloprost
Subsequent treatments (years since starting treatment)
Initial treatment
9.1
3.7
4.9
2.1
8.6
9.5
1.3
2.7
2
4.1 4.7
4.5
5.1
8.2
6.4
0.1
11 10
11.7
12.8
Follow-up period (years)
4 Moreno-Galdo et al.
2005 2.41 M 221
BPD, bronchopulmonary dysplasia; CHD, congenital heart disease; F, female; IPAH, idiopathic pulmonary arterial hypertension; M, male; mPAP, mean pulmonary arterial pressure; NR, not recorded; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PVOD, pulmonary veno-occlusive disease. 1 Atrial septostomy performed. 2 Positive result of vasodilation test. 3 Nifedipine was initiated elsewhere and was stopped in our center after a negative result in a vasodilation test. 4 End of treatment. 5 End of treatment due to a side effect (recurrent abdominal pain). 6 Time of the transplantation since starting treatment (years). 7 Condition improved, patient’s functional class improved; condition stabilized, patient’s functional class remained in the same; condition deteriorated, patient’s functional class worsened.
7.7 Bosentan (2) iloprost (3) III
III
40
Sildenafil
Condition improved
9.5 Condition improved Bosentan (1) Iloprost 2.58 21
F
2003
Associated with CHD and BPD Associated with left heart BPD and CHD
III
III
30
Subsequent treatments (years since starting treatment) Gender Patient no.
Age at diagnosis (years)
TABLE 2— (Continued)
Year of diagnosis
Type of PH
Functional class at diagnosis
Functional class when iloprost started
mPAP (mmHg)
Initial treatment
Course7
Follow-up period (years)
Inhaled Iloprost in Children With PH
5
patients were asymptomatic and were diagnosed with PH when being assessed for another reason. The most frequent clinical presentation was dyspnea and restricted physical activity. Nine patients were diagnosed in the early stages of the disease (functional classes I and II), 11 were in functional class III and two were in functional class IV (Table 2). The echocardiographic examination that led to the diagnosis of PH detected dilation of the right ventricle in all patients, with a median systolic pulmonary arterial pressure of 72.5 mmHg (interquartile range 55– 87.5 mmHg). Right-heart catheterization of 18 patients found a median mean pulmonary arterial pressure of 55 mmHg (interquartile range 41–64 mmHg). Median pulmonary vascular resistance was 15.5 Wood Units (WU) (interquartile range 12–21 WU). A positive pulmonary vasodilation test result was obtained in only one patient, with IPAH. Eight patients (median age 4.5 years; interquartile range 3.4–7.0 years) completed the 6min walk test at the start of the study, the remainder being clinically unstable or too young. The median distance traveled was 257 m (interquartile range 237–317 m). Median minimum hemoglobin saturation was 90% (interquartile range 86.8–93.0%). Treatment
Iloprost was administered as the initial treatment for PH in 14 patients (63.6%); in eight cases as monotherapy and in six cases in combination with other drugs (Fig. 1). In the remaining eight patients, iloprost was added during follow-up in combination with the established treatments nifedipine, bosentan, sildenafil, epoprostenol, or treprostinil (Fig. 2). Overall, at the time that iloprost was introduced, three patients (13.6%) were in functional class II, 17 patients (77.3%) in functional class III, and two (9%) in functional class IV. Over the course of the study period, four patients were treated with inhaled iloprost as monotherapy and 18 patients received iloprost in combination with either one (n ¼ 10), two (n ¼ 7), or four (n ¼ 1) drugs. Iloprost was replaced with intravenous epoprostenol in three patients whose condition deteriorated and who required mechanical ventilation. In four cases, an atrial septostomy was performed due to the presence of severe PH with syncope that could not be controlled with pharmacological treatment. Other adjuvant treatments during the course of the condition were anticoagulants or antiplatelet drugs (10 patients), diuretics (11 patients), and digoxin (four patients). Course of the Disease
During the follow-up period, it was reported that inhaled iloprost was well tolerated, except in one case in Pediatric Pulmonology
6
Moreno-Galdo et al. Monotherapy (n = 2) Monotherapy (n = 8) In combination (n = 6)
Iloprost initial treatment (n = 14)
Stop Iloprost + Epoprostenol (n = 1) + Sildenafil + Bosentan (n = 2)
+ Bosentan (n = 3) Iloprost Bosentan (n = 1) In combination (n = 6) Iloprost Sildenafil (n = 5)
+ Bosentan (n = 2)
+ Bosentan (n = 1)
Stop Iloprost + Epoprostenol
= Iloprost = Sildenafil (n = 2) Fig. 1. Use of iloprost in monotherapy and in combination, when used as the initial treatment.
which treatment was discontinued due to recurrent abdominal pain. In patients who used a nebulizer face mask, transient perioral erythema was observed after inhalation, which could be prevented by using a barrier cream. Furthermore, treatment with iloprost was stopped in two patients after improvement in the underlying bronchopulmonary dysplasia that led to resolution of PH. No patients discontinued treatment due to poor adherence. After a median follow-up time of 5.8 years (range 2– 12.8 years), 19 patients (86.4%) had survived (Fig. 3). One patient was lost to follow-up after 1.3 years of treatment. Most patients received a combination of treatments during the study period. Two children, whose PH resolved, were treated with iloprost monotherapy. Since the beginning of iloprost treatment, 10 patients (45.4%) showed an improvement in functional capacity, as evidenced by a reduction in NYHA functional class from III to II, and three patients (13.6%) stabilized (remained in the same functional class), two in functional class II and one in class III. Six patients (27.3%) did not respond to treatment and their condition deteriorated. Of those who deteriorated, two patients died due to episodes of PH that did not respond to treatment (one patient Pediatric Pulmonology
classified as having IPAH and one patient with PH secondary to bronchiolitis obliterans). A double-lung transplant was received by one patient and another had a heart and lung transplant, but died 4 years after the procedure. DISCUSSION
The guidelines for the treatment of PH in children are similar to those for adults, as most research has been conducted in adults and the results extrapolated to the pediatric population. Given that few studies have examined the effect of iloprost in children, our aim was to review a cohort of pediatric patients with PH treated with inhaled iloprost, as a monotherapy and in combination with other drugs, to assess the tolerability and effectiveness of this treatment in children. Some of the endpoints used in adults to evaluate the response to treatment (such as 6-min walk test, echocardiographic parameters, and hemodynamic data), can be difficult to assess in the pediatric population,24 and there are not acceptable surrogates for endpoints such as survival and functional class.25 Furthermore, some consider NYHA functional class to be an unsuitable measure of PH disease
Inhaled Iloprost in Children With PH + Iloprost + Bosentan Nifedipine Stop
Nifedipine1 (n = 2)
Iloprost added in the follow-up (n = 8)
7
Bosentan (n = 1)
+ Iloprost + Sildenafil
Nifedipine1 (n = 1)
+ Iloprost Nifedipine Stop
Sildenafil (n = 1)
+ Iloprost
Sildenafil (n = 1)
+ Iloprost
Sildenafil (n = 1)
+ Iloprost + Bosentan
Sildenafil Nifedipine (n = 1)
+ Iloprost + Bosentan
Stop Iloprost + Epoprostenol
+ Treprostinil
Fig. 2. Use of iloprost in monotherapy, and in combination, when added during follow-up treatment. 1Nifedipine was initiated elsewhere and was stopped at our center after a negative result in a vasodilation test.
100 90 Survival probability (%)
80 70 60 50 40 30 20 10 0
0
1
2
3 4 5 Time (years)
6
7
8
12
11
10
9
10
9
9
8
Number at risk Group: Overall survival 22 21 19 17 16 Group: Transplant-free survival 22 20 17 15 14
Fig. 3. Cumulative overall survival probability and transplantfree survival probability during the period 2000–2012.
status in children.26 Therefore, we have chosen to base the assessment of patient outcomes on the clinical status and survival or transplantation data, and we have used a modified NYHA classification, similar to that published recently by Lammers et al.26 The data obtained in our study suggest a long-term beneficial effect of iloprost (median follow-up of 5.8 years), with clinical improvement (excluding the patient lost to follow-up) in 12 patients (57.1%) and stabilization in three patients (14.3%). Iloprost appears to be an effective and well tolerated drug in children, as both a monotherapy and in combination with other treatments, with few side effects. However, owing to the retrospective nature of this study and the lack of a comparator group, the validity of our findings are limited. As PH is a serious disease, most of the patients monitored in this study received iloprost alongside other therapies. Nevertheless, despite the use of combined therapy, poor responses were observed in six patients; the condition of six patients deteriorated, two died and two required lung or heart– lung transplants. Treatment choice was based on the functional and hemodynamic status of the patient, and evolved in the study period according to the availability of new drugs and new information regarding the treatment of PH. In Pediatric Pulmonology
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Moreno-Galdo et al.
agreement with guidelines, the majority of patients (77.3%) who started inhaled iloprost were in functional class III. However, three patients began iloprost treatment when in functional class II and, due to rapid disease progression, two patients were started on iloprost therapy when in functional class IV. One of the patients in functional class IV (patient 15) was a child with bronchopulmonary dysplasia, who had high oxygen requirements and received mechanical ventilation. Iloprost therapy, rather than intravenous epoprostenol, was preferentially used in this patient, to avoid clinical worsening of hypoxemia due to intrapulmonary shunt, and led to patient improvement. The other patient (patient 4), with IPAH, presented with intermittent episodes of hypoxemia and was quickly switched to intravenous epoprostenol after a week of treatment with iloprost, sildenafil, and bosentan without any improvement. However, after approximately 8 weeks, a lung transplant was required by this patient, following no improvement with epoprostenol treatment. Iloprost therapy was offered to two of the patients (patients 2 and 3) in functional class II as they were diagnosed in 2001, when there was also little experience of using oral medications for children with PH. The third patient (patient 10) in functional class II, who was suffering from pulmonary veno-occlusive disease, was treated with iloprost and assessed to ensure that therapy was well tolerated and did not result in pulmonary edema. In this case, there was clinical improvement of the patient. The introduction of new pulmonary vasodilators over the course of the study led to some changes in the treatment strategy. With the advent of bosentan therapy in 2002 and sildenafil therapy in 2005, therapeutic strategies were developed that combined drugs with different mechanisms of action, with a view to increasing efficacy. During the study period, eight patients were treated initially with inhaled iloprost as monotherapy. The majority (six patients) required combination treatment with further drugs. At present, our treatment strategy is to use iloprost for children in functional class III, and always as a combined treatment. Two of the patients in our study were suffering from severe bronchopulmonary dysplasia and needed mechanical ventilation and 100% oxygen. Iloprost monotherapy resulted in a highly marked clinical improvement that meant that these patients could be weaned off mechanical ventilation, subsequently progressing to resolution of PH. Sildenafil is currently the most commonly prescribed treatment for PH associated with bronchopulmonary dysplasia.27 However, in severe cases or those that do not respond to sildenafil, we suggest that the use of iloprost should be considered as, when administered via nebulization, iloprost has the added advantage of pulmonary selectivity unlike vasodilators such as epoprostenol. Pediatric Pulmonology
The results obtained in our study are similar to those of the two single series published previously, and corroborate the beneficial effect of iloprost treatment.21,22 In the multicentre study by Ivy et al.,21 examining the use of inhaled iloprost where intravenous prostanoid therapy was unsuitable, functional class improved in 35% of children and remained unchanged in 50% after 6 months. Some of the children (27%) deteriorated while receiving inhaled iloprost and were transitioned to epoprostenol therapy, resulting in a global survival of 91%. In the series by Alehan et al.,22 after a 1.5 year median follow-up, 15 out of 20 patients had used iloprost combined with an endothelin receptor antagonist or phosphodiesterase-type 5 inhibitor, with a 70% survival rate. These two published studies differ in regards to the age of the children included. In the Ivy et al. study, children aged 4.5–17.7 years were included, and in the study by Alehan et al., the age range of patients was 4 months to 19 years. Similar to the latter study, our series also included young children (age range 3.6 months to 12.8 years), with seven children under 1 year of age at the time of diagnosis. As iloprost dosing and pharmacokinetic studies have not been conducted in children, the doses used were extrapolated from studies carried out in adults. There is no consistent approach to the extrapolation of the dose of aerosolized agents from adults to children. Some authors recommend prescribing aerosolized drugs in doses adjusted to age or body weight.28 This assumes that a fixed fraction of the prescribed dose of aerosol reaches the lungs irrespective of age, to provide similar drug concentrations in patients of different ages. However, for anatomical and physiological reasons, it is more likely that drug deposition in the lung is age dependent.29 Several studies have found that for nasally administered aerosols, drug deposition in the lung is reduced in infants compared with older children. In the study of Chua et al.,28 the dose of a nasally administered aerosol deposited in the lungs of infants (median age 0.8 years) with cystic fibrosis was approximately half that for older children with cystic fibrosis (median age 10.8 years). In infants, the rate of nebulizer flow may be higher than the speed of inhalation, resulting in deposition of a lower dose in the lung than anticipated.30 In another study, the systemic exposure of budesonide was similar in young children and adults who inhaled a fixed dose, suggesting an increased capacity for drug deposition in the lung with increasing age, and that from a safety perspective, similar doses may be prescribed in young children and adults without a risk of increased exposure.29 In contrast, a study with inhaled salbutamol using a fixed dose found a higher systemic exposure in younger children compared with older children, suggesting the need to adjust the dose for age in this instance.31 There are no similar data for iloprost in the literature. As the literature data regarding
Inhaled Iloprost in Children With PH
age and drug deposition in the lung are contradictory, research into the dosage regimens of iloprost in children is needed to provide evidence for the optimal treatment dose. In our case, the dose of iloprost used in the children over 7 years old was similar to that used in adults and in the Ivy et al. study (5 mg per nebulization, effective dose). In young children, we followed a fixed dosage regimen irrespective of age, and administered a dose of 20 mg in the medication chamber (100–160 mg/day) via a continuous flow nebulizer, as it is generally assumed that approximately one-quarter of the dose reaches the patient when using a continuous flow nebulizer and a mask.22 These doses were higher than those used in the Alehan et al. study, which used a dose based on body weight.22 The doses ranged from 30 mg/day in those weighing
