G.B. Mallory

Short- and Long-Term Effects of Inhaled Iloprost Therapy in Children With Pulmonary Arterial Hypertension

OBJECTIVES This study investigated the short- and long-term outcome of children with pulmonary arterial hypertension (PAH) treated with inhaled iloprost. BACKGROUND Inhaled iloprost has been approved for the treatment of adults with PAH, but little is known about the effects in children with PAH. METHODS We evaluated the acute effects of inhaled iloprost on hemodynamic status and lung function and the response to long-term therapy in 22 children (range 4.5 to 17.7 years) with PAH (idiopathic, n = 12; congenital heart disease, n = 10). Cardiac catheterization, standard lung function testing before and after iloprost inhalation, 6-min walk test, World Health Organization functional class, and hemodynamic parameters were monitored. RESULTS Acute administration of inhaled iloprost lowered mean pulmonary artery pressure equivalent to the response to inhaled nitric oxide with oxygen. Acute iloprost inhalation reduced forced expiratory volume in 1 s and mid-volume forced expiratory flow by 5% and 10%, respectively, consistent with acute bronchoconstriction. At 6 months, functional class improved in 35%, decreased in 15%, and remained unchanged in 50% of children. Sixty-four percent of patients continued receiving long-term iloprost therapy, 36% stopped iloprost, due to lower airway reactivity, clinical deterioration, or death. In 9 patients on chronic intravenous prostanoids, 8 transitioned from intravenous prostanoids to inhaled iloprost, which continued during follow-up. CONCLUSIONS Inhaled iloprost caused sustained functional improvement in some children with PAH, although inhaled iloprost occasionally induced bronchoconstriction. Most patients tolerated the transition from intravenous to inhaled prostanoid therapy. Clinical deterioration, side effects, and poor compliance, owing to the frequency of treatments, could limit chronic treatment in children.

Acute Vasodilator Response in Pediatric Pulmonary Arterial Hypertension: Current Clinical Practice From the TOPP Registry

BACKGROUND In pulmonary arterial hypertension (PAH), acute vasodilator response testing (AVT) is considered important to identify adult patients with favorable prognosis using calcium-channel blocker (CCB) therapy. However, in pediatric PAH, criteria used to identify acute responders and CCB use are insufficiently studied. OBJECTIVES This study sought to describe current clinical practice of AVT and subsequent treatment decisions in pediatric PAH. METHODS From January 2008 to May 2013, 529 consecutive children with confirmed pulmonary hypertension were enrolled in an international registry. We analyzed those children with evaluable AVT. RESULTS Of 382 children with evaluable AVT, 212 had idiopathic/familial PAH (IPAH/FPAH) and 105 had PAH associated with congenital heart disease (PAH-CHD). In 70% of the patients, AVT was performed using inhaled nitric oxide; other agents were used in the remaining patients. In IPAH/FPAH patients, 78 (37%) patients were acute responders according to their physician, 62 (30%) according to REVEAL (Registry-to-Evaluate-Early-And-Long-term PAH disease management)-pediatric criteria, and 32 (15%) according to Sitbon criteria. For PAH-CHD patients, the numbers of AVT responders were 38 (36%), 14 (13%), and 7 (7%) respectively. Correlation between AVT responder status as judged by the treating physician and by published response criteria was poor. Moreover, of the IPAH/FPAH patients judged by the treating physician as acute responders, only 23% were treated with CCB without additional PAH-targeted therapy. The Sitbon criteria selected patients with better prognosis who had excellent outcome when treated with CCB. CONCLUSIONS The current practice of identifying responders to AVT and subsequent treatment with CCB therapy demonstrated large discrepancies with current international guidelines. Also, in pediatric IPAH, the Sitbon criteria are the criteria of choice to identify patients with excellent survival when treated with CCB therapy.

Treatment of Severe Pulmonary Hypertension in the Setting of the Large Patent Ductus Arteriosus

Treatment of the large patent ductus arteriosus (PDA) in the setting of pulmonary hypertension (PH) is challenging. Left patent, the large PDA can result in irreversible pulmonary vascular disease. Occlusion, however, may lead to right ventricular failure for certain patients with severe PH. Our center has adopted a staged management strategy using medical management, noninvasive imaging, and invasive cardiac catheterization to treat PH in the presence of a large PDA. This approach determines the safety of ductal closure but also leverages medical therapy to create an opportunity for safe PDA occlusion. We reviewed our experience with this approach. Patients with both severe PH and PDAs were studied. PH treatment history and hemodynamic data obtained during catheterizations were reviewed. Repeat catheterizations, echocardiograms, and clinical status at latest follow-up were also reviewed. Seven patients had both PH and large, unrestrictive PDAs. At baseline, all patients had near-systemic right ventricular pressures. Nine catheterizations were performed. Two patients underwent 2 catheterizations each due to poor initial response to balloon test occlusion. Six of 7 patients exhibited subsystemic pulmonary pressures during test occlusion and underwent successful PDA occlusion. One patient did not undergo PDA occlusion. In follow-up, 2 additional catheterizations were performed after successful PDA occlusion for subsequent hemodynamic assessment. At the latest follow-up, the 6 patients who underwent PDA occlusion are well, with continued improvement in PH. Five patients remain on PH treatment. A staged approach to PDA closure for patients with severe PH is an effective treatment paradigm. Aggressive treatment of PH creates a window of opportunity for PDA occlusion, echocardiography assists in identifying the timing for closure, and balloon test occlusion during cardiac catheterization is critical in determining safety of closure. By safely eliminating the large PDA, this treatment algorithm can halt the perilous combination of the large shunting from the PDA and PH in a population at high risk of morbidity and mortality.

Pulmonary hypertension in early life

Pulmonary hypertension is an uncommon disease that aff ects infants, children, adolescents, and adults. The disorders that lead to pulmonary hypertension have been defi ned by an increasingly exhaustive and widely accepted classifi cation scheme, most recently published in 2009 under the auspices of WHO. Most of these disorders are associated with pulmonary arterial hypertension (PAH). PAH is a disease process that can present at any age with the gradual onset of either nonspecifi c symptoms, such as dyspnoea, or very pronounced symptoms such as frank right heart failure. Morbidity and mortality are substantial for children with PAH; in the early 1990s, median survival was 2·3 years. There are limited data about the burden of PAH in childhood, but some country-specifi c studies suggest that it is probably less common in childhood than in adulthood (<10% of adult incidence in the USA and Israel). Assessment and treatment of pulmonary hypertension has been progressively refi ned and ex panded in national and international guidelines. Although paediatric pul monary hypertension is in cluded in classifi cation schemes and clinical guidelines, characterisation of the dis order early in life has lagged behind the progress made in adults owing to the higher prevalence in adulthood. In The Lancet, Rolf Berger and colleagues from Europe, North America, and China report results from an international patient registry, the Global Registry Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP). Right heart catheter isation was required for study inclusion, so patients with PAH who had not undergone right heart catheterisation were excluded—in most centres in this registry children with congenital diaphragmatic hernia and broncho pulmonary dysplasia did not undergo right heart catheterisation before initiation of therapy. Nonetheless, 362 patients from 31 centres in 19 countries were in cluded in the study, a remarkable international sample. Data at diagnosis were obtained for 102 patients who were incident cases (diagnosis within 3 months of enrolment) and retrospectively for 260 patients who were prevalent cases (diagnosed more than 3 months before enrolment). collaboration at an international scale through linked Down’s syndrome research networks. Despite these issues, there is optimism that the cognitive problems and neurodegeneration of Down’s syndrome (which were previously regarded as intractable) can be improved with pharmacological treatments, but there is a need for cellular studies and studies in animals to explore the potential eff ects of new treatment options thoroughly before undertaking clinical trials. The MEADOWS trial shows that randomised trials are possible in this population and should encourage future trials of potential drugs that are based on strong experimental evidence.

Waitlist Outcomes in Pediatric Lung Transplantation: Poor Results for Children Listed in Adult Transplant Programs

BACKGROUND Low case volume has been associated with lower survival after pediatric lung transplantation. Our aim was to analyze waitlist outcomes among pediatric lung transplant centers in the USA. METHODS We studied a cohort of 1,139 pediatric candidates listed in the Organ Procurement and Transplantation Network for lung transplantation between 2002 and 2014. Of these candidates, 720 (63.2%) received a transplant. Candidates were divided into groups according to the clinical activity of the center of listing: high-volume pediatric (≥4 transplants per year); low-volume pediatric (<4 transplants per year); and adult (transplant volume predominantly in adults). We used multivariate Cox regression analysis to identify independent risk factors for waitlist mortality. We also determined the transplant rate-or likelihood of transplant after listing-over the study period. RESULTS Fifty-eight percent of the children and adolescents were listed in adult centers where the resultant transplant rate was low-only 42% received a transplant compared with 93% in pediatric programs. Listing in an adult program was also the most significant risk factor for death on the waiting list (hazard ratio 15.6, 95% confidence interval 5.8 to 42.1). CONCLUSIONS Most children (58%) are listed for lung transplantation in adult centers and have a reduced rate of transplantation and a greater chance of waitlist mortality.

Acute vasodilator response in pediatric pulmonary arterial hypertension current

BACKGROUND In pulmonary arterial hypertension (PAH), acute vasodilator response testing (AVT) is considered important to identify adult patients with favorable prognosis using calcium-channel blocker (CCB) therapy. However, in pediatric PAH, criteria used to identify acute responders and CCB use are insufficiently studied. OBJECTIVES This study sought to describe current clinical practice of AVT and subsequent treatment decisions in pediatric PAH. METHODS From January 2008 to May 2013, 529 consecutive children with confirmed pulmonary hypertension were enrolled in an international registry. We analyzed those children with evaluable AVT. RESULTS Of 382 children with evaluable AVT, 212 had idiopathic/familial PAH (IPAH/FPAH) and 105 had PAH associated with congenital heart disease (PAH-CHD). In 70% of the patients, AVT was performed using inhaled nitric oxide; other agents were used in the remaining patients. In IPAH/FPAH patients, 78 (37%) patients were acute responders according to their physician, 62 (30%) according to REVEAL (Registry-to-Evaluate-Early-And-Long-term PAH disease management)-pediatric criteria, and 32 (15%) according to Sitbon criteria. For PAH-CHD patients, the numbers of AVT responders were 38 (36%), 14 (13%), and 7 (7%) respectively. Correlation between AVT responder status as judged by the treating physician and by published response criteria was poor. Moreover, of the IPAH/FPAH patients judged by the treating physician as acute responders, only 23% were treated with CCB without additional PAH-targeted therapy. The Sitbon criteria selected patients with better prognosis who had excellent outcome when treated with CCB. CONCLUSIONS The current practice of identifying responders to AVT and subsequent treatment with CCB therapy demonstrated large discrepancies with current international guidelines. Also, in pediatric IPAH, the Sitbon criteria are the criteria of choice to identify patients with excellent survival when treated with CCB therapy.

Acute Vasodilator Response in Pediatric Pulmonary Arterial Hypertension

BACKGROUND In pulmonary arterial hypertension (PAH), acute vasodilator response testing (AVT) is considered important to identify adult patients with favorable prognosis using calcium-channel blocker (CCB) therapy. However, in pediatric PAH, criteria used to identify acute responders and CCB use are insufficiently studied. OBJECTIVES This study sought to describe current clinical practice of AVT and subsequent treatment decisions in pediatric PAH. METHODS From January 2008 to May 2013, 529 consecutive children with confirmed pulmonary hypertension were enrolled in an international registry. We analyzed those children with evaluable AVT. RESULTS Of 382 children with evaluable AVT, 212 had idiopathic/familial PAH (IPAH/FPAH) and 105 had PAH associated with congenital heart disease (PAH-CHD). In 70% of the patients, AVT was performed using inhaled nitric oxide; other agents were used in the remaining patients. In IPAH/FPAH patients, 78 (37%) patients were acute responders according to their physician, 62 (30%) according to REVEAL (Registry-to-Evaluate-Early-And-Long-term PAH disease management)-pediatric criteria, and 32 (15%) according to Sitbon criteria. For PAH-CHD patients, the numbers of AVT responders were 38 (36%), 14 (13%), and 7 (7%) respectively. Correlation between AVT responder status as judged by the treating physician and by published response criteria was poor. Moreover, of the IPAH/FPAH patients judged by the treating physician as acute responders, only 23% were treated with CCB without additional PAH-targeted therapy. The Sitbon criteria selected patients with better prognosis who had excellent outcome when treated with CCB. CONCLUSIONS The current practice of identifying responders to AVT and subsequent treatment with CCB therapy demonstrated large discrepancies with current international guidelines. Also, in pediatric IPAH, the Sitbon criteria are the criteria of choice to identify patients with excellent survival when treated with CCB therapy.