Mary P. Mullen

Pulmonary Artery Hypertension in Formerly Premature Infants With Bronchopulmonary Dysplasia : Clinical Features and Outcomes in the Surfactant Era

BACKGROUND. Although abnormal pulmonary vascular structure and function in preterm infants with bronchopulmonary dysplasia may predispose infants to pulmonary artery hypertension, little is known about the characteristics and outcomes of bronchopulmonary dysplasia-associated pulmonary artery hypertension in the surfactant era. METHODS. We studied 42 premature infants (<32 weeks of gestation) with bronchopulmonary dysplasia who were diagnosed as having pulmonary artery hypertension ≥2 months after birth, between 1998 and 2006, at a median age of 4.8 months. Pulmonary artery hypertension was graded through echocardiography for all patients; 13 patients also underwent cardiac catheterization. RESULTS. Eighteen (43%) of 42 patients had severe pulmonary artery hypertension (systemic or suprasystemic right ventricular pressure). Among 13 patients who underwent catheterization, the mean pulmonary artery pressure was 43 ± 8 mmHg and the pulmonary vascular resistance index was 9.9 ± 2.8 Wood units. In 12 patients, pulmonary artery pressure and pulmonary vascular resistance improved with 100% oxygen and 80 ppm inhaled nitric oxide but remained elevated. The pulmonary vascular resistance index decreased to 7.9 ± 3.8 Wood units in 100% oxygen and to 6.4 ± 3.1 Wood units with the addition of nitric oxide. Sixteen patients (38%) died during the follow-up period. Estimated survival rates were 64% ± 8% at 6 months and 53% ± 11% at 2 years after diagnosis of pulmonary artery hypertension. In multivariate analyses, severe pulmonary artery hypertension and small birth weight for gestational age were associated with worse survival rates. Among 26 survivors (median follow-up period: 9.8 months), pulmonary artery hypertension was improved, relative to its most severe level, in 24 patients (89%). CONCLUSION. Premature infants with bronchopulmonary dysplasia and severe pulmonary artery hypertension are at high risk of death, particularly during the first 6 months after diagnosis of pulmonary artery hypertension.

Pediatric Pulmonary Hypertension Guidelines From the American Heart Association and American Thoracic Society

Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension.

Implications of the U.S. Food and Drug Administration Warning against the Use of Sildenafil for the Treatment of Pediatric Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.

Transcatheter Potts shunt creation in patients with severe pulmonary arterial hypertension: Initial clinical experience

BACKGROUND Patients with severe pulmonary arterial hypertension (PAH) face significant morbidity and death as a consequence of progressive right heart failure. Surgical shunt placement between the left PA and descending aorta (Potts shunt) appears promising for PAH palliation in children; however, surgical mortality is likely to be unacceptably high in adults with PAH. METHODS We describe a technique for transcatheter Potts shunt (TPS) creation by fluoroscopically guided retrograde needle perforation of the descending aorta at the site of apposition to the left PA to create a tract for deployment of a covered stent between these vessels. This covered stent-anchored by the vessel walls and surrounding tissue-serves as the shunt. RESULTS TPS creation was considered in 7 patients and performed in 4. The procedure was technically successful in 3 patients; 1 patient died during the procedure as a result of uncontrolled hemothorax. One acute survivor, critically ill at the time of TPS creation, later died of comorbidities. The 2 mid-term survivors (follow-up of 10 and 4 months) are well at home, with symptomatic improvement and no late complications. The 3 candidate patients in whom the procedure was not performed died within 1 month of consideration, underscoring the tenuous nature of this population. CONCLUSIONS TPS creation is feasible and may offer symptomatic relief to select patients with refractory PAH. Further study of this innovative approach is warranted.

Effect of inhaled iloprost on the exercise function of Fontan patients: A demonstration of concept

BACKGROUND Exercise capacity following Fontan surgery is often depressed. An inability to reduce pulmonary vascular resistance appropriately during exercise may contribute to this phenomenon. The aim of this study was to determine whether administration of iloprost, a selective pulmonary vasodilator, would improve exercise function after Fontan procedure. METHODS Double-blind, randomized, placebo controlled, crossover trial. Patients performed two cardiopulmonary exercise tests (CPX) separated by <1 month. A single nebulizer treatment (iloprost or placebo) was administered before each CPX. RESULTS 18 patients aged 12-49 (median 17) years were recruited. Mild throat discomfort developed in 10/18 patients during iloprost administration; all but 1 were able to complete treatment. No symptoms developed during placebo treatments (p<0.001). Two additional patients did not complete CPX: one with atrial flutter; another with developmental issues that precluded adequate CPX. In the 15 remaining subjects oxygen pulse (a surrogate for forward stroke volume) at peak exercise was higher following iloprost (median increase 1.2 ml/beat; p<0.001). Peak VO2 also rose (median increase 1.3 ml/kg/min; p<0.04). Nine patients had peak VO2 <30 ml/kg/min; each of these patients had higher peak VO2 following iloprost. Only 3/6 patients with peak VO2 >30 ml/kg/min had higher peak VO2 following iloprost (p<0.04). CONCLUSIONS Iloprost improves the peak oxygen pulse and peak VO2 of patients with Fontan physiology and appears to be particularly beneficial among patients with impaired exercise function. Treatment is associated with minor side effects. These findings support the concept of pulmonary vasodilator therapy in Fontan patients with limited functional capacity.

Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield

BackgroundCongenital heart defects (CHD), as the most common congenital anomaly, have been reported to be frequently associated with pathogenic copy number variants (CNVs). Currently, patients with CHD are routinely offered chromosomal microarray (CMA) testing, but the diagnostic yield of CMA on CHD patients has not been extensively evaluated based on a large patient cohort. In this study, we retrospectively assessed the detected CNVs in a total of 514 CHD cases (a 422-case clinical cohort from Boston Childrens Hospital (BCH) and a 92-case research cohort from Shanghai Children’s Medical Center (SCMC)) and conducted a genotype-phenotype analysis. Furthermore, genes encompassed in pathogenic/likely pathogenic CNVs were prioritized by integrating several tools and public data sources for novel CHD candidate gene identification.ResultsBased on the BCH cohort, the overall diagnostic yield of CMA testing for CHD patients was 12.8(pathogenic CNVs)-18.5% (pathogenic and likely pathogenic CNVs). The diagnostic yield of CMA for syndromic CHD was 14.1-20.6% (excluding aneuploidy cases), whereas the diagnostic yield for isolated CHD was 4.3-9.3%. Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls. These regions are considered as novel CHD loci. We further identified 20 genes as the most likely novel CHD candidate genes through gene prioritization analysis.ConclusionThe high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients. The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation.

Cardiovascular malformations in Fryns syndrome: is there a pathogenic role for neural crest cells?

We performed a comprehensive literature and case report review to characterize the cardiovascular malformations (CVMs) associated with Fryns syndrome (OMIM #229850), a multiple congenital anomaly/mental retardation syndrome consisting of diaphragmatic defects, significant pulmonary hypoplasia, distinctive facial appearance, distal digital hypoplasia, and numerous other external and internal anomalies. A total of 112 patients meeting diagnostic guidelines for Fryns syndrome were identified, of whom 82 met narrowly defined criteria (Group I) and 30 met broader diagnostic criteria (Group II). Twelve patients reported as having Fryns syndrome with atypical features (Group III) were also analyzed. A CVM was reported in 51% (42 of 82) of Group I patients, most commonly an atrial or ventricular septal defect (VSD) (23 of 42, 55%). Conotruncal and aortic arch CVMs were common (11 of 42, 26%), but not significantly so compared to the general population of infants to age 1 year [Ferencz et al., 1997 ]. Recognizing that minor septal defects associated with congenital diaphragmatic hernia (CDH) may occur in response to altered hemodynamics (instead of being a bonafide CVM), we excluded four patients reported as having hemodynamically insignificant VSDs. Following these exclusions, conotruncal CVMs were found more commonly than in the general population (11 of 38, 29%, P ≤ 0.025). In Group II, 9 of 30 (30%) had a CVM with no predominant type among the small number of cases reviewed. Among the atypical Fryns syndrome patients in Group III, half (6 of 12, 50%) had a CVM; most (4 of 6, 67%) were conotruncal, in particular, type B interrupted aortic arch (3 of 4). Patients with Fryns syndrome have a high rate of CVMs, warranting thorough cardiac evaluation including echocardiogram (fetal and/or postnatal) in all patients, similar to the evaluation for other patients with diaphragmatic hernia. The possible association between conotruncal CVMs and Fryns syndrome may provide additional support for an etiologic role of genes related to neural crest cell development in the pathogenesis of Fryns syndrome and hence, congenital diaphragmatic hernia.

Treatment of segmental pulmonary artery hypertension in adults with congenital heart disease.

INTRODUCTION Pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) usually has a homogeneous pressure distribution. More rarely, complex CHD patients have segmental PAH. This is often post-surgically. The characteristics of these patients and their responsiveness to specific pulmonary vasodilator therapy have not been described. METHODS Seven adults with segmental PAH complicating CHD were treated at 3 specialized adult CHD centers between January 2006 and December 2010. Clinical characteristics, six minute walking distances (6 MWD), laboratory tests and images were obtained from medical records and the responses to Bosentan, an endothelin-1 receptor antagonist, were assessed. RESULTS All patients (mean age 32 (23-42) years, five females) had a primary diagnosis pulmonary atresia (PA), four with major aortopulmonary collateral arteries (MAPCAs). Four segmental PAH patients had a right pulmonary artery stenosis, two a left pulmonary artery stenosis and one a unilateral MAPCA stenosis. All patients were symptomatic (functional class II or III) and bosentan was started empirically. Bosentan treatment led to a significant improvement in functional class compared to baseline (1.7 ± 0.5 versus 2.4 ± 0.5; p<0.01). Mean 6 MWD (available in 6 patients) increased by 62 m (22-150 m) from 386 ± 135 to 448 ± 133 m (p=0.03) after 12 months treatment. Most improvement was seen in patients with low baseline 6 MWD. Higher baseline exercise heart rate was significantly associated with lesser improvement in 6 MWD (r=-0.91 p=0.01). Laboratory results did not change after initiation of bosentan treatment. CONCLUSION This small retrospective case series suggested a significant improvement of functional class and exercise capacity after bosentan treatment in patients with segmental PAH. These findings warrant a prospective study of the potential benefit of selective pulmonary vasodilator therapy in these complex patients. Therefore, we call on treating physicians to share similar cases.

The incidence and implications of anti-heparin-platelet factor 4 antibody formation in a pediatric cardiac surgical population.

BACKGROUND: The incidence and implications of anti-heparin-platelet factor 4 (PF4) antibody seroconversion in the pediatric cardiac surgical population remain largely unexplored. We sought to prospectively characterize the incidence of seroconversion in two populations: neonates undergoing primary cardiac surgery and children undergoing reoperative cardiac surgery with a history of unfractionated heparin (UFH) exposure. METHODS: One hundred and thirty-five consecutive patients were studied: Neonatal = 60 neonates, first time cardiac surgery. Reoperative (ReOp) = 75 children, reoperative cardiac surgery. Preoperative and postoperative day (POD) 5 and 10 blood samples were used to determine the presence of PF4 immunoglobulin (Ig)G, IgA, and IgM antibodies with enzyme-linked immunosorbent assay. RESULTS: No anti-heparin/PF4 antibodies were detected preoperatively in either group. On POD 5, antibodies were present in 1 of 60 (1.7%) Neonatal; and in 12 of 75 (16%) ReOp; P = 0.006. On POD 10, antibodies were present in 1 of 60 (1.7%) Neonatal; and in 39 of 75 (52%) ReOp; P < 0.001. Seroconversion in ReOp patients on POD 10 was significantly associated (P = 0.03) with previous UFH exposures. Heparin-induced thrombocytopenia (HIT) was not diagnosed in any Neonatal patients. One ReOp patient (1.3%) seroconverted and developed HIT without thrombosis or skin lesions. CONCLUSIONS: HIT is a rare occurrence in pediatric cardiac surgical patients. The incidence of anti-heparin-PF4 antibody seroconversion in children undergoing reoperation is approximately 50% at 10 days postoperatively, a finding similar to that reported in adult cardiac surgical patients. Both age and previous UFH exposure correlate with this rate of seroconversion. In contrast, the rate of seroconversion in neonates undergoing first time surgery is substantially lower.

Brief report free-play behavior in inhibited and uninhibited children

Four-month-old infants were classified on motor activity and frequency of crying to visual and auditory stimuli. The subgroups that were either high or low on both variables were observed at 14 months during a free-play period in an unfamiliar playroom. Five free-play variables were combined to produce a composite on which a high score was indicative of behavioral inhibition. The infants who had been high in motor activity and crying at 4 months had higher inhibition scores than did the infants with the opposite profile.