Brian D. Hanna

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.

Impact of Oral Sildenafil on Exercise Performance in Children and Young Adults After the Fontan Operation A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Background— Children and young adults with single-ventricle physiology have abnormal exercise capacity after the Fontan operation. A medication capable of decreasing pulmonary vascular resistance should allow improved cardiac filling and improved exercise capacity. Methods and Results— This study was a double-blind, placebo-controlled, crossover trial conducted in children and young adults after Fontan. Subjects were randomized to receive placebo or sildenafil (20 mg three times daily) for 6 weeks. After a 6-week washout, subjects crossed over for an additional 6 weeks. Each subject underwent an exercise stress test at the start and finish of each phase. After taking sildenafil, subjects had a significantly decreased respiratory rate and decreased minute ventilation at peak exercise. At the anaerobic threshold, subjects had significantly decreased ventilatory equivalents of carbon dioxide. There was no change in oxygen consumption during peak exercise, although there was a suggestion of improved oxygen consumption at the anaerobic threshold. Improvement at the anaerobic threshold was limited to the subgroup with single left or mixed ventricular morphology and to the subgroup with baseline serum brain natriuretic peptide levels ≥100 pg/mL. Conclusions— In this cohort, sildenafil significantly improved ventilatory efficiency during peak and submaximal exercise. There was also a suggestion of improved oxygen consumption at the anaerobic threshold in 2 subgroups. These findings suggest that sildenafil may be an important agent for improving exercise performance in children and young adults with single-ventricle physiology after the Fontan operation. Clinical Trial Registration— URL: . Unique identifier: [NCT00507819][1]. # Clinical Perspective {#article-title-31} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00507819&atom=%2Fcirculationaha%2F123%2F11%2F1185.atomBackground— Children and young adults with single-ventricle physiology have abnormal exercise capacity after the Fontan operation. A medication capable of decreasing pulmonary vascular resistance should allow improved cardiac filling and improved exercise capacity. Methods and Results— This study was a double-blind, placebo-controlled, crossover trial conducted in children and young adults after Fontan. Subjects were randomized to receive placebo or sildenafil (20 mg three times daily) for 6 weeks. After a 6-week washout, subjects crossed over for an additional 6 weeks. Each subject underwent an exercise stress test at the start and finish of each phase. After taking sildenafil, subjects had a significantly decreased respiratory rate and decreased minute ventilation at peak exercise. At the anaerobic threshold, subjects had significantly decreased ventilatory equivalents of carbon dioxide. There was no change in oxygen consumption during peak exercise, although there was a suggestion of improved oxygen consumption at the anaerobic threshold. Improvement at the anaerobic threshold was limited to the subgroup with single left or mixed ventricular morphology and to the subgroup with baseline serum brain natriuretic peptide levels ≥100 pg/mL. Conclusions— In this cohort, sildenafil significantly improved ventilatory efficiency during peak and submaximal exercise. There was also a suggestion of improved oxygen consumption at the anaerobic threshold in 2 subgroups. These findings suggest that sildenafil may be an important agent for improving exercise performance in children and young adults with single-ventricle physiology after the Fontan operation. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00507819.

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.

Use of angiographic CT imaging in the cardiac catheterization laboratory for congenital heart disease.

OBJECTIVES This study sought to retrospectively evaluate our initial experience using angiographic computed tomography (ACT) in a pediatric cardiac catheterization laboratory. BACKGROUND ACT provides cross-sectional CT images from a rotational angiography run using a C-arm mounted flat-panel detector in the interventional suite. A 3-dimensional (3D) angiographic image can be created from the CT volume set and used in real time during the procedure. To our knowledge, its use has never previously been described for congenital heart disease. METHODS 3D reconstructions were created and we retrospectively reviewed cases during our first year of ACT use. Images obtained were independently evaluated to determine their diagnostic utility. Radiation dose reduction protocols were defined using phantom testing and radiation dose calculation. RESULTS ACT was used during 41 cardiac catheterizations in patients at a median age of 5.1 years (range: 0.4 to 58.8 years) for evaluation of: right ventricular outflow tract (RVOT)/central pulmonary arteries (PAs) in 20; cavopulmonary connection (CPC) in 11; pulmonary veins in 5; distal PAs in 4; and other locations in 5. Four subjects had 2 anatomic areas studied by ACT. The mean contrast volume for ACT was 1.2 ± 0.4 ml/kg. Diagnostic-quality imaging was obtained in 71% of cases: 13/20 RVOT/central PAs; 9/11 CPC; 4/5 pulmonary veins; 2/4 distal PAs; and 4/5 others. In 12 cases, ACT contributed to clinical outcomes beyond standard angiography. Radiation dose reduction protocols allowed ACT to be comparable in exposure to a standard biplane cineangiogram. CONCLUSIONS Diagnostic-quality imaging can be obtained using ACT in 71% of cases without a significant increase in contrast or radiation exposure. In certain cases, ACT provides additional anatomic detail and may aid complex catheter manipulations. Future work is needed to continue to define applications of this new technology.

Ventricular assist device-associated anti-human leukocyte antigen antibody sensitization in pediatric patients bridged to heart transplantation

BACKGROUND Ventricular assist devices (VAD) are associated with the formation of antibodies to anti-human leukocyte antigens (HLA) or sensitization. The incidence and effects of VAD-associated anti-HLA sensitization have not been well studied in the pediatric population. METHODS A retrospective review of all patients undergoing VAD implant at our institution from 1998 to 2008 was performed. Panel reactive antibody (PRA) results before VAD implant, after VAD implant, and after orthotopic heart transplantation (OHT) were recorded. Patients who became sensitized (PRA for class I and/or II immunoglobulin G antibodies >or= 10%) on VAD support were compared with non-sensitized patients with regard to demographics, diagnosis, device type, and blood product exposure on VAD support. Outcomes after OHT were also compared between groups. RESULTS VAD support was initiated in 20 patients (median age, 14.4 years), with 75% survival to OHT or recovery. PRA data before and after VAD implant were available for 17 patients. VAD-associated sensitization developed in 35% of recipients. There were no differences between those sensitized in association with VAD support and non-sensitized patients with regard to age, gender, diagnosis, device type, extracorporeal membrane oxygenation use, or blood product exposure on VAD support. Black race predicted sensitization on VAD (p = 0.02). There were no differences in survival or rejection between groups. CONCLUSIONS VAD therapy was associated with the development of anti-HLA sensitization in 35% of recipients. Black race predicted sensitization, but there were no differences in overall survival or outcomes after OHT.

Predictors of Catastrophic Adverse Outcomes in Children with Pulmonary Hypertension Undergoing Cardiac Catheterization: A Multi-Institutional Analysis From The Pediatric Health Information Systems Database

BACKGROUND Cardiac catheterization is the standard of care procedure for diagnosis, choice of therapy, and longitudinal follow-up of children and adults with pulmonary hypertension (PH). However, the procedure is invasive and has risks associated with both the procedure and recovery period. OBJECTIVES The purpose of this study was to identify risk factors for catastrophic adverse outcomes in children with PH undergoing cardiac catheterization. METHODS We studied children and young adults up to 21 years of age with PH undergoing 1 or more cardiac catheterization at centers participating in the Pediatric Health Information Systems database between 2007 and 2012. Using mixed-effects multivariable regression, we assessed the association between pre-specified subject- and procedure-level covariates and the risk of the composite outcome of death or initiation of mechanical circulatory support within 1 day of cardiac catheterization after adjustment for patient- and procedure-level factors. RESULTS A total of 6,339 procedures performed on 4,401 patients with a diagnosis of PH from 38 of 43 centers contributing data to the Pediatric Health Information Systems database were included. The observed risk of composite outcome was 3.5%. In multivariate modeling, the adjusted risk of the composite outcome was 3.3%. Younger age at catheterization, cardiac operation in the same admission as the catheterization, pre-procedural systemic vasodilator infusion, and hemodialysis were independently associated with an increased risk of adverse outcomes. Pre-procedural use of pulmonary vasodilators was associated with reduced risk of composite outcome. CONCLUSIONS The risk of cardiac catheterization in children and young adults with PH is high relative to previously reported risk in other pediatric populations. The risk is influenced by patient-level factors. Further research is necessary to determine whether knowledge of these factors can be translated into practices that improve outcomes for children with PH.

Prevalence of and risk factors for acute occlusive arterial injury following pediatric cardiac catheterization: A large single‐center cohort study

To describe the prevalence of and identify risk factors for acute occlusive arterial injury (AOAI) in a large volume pediatric cardiac catheterization laboratory.

Too Fat or Too Thin? Body Habitus Assessment in Children Listed for Heart Transplant and Impact on Outcome

BACKGROUND Body habitus assessment (BHA), be it wasted or obese, is a useful marker of nutritional status and overall medical condition. Wasting and obesity pre-heart transplant adversely affects outcomes in adults. The utility of BHA as a prognostic factor in children post-transplant is unknown. METHODS Weight and height at listing and standard growth charts were used to determine the ideal body weight (%IBW) and percentiles for body mass index for age (BMI%) and weight-for-length (W:L%). Wasting was defined as <90%IBW and/or <or=5th percentile for BMI% or W:L%. Obesity was defined as >120%IBW and/or >or=95th percentile BMI% or W:L%. Outcomes of cohorts based on these criteria were compared. RESULTS From June 1990 to December 2006, 180 children, aged 5.81 +/- 6 years, were listed for transplant. Wasting occurred in 66 (37%) and obesity in 22 (12%) children, without differences between diagnoses of cardiomyopathy or congenital heart disease. %IBW was a prognostic factor for survival post-transplant on multivariate analysis: obese patients had a hazard ratio (HR) of 3.82 (95% confidence interval [CI] 1.81 to 8.06) compared with normal BHA (p < 0.001). Wasting had a survival advantage compared with normal BHA (HR 0.51, 95% CI 0.27 to 0.94, p = 0.032). There were no significant differences between cohorts in incidence of infections, first-year rejections or graft vasculopathy. CONCLUSIONS Abnormal BHA at listing was a prognostic factor for survival post-transplant. Obese children had increased mortality, but wasting did not adversely affect post-transplant survival in our population. Body habitus assessment may risk-stratify children at listing, potentially providing a complex target for intervention.

Aortic Stenosis: The Spectrum of Practice

There is significant variation in practice patterns in managing congenital aortic valve stenosis. Review of medical literature reveals no significant information regarding the current practice methods in the treatment of a simple lesion such as aortic stenosis (AS). Therefore, this survey-based study was conducted in an attempt to better understand the uniformity or heterogeneity of practice in treating AS. A questionnaire was prepared to evaluate the style of management of AS. This survey was designed to assess the practice of follow-up visitations, type and frequency of investigative studies, pharmacological therapy, and exercise recommendations. Questions about therapeutic intervention included those of timing and type of intervention. Questionnaires were sent to all academic pediatric cardiology programs in the United States (48 program) and selected international programs from Europe, Asia, and Australasia (19 program). The total number of surveys sent out was 67, and the total number of respondents was 25 (37%), 15 (31%) from the United States and 9 (53%) from outside the United States. The definition of moderate AS varied among respondents. The range provided for mild AS was identified as that with a peak-to-peak pressure gradient of < 25–30 mmHg, peak instantaneous Doppler gradient of < 36–50 mmHg, or mean Doppler gradient of < 25–40 mmHg. On the other hand, severe AS was defined as that with a peak-to-peak gradient of > 50–60 mmHg, peak instantaneous Doppler gradient of > 64–80 mmHg, or mean Doppler gradient of > 45–64 mmHg. In assessing follow-up patterns, 84% of respondents recommended seeing patients with mild AS annually, the longest time of follow-up listed in the questionnaire, whereas 20% suggested follow-up every 6 months. There was no consensus among survey centers regarding follow-up of patients with moderate AS. For severe AS, 16% recommend immediate intervention, 16% arrange follow-up every 6 months, and 56 and 28% recommend follow-up in 3 and 1 month(s), respectively. In making the decision to proceed with biventricular versus univentricular repair in patients with AS in the neonatal period, many factors were considered. Ninety-two percent of respondents rely on mitral valve z score, 84% on aortic valve z score, 52% on left ventricle length, 48% on the presence of antegrade ascending aorta flow, and only 32% considered significant endocardial fibroelastosis as a factor. Rhodes score was used by 20% of respondents in decision making regarding the approach to management of this subset of AS. This study shows that there is consensus in the management of mild and severe forms of AS. As expected, disagreement is present in the definition, evaluation, and therapy of moderate aortic valve stenosis. There is a tendency for catheter intervention except in the presence of dysplastic aortic valve or moderate to severe aortic regurgitation. There is also disagreement regarding methods used to determine biventricular versus univentricular repair of a borderline hypoplastic left heart.

Heart Rate Variability Following Neonatal Heart Surgery for Complex Congenital Heart Disease

Background: Altered cardiac autonomic control may play a role in the morbidity and mortality suffered by neonates who undergo surgery for complex congenital heart disease (CHD). The purpose of this study was to evaluate cardiac autonomic activity, as measured by spectral indices of heart rate variability (HRV), prior to and early after infant surgery for CHD and attempt to correlate HRV indices with clinical outcome. In addition, we assessed the hypothesis that single‐ventricle physiology and surgical interruption of the great arteries negatively affects HRV.