Abstract
Address correspondence to Dr. Jeffrey Fineman, UCSF Benioff Children's Hospital, 513 Parnassus Avenue, HSE-1418, Box 1346, San Francisco, California 94143-1346, USA. E-mail:
E Olson, LA Lusk, JR Fineman, LR Robertson, RL Keller
Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, California, USA
Congenital diaphragmatic hernia (CDH) occurs in 1 of 4,000–5,000 live births. Despite advances in the care of these infants, pulmonary hypoplasia and resulting pulmonary hypertension (PH) carry significant morbidity and mortality. Thus, additional therapeutic strategies are needed. The use of continuous treprostinil for chronic pediatric pulmonary hypertensive disorders is increasing. However, its use for acute therapy is limited. We describe two 6-week-old infants with CDH and severe pulmonary hypertension treated with treprostinil. Rapid and dramatic clinical and hemodynamic improvement occurred in both cases. Both infants were weaned off the drug, representing the first reports of successful short-term treprostinil use in neonates with CDH. Case 1 was a female infant born at 37 weeks' gestation, after a pregnancy complicated by late prenatal care, with left-sided, liver-up CDH. Patient underwent an uncomplicated hernia repair of DOL 3. Cardiac echo demonstrated suprasystemic RVp, requiring intubation with iNO. Patient was treated with PGE1 to maintain ductal patency with improvement in respiratory function and echo estimate of RVp. However, at 4 weeks of age, the child's status deteriorated with a PH crises. At 6 weeks of age, cardiac catheterization measured suprasystemic PAp with severely elevated PVR of 13.5 Wood units; minimal PVR was 9.9 with vasodilators. Continuous IV epoprostenol was started, with transition to IV treprostinil after 48 hours. The dose was titrated over the next 4 weeks to a peak dose of 48 ng/kg/min, with minimal side effects. This resulted in significant clinical improvement and a decrease in BNP from 4,080 to 25 pg/mL. At 10 weeks, the patient was weaned off treprostinil, and treprostinil therapy was discontinued 30 days later. The infant was discharged at 5 months of age on bosentan and 0.5 LPM NC oxygen. Repeat cardiac catheterization at 7 months demonstrated a PVR of 3.7 Wood units. At 1-year follow-up, the infant was weaned off both oxygen and bosentan and continues to grow and develop well, with normal pulmonary pressures estimated by echo. Case 2 was a full-term female infant with prenatally diagnosed severe, left-sided, liver-up CDH. Echo on DOL 1 demonstrated suprasystemic RVp and decreased function. Patient underwent hernia repair with internal oblique muscle flap on DOL 2. Infant was supported on HFOV, FiO2 of 100%, 20-ppm iNO, and PGE. Patient was extubated to NCPAP at 2 weeks but continued on iNO, PGE, and milrinone. Repeat echo at 6 weeks was unchanged, with suprasystemic RVp and decreased function. At 6.5 weeks of age, cardiac catheterization measured systemic pulmonary pressures at baseline, with elevated PVR of 7.1 Wood units; minimal PVR was 5.8 with vasodilators. Continuous SC treprostinil was initiated and titrated up over the next 5 weeks to a peak dose of 52 ng/kg/min. This resulted in significant clinical improvement, including a successful weaning off PGE, milrinone, and iNO within 2 weeks. BNP decreased from 143 to 5 pg/mL. Patient was discharged home at 3.5 months of age on 0.5 L/min O2 and SC treprostinil. Bosentan was initiated at 6 months in anticipation of treprostinil weaning, and repeat cardiac catheterization at 8 months of age on room air demonstrated normal pulmonary pressures and a PVR of 4.3 Wood units. Patient was successfully weaned off treprostinil over the next 4 weeks and is maintained on bosentan, with excellent growth and development and normal pulmonary pressures estimated by echo. In conclusion, these 2 cases demonstrate the benefit of short-term treprostinil use initiated at 6–8 weeks of age in neonates with severe PH following CDH repair. These cases are consistent with our prior report demonstrating pulmonary vascular reactivity in infants with CDH at 2–3 months of age. Further, the successful use of SC treprostinil improves the safety of administration of prostacyclins in this vulnerable population, eliminating the need for a central line and its associated risks and allowing for outpatient therapy in a young infant.
BA Coleman, M Calderbank, DD Ivy
Department of Pediatric Cardiology, Children's Hospital Colorado, University of Colorado Denver, Aurora, Colorado, USA
The specific aims of this retrospective study were to evaluate (1) dosing and tolerance of oral treprostinil in patients 10–20 years old with weight > 25 kg and (2) clinical stability of pulmonary arterial hypertension (PAH) with transition from parenteral/inhaled treprostinil to or add-on initiation of oral treprostinil. PAH is an important cause of morbidity and mortality in pediatric patients. Advances in understanding the pathobiology of PAH have led to novel therapies. Administration of drug therapies targeting the prostacyclin pathway have historically been complex, requiring an indwelling central venous line, with risk of line infection and dislodgement, or placement of a subcutaneous catheter, complicated by site pain and skin infections. Inhaled therapies require frequent dosing, with compliance issues. These factors have increased the risk for delivery of prostacyclin therapy as well as affected patients' quality of life. In December 2013, oral treprostinil (UT-15C) received FDA approval as the first orally administered prostacyclin for any disease. We conducted a retrospective chart review of 8 patient initiations (5 IPAH, 3 CHD). All patients were WSPH group I. Patient selection was based on clinician assessment of clinical stability, including WHO FC II–III, 6MWD > 425 m, absence of RV failure, and IV/SQ dose < 125 ng/kg/min. All patients were on background ERA, PDE5i, and/or CCB therapy. Seven patients transitioned from prostacyclin (5 inhaled treprostinil, 1 inhaled iloprost, 1 SQ treprostinil). In 1 patient, UT-15C was added to background therapy. Seven transitions were successful and did not require change in therapy. In 1 patient admitted for SQ-to-oral transition, clinical deterioration occurred during downtitration of SQ therapy and uptitration of UT-15C, resulting in immediate reinitiation of SQ therapy. One patient discontinued UT-15C after 4 months because of recurrent migraines. Six-minute walk distance improved in 4 of the 5 patients with repeat measurement. Most common adverse events (AEs) included headaches (88%), flushing (88%), nausea and vomiting (75%), migraines (25%), heartburn (25%), anorexia (25%), and diarrhea (25%). Most AEs were moderate and transient and improved with slowing uptitration. In conclusion, oral treprostinil was well tolerated in some pediatric PAH patients, with clinical stability or improvement in 75%. Twenty-five percent of patients discontinued UT-15C because of worsening PAH and migraines.
SM White, S Wedgwood, RH Steinhorn
Division of Neonatology, Department of Pediatrics, UC Davis Children's Hospital, University of California at Davis Medical Center, Sacramento, California, USA
Between 25% and 35% of premature infants with moderate-to-severe bronchopulmonary dysplasia (BPD) develop pulmonary hypertension (PH) and right ventricular hypertrophy (RVH), although the underlying mechanisms remain poorly understood. Recent studies identified low birth weight as a predictor of PH in premature infants with BPD, but the potential benefits of nutritional enhancement after birth are unknown. We hypothesized that increased postnatal nutritional intake attenuates oxygen-induced PH in neonatal rats. Sprague-Dawley rat pups were randomized at birth to litters maintained in room air (Air) or 75% oxygen (Hyperoxia), together with litters of normal (10 pups) or enhanced (5 pups) nutritional intake. At day 14, pups were euthanized, and hearts and lungs were isolated for lung inflations or tissue analysis. Inflated lungs were fixed, sectioned, and stained for von Willebrand factor. RVH was determined by calculating the Fulton index (the ratio of the weight of the right ventricle divided by the weight of the left ventricle plus septum). Lung tissue was homogenized and lung protein analyzed by Western blotting. At day 14, Air-Normal, Hyperoxia-Normal, and Hyperoxia-Enhanced pups weighed 29 ± 0.7, 28 ± 0.3, and 34 ± 1.7 g, respectively. In Hyperoxia-Normal versus Air-Normal pups, hyperoxia significantly increased the Fulton index (0.19 ± 0.01 vs. 0.32 ± 0.02), reduced vascular density (27.5 ± 1.6 vs. 14.7 ± 0.7 vessels), increased medial-wall thickness (31.2 ± 1.2 vs. 36.4 ± 1.8), decreased angiogenesis as detected by decreased VEGFR2 protein (63% ± 10% reduction), and increased oxidative stress as detected by increased 3-nitrotyrosine protein (259% ± 82%). Nutritional enhancement in Hyperoxia pups significantly decreased the Fulton index to 0.24 ± 0.02, increased vessel density by 34% ± 8%, normalized VEGFR2 (308% ± 54%), and reduced 3-nitrotyrosine by 32% ± 18% (all compared to Hyperoxia–Normal intake pups). Nutritional enhancement had no effect on medial-wall thickness (36.3 ± 1.9). In conclusion, enhanced postnatal nutritional intake partially protects against oxygen-induced PH in neonatal rats. This may be due in part to increased angiogenesis via VEGF signaling, in addition to decreased oxidative stress. Further studies are warranted to identify the underlying mechanisms. Nutritional intervention may be effective in attenuating the risk of developing PH in premature infants with BPD.
L Guo, S Kumar, J Keis, W Andrea, JY Coe, J Rutledge, I Adatia
Pediatric Cardiology and Cardiac Critical Care, Department of Pediatrics and Anaesthesia, Stollery Children's Hospital and Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada
High inspired oxygen concentration (FiO2), with or without inhaled nitric oxide (iNO), is administered to test pulmonary vasoreactivity in children with pulmonary hypertension (PH). Oxygen consumption (VO2) cannot be measured accurately in FiO2 > 0.8 in routine clinical practice. It is assumed that VO2 is unchanged during hyperoxia. Our preliminary data suggests that VO2 changes substantially in hyperoxia. Carbon dioxide production (V
Presentation of this work at the 8th International Conference on Neonatal and Childhood Pulmonary Vascular Disease was made possible through the generous support of Ikaria Canada's Ambassador Program.
MJ del Cerro,1, P Lopez,2, L Fernandez Garcia-Moya,3, C Labrandero, C Zozaya,2, M Alvarez,1, RM Regojo,3, L Moreno,4, M Ramirez Orellana5
1Pediatric Cardiology, Department of Pediatrics, Ramón y Cajal University Hospital, Madrid, Spain;
2Department of Neonatology, La Paz University Hospital, Madrid, Spain;
3Departments of Genetics, Pediatric Cardiology, and Histopathology, La Paz University Hospital, Madrid, Spain;
4Department of Pharmacology, Faculty of Medicine, Complutense University, Madrid, Spain;
5Department of Haematology, Niño Jesus University Hospital, Madrid, Spain
There is a lack of effective preventative or therapeutic strategy for bronchopulmonary displasia (BPD). Mesenchymal stem cell (MSC) administration has shown the ability to prevent/revert the histological lesions in rodent hyperoxia models of BPD, but only one clinical trial has explored the safety of MSCs in preterm babies. Our objective was to report our experience with MSC compassionate treatment in an infant with severe BPD. We describe the clinical course, temporal profile of serum cytokines and growth factors, and results of histology and molecular cytogenetic study of the lung. The patient was a female baby born at 24+3 weeks GA, birth weight 695 g (p50), by urgent Caesarean section. The clinical course was unfavorable, and at 5 months of age she was still on mechanical ventilation with 100% oxygen and had severe pulmonary hypertension and CT scan evidence of severe parenchymal disease. The parents were offered and agreed to off-label treatment with heterologous, human male bone marrow–derived MSCs. Increasing weekly doses were administered intravenously up to 5 doses. Before each MSC dose, serum expression of VEGF, PDGF, FGF, TGF-β, MEOX2, SHH, GREMLIN-1; adhesion molecules (VCAM-1, ICAM-1); nitric oxide pathway (eNOS, sGC, PDE1, PDE5, PKG); surfactant proteins (SP-A, SP-B, SP-C, SP-D); and inflammatory markers (IL-1β, IL-6, IL-8, IL-10, TGF-β, TNF-α, GM-CSF) were analyzed. The girl died 6 weeks after start of therapy, without showing either clear improvement in the respiratory function or side effects of the MSC administration. Molecular cytogenetic study of the lung ruled out engraftment of the MSCs. In conclusion, the observed profile of inflammation markers, short-term safety, and absence of engraftment following
MSC administration could serve in the design of future trials on MSC therapy for BPD.
D Yung, A Davis, R Stark, P Javid, A Goldin, D Ledbetter
Pediatric Cardiology and Surgery, Seattle Children's Hospital and University of Washington, Seattle, Washington, USA
Pulmonary hypertension (PH) is a leading cause of death in congenital diaphragmatic hernia (CDH) due to abnormal lung development and leads to right heart failure. Unlike other forms of PH in infants, it does not respond as well to inhaled nitric oxide (iNO), and ECMO is frequently used. Prostacyclins are used to treat PH, and subcutaneous (SQ) treprostinil use has been described in infants with bronchopulmonary dysplasia. We hypothesized that SQ treprostinil may be effective for use in infants with CDH and severe PH. We describe 4 infants at our hospital between 2012 and 2014 who underwent CDH repair and had evidence of PH and heart failure on echocardiogram. SQ treprostinil was initiated in consultation with the surgery team as an option instead of progression to ECMO. In conclusion, SQ treprostinil was generally well tolerated, and in all cases, there was no progression to ECMO after initiation. In the future, initiation could be considered earlier.
EC Kirkpatrick,1, M Aggarwal,1, K Tillman,1, M Uhing,1, G Konduri,1, A Szabo2
1Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA;
2Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Very-low-birth-weight (VLBW) infants with bronchopulmonary dysplasia (BPD) are at increased risk of developing pulmonary hypertension (PH). Because PH may develop over time, we hypothesize that a serial echocardiography protocol, along with clinical and lab data, is needed to identify PH. Initial screening echocardiogram, b-type natriuretic peptide (BNP) level, and capillary pCO2 were obtained at 2 months of age in all VLBW infants with BPD (oxygen dependence at 28 days of age). Infants with complex congenital heart disease were excluded. Patients were rescreened if negative every 3 months, or earlier if there were clinical concerns while inpatient and on supplemental oxygen. Echos were considered positive for PH if any of the following were present: tricuspid regurgitation gradient > 30 mmHg, systolic interventricular septal flattening, or RV dilation. Sixty-three infants with 148 total echos were included. PH was found by echo in 19 (30%). Fourteen (73.7%) positive echos were found on initial screening, while 4 (21.1%) were found on the second screening, and 1 was found after 4 screenings. Mean gestational age (GA) was lower in patients with PH (24.8 ± 1.1 vs. 26.1 ± 1.9 weeks; P = 0.007). At the time of each evaluation, PH-positive echos were associated with a need for mechanical ventilation (MV; P = 0.001), a higher median BNP level (47 vs. 15 pg/mL; P = 0.002), higher mean pCO2 (61.7 ± 11.4 vs. 57.3 ± 8.9 mmHg; P = 0.032), and open PDA (P = 0.019). The highest odds ratios for a positive echo include GA < 25 weeks (4.57 [95% CI: 1.45–14.35]), BNP > 50 (3.67 [95% CI: 1.46–9.24]), concurrent MV (3.51 [95% CI: 1.63–7.55]), and PDA (3.2 [95% CI: 1.26–8.12]). BNP values had a low AUC of 0.61 because of high false positives and negatives for predicting PH. In conclusion, serial screening is needed to identify premature-infant PH. Extreme prematurity, elevated BNP, and mechanical ventilation are associated with echo diagnosis of PH, but BNP itself has low predictability.
LO Jorgensen, RW Day
Primary Children's Hospital and the University of Utah, Salt Lake City, Utah, USA
Oral treprostinil was recently approved for the treatment of pulmonary arterial hypertension (PAH). The absorption of treprostinil is affected by food. The medication may also cause gastrointestinal symptoms that may influence appetite. The influence of oral therapy on growth is not known. We sought to determine whether patients experienced a change in body mass index (BMI) during the transition from inhaled to oral treprostinil. Six patients with PAH and a median age of 15 years (7–21 years) were transitioned from inhaled to oral therapy after August 2014. On average, patients were transitioned from an inhaled dose of 172 μg/day to an oral dose of 0.83 mg/ day. There was no overlap in treatment with the inhaled and oral therapies. We tracked BMI from 3–15 months before the onset to 1–7 months after the onset of oral therapy. The dose was increased to 3.5 mg/day after 1–7 months of oral therapy. All patients made the transition without reverting to inhaled therapy or starting parenteral therapy. BMI measurements were 19.3 ± 2.2 kg/m2 3–15 months before, 20.1 ± 2.3 kg/m2 at the onset, and 20.1 ± 2.4 kg/m2 1–7 months after the transition to oral therapy. BMI decreased more than 2 kg/m2 in 1 patient and increased more than 2 kg/m2 in 1 patient. Both patients had similar trends before the onset of oral therapy. Three patients experienced nausea, diarrhea, or loss of appetite. Sudden death occurred in the patient whose BMI decreased more than 2 kg/m2. All patients were pleased with the convenience of oral therapy. In conclusion, collectively, our patients maintained a stable BMI during the early transition from inhaled to oral treprostinil. A substantial decrease in BMI may result from an adverse effect of treatment or progression of disease during therapy.
G Challapudi, DA Hayes, K Sharma, D Gruber, D Patel, I Gershkovich, EK Fiorino, S Epstein
Pediatric Cardiology, Cohen Children's Medical Center of New York, New Hyde Park, New York, USA
Transthoracic echocardiography is the most common noninvasive modality used to assess for pulmonary hypertension (PH) in the pediatric population. This study aimed to compare plasma N-terminal pro-B-type natriuretic peptide (proBNP) levels to echocardiographic pulmonary artery (PA) pressure estimates in infants and young children with suspected PH. This is a retrospective study of patients ≤3 years of age with clinically suspected PH for whom proBNP levels had been obtained. Echocardiograms performed within 4 days of each proBNP measurement were interpreted by a blinded reviewer and were grouped according to PA pressure as estimated by tricuspid regurgitation peak systolic velocity or interventricular septal configuration (group 1: less than half systemic, group 2: half systemic to systemic, group 3: suprasystemic). Forty-four subjects (20 male) with a total of 76 paired proBNP values and echocardiograms were identified. Primary diagnoses included prematurity/bronchopulmonary dysplasia (n = 31), persistent pulmonary hypertension of the newborn (n = 7), congenital diaphragmatic hernia (n = 1), and others (n = 5). The number of proBNP values obtained in each group were 32 for group 1, 22 for group 2, and 22 for group 3. Median proBNP was 689 pg/mL (range: 66–6,767) in group 1, 2,055 pg/mL (394–26,290) in group 2, and 6,024 pg/mL (506–36,524) in group 3. Group 3 had significantly higher proBNP levels than groups 1 (P < 0.001) and 2 (P = 0.006), and group 2 had significantly higher proBNP levels than group 1 (P < 0.001). A proBNP value less than 568 pg/mL identifies subjects with less than half systemic-level PA pressure estimates (sensitivity: 91%, specificity: 44%). Increasing the cutoff value to 935 pg/mL changes sensitivity and specificity to 86% and 75%, respectively. In conclusion, higher proBNP levels are associated with higher echocardiographic estimates of PA pressure in infants and young children with suspected PH. ProBNP may serve as a useful adjunctive screening tool in this population.
Dominique D. Bailey, Jennifer Duchon, Christiana R. Farkouh-Karoleski, Usha Krishnan
Departments of General Pediatrics, Pediatric Infectious Disease, Neonatology and Perinatology, and Pediatric Cardiology, Columbia University Medical Center, New York, New York, USA
Pulmonary vein stenosis (PVS) is a rare and often lethal condition. Recent research suggests that PVS may develop postnatally and may be due to the expansion of the pulmonary venous intima, with progressive occlusion of the vessel lumen. Prematurity and associated inflammatory disease states mediated by VEGF, such as ROP and CLD, are possible risk factors for the development of PVS. In a prior case series from our institution, 50% of infants with PVS had necrotizing enterocolitis (NEC). Our objective was to investigate the relationship and risk factors associated with PVS, particularly gastrointestinal (GI) pathology in premature infants. We performed a case-control study, matched by gestational age, at our institution from January 2006 to July 2013. Cases were selected by review of existing pediatric cardiology service logs with a diagnosis of PVS. Control infants were selected from a cohort of infants in our institution collected under the auspices of a prior NIH-funded, IRB-approved study. PVS was diagnosed by echocardiogram or cardiac catheterization. Charts were reviewed for documentation of inflammatory disease states, including NEC, ROP, CLD, and GI pathology. GI pathology was defined as congenital anomalies (e.g., tracheoesophageal fistula, gastroschisis, omphalocele, intestinal atresias, diaphragmatic hernia) or NEC. Infants were considered to have NEC if they fulfilled the National Healthcare Safety Network definition. Candidate variables were explored by bivariate logistic regression. Variables with P values < 0.05 were entered into a multivariable logistic regression model. Twenty-four cases of PVS and 66 controls were identified. Mean GA of the cohort was 29.3 weeks. Birth weights did not differ between groups. On bivariate analysis, pulmonary hypertension (PHTN; P < 0.001; OR: 3.2 [CI: 1.95–5.2]), maximum C-reactive protein (P = 0.0038; OR: 1.011 [CI: 1.004–1.019]), GI pathology (P < 0.001; OR: 12 [CI: 3.9–37.1]), and CLD (P = 0.0049; OR: 4.47 [CI: 1.7–13.4]) were each significantly associated with PVS. On multivariable analysis including ROP, CLD, PHTN, and GI pathology, GI pathology remained the only predictor significantly associated with PVS (P = 0.0075; OR: 32.8 [CI: 2.6–424.8]). In conclusion, GI pathology in premature infants is a strong predictor of PVS. All premature infants who experience GI pathology should be screened and monitored for the development of PVS.
JK Harrington, Z Jin, C Mardy, S Kobsa, MT Lee, U Krishnan
Divisions of Pediatric Cardiology and Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, New York, USA
Cardiac abnormalities in sickle cell disease (SCD) begin in childhood. Certain abnormalities, such as the development of pulmonary hypertension (PH), are associated with increased mortality. Longitudinal studies investigating serial changes in echocardiographic parameters in children are lacking, and practice guidelines are unclear as to when screening should begin. Our objective was to determine when children with SCD develop cardiac abnormalities. A retrospective analysis of serial echocardiograms on pediatric patients with SCD followed at our institution was performed. Left heart parameters included left ventricular end-systolic (LVES) and end-diastolic (LVED) diameters, fractional shortening (LVFS), and mass (LVM). Right ventricular pressure was estimated by tricuspid regurgitation gradient (TR). LVFS < 32%, TR ≥ 25 mmHg, and a z score ≥ 2 for LV parameters were considered abnormal. GEE methods were used to examine associations with age, oxygen saturation (O2), hemoglobin (Hgb), white blood cell count (WBC), platelet count (Plt), total bilirubin (Tbili), and treatment with hydroxyurea (HU). There were 938 outpatient echocardiograms analyzed for 185 patients (53% male, 69.2% HgbSS). Mean age at first echocardiogram was 6.93 ± 4.59 years, with an average of 5.07 ± 3.32 studies performed per patient over 6.44 ± 5.23 years. Kaplan-Meier analysis showed that by age 5, 4.5%, 11.1%, 12.2%, and 5.1% had abnormal LVM, LVES, LVED, and LVFS, respectively, but only 1.5% had abnormal TR. At ages 16.8, 12.3, 19.9, and 18.7 years, half of the patients had abnormal values for LVES, LVED, LVFS, and TR, respectively. Age, WBC, Plt, and Tbili were positively, while Hgb, O2,, and HU were negatively associated with cardiac abnormalities. In conclusion, cardiac abnormalities begin early in childhood and progressively increase with age, with PH occurring later than LV changes. Early screening could enable intervention with SCD-directed treatment, such as HU therapy, to prevent progression of cardiac abnormalities.
DA Hayes
Pediatric Cardiology, Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, New York, USA
Sildenafil is a phosphodiesterase-5 inhibitor used off-label in pediatric pulmonary hypertension (PH). In critically ill infants with suboptimal absorption of enteral medications or intolerance of the acute systemic vasodilatory effects of bolus intravenous (IV) sildenafil, a continuous infusion is a possible alternative. We describe a single-center experience with continuous IV sildenafil in infants with PH. This is a retrospective study of infants less than 6 months old who received continuous IV sildenafil for PH from 2011 to 2015. Twenty subjects (9 male) were identified. Primary diagnoses included meconium aspiration (n = 11), prematurity/bronchopulmonary dysplasia (n = 3), congenital diaphragmatic hernia (n = 2), congenital heart disease (n = 2; transitional atrioventricular canal defect and aortic coarctation), omphalocele with pulmonary hypoplasia (n = 1), and viral bronchiolitis (n = 1). Median age at diagnosis was 0 days (range: 0–171). Eleven subjects required extracorporeal membrane oxygenation (ECMO); 1 started sildenafil before cannulation, 7 during ECMO support, and 3 after decannulation. Median dose was 1.6 mg/kg/day (1.2–1.6), and 6 subjects received a 0.4-mg/kg IV loading dose. Median length of infusion was 5 days (1–92). Side effects included hypotension (n = 4, none of whom had received a loading dose) and hypoxia from ventilation-perfusion mismatch (n = 1). Two of these required discontinuation. All subjects were concomitantly treated with inhaled nitric oxide; some also received inhaled iloprost (n = 5) and/or IV epoprostenol (n = 4). Five subjects died during hospitalization. After recovery, 11 survivors were transitioned to oral sildenafil and 2 stopped treatment. There were no late deaths at a median follow-up duration of 14.9 months (0.2–43.1). In conclusion, continuous IV sildenafil is a feasible alternative to enteral or intermittent IV dosing in the critically ill infant with PH. Further studies of safety and efficacy are warranted. As with all systemically administered pulmonary vasodilators, careful monitoring for hypotension and worsening hypoxemia is imperative.
L Mahgoub,1, T Kaddoura,2, A Kakadekar,3, F Dicke,4, Paloma Lopez Ortego,5, R Kameny,6, Maria Jesus del Cerro,7, J Fineman,6, A Redington,8, I Adatia1
1Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada;
2Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada;
3Department of Pediatrics, Royal University Hospital, Saskatoon, Saskatchewan, Canada;
4Department of Pediatrics, Alberta Children's Hospital, Calgary, Alberta, Canada;
5Department of Neonatology, La Paz University Hospital, Madrid, Spain;
6Department of Pediatrics, University of California San Francisco Children's Hospital, San Francisco, California, USA;
7Department of Pediatrics, University Hospital Ramón y Cajal, Madrid, Spain;
8Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
We sought to investigate the hypothesis that premature birth may be associated with pulmonary vein stenosis (PVS). We undertook a retrospective multicenter cohort study of patients born prematurely and diagnosed with PVS between 2000 and 2014. We excluded total anomalous pulmonary venous drainage, heterotaxy, or gestational age ≥ 37 weeks. We identified 39 patients: 67% were male, median gestational age was 28 weeks (range: 22–36 weeks), and mean birth weight was 1.1 kg (433–2,645 g). Fifteen patients (38%) were one of twins whose twin siblings were unaffected. At diagnosis, 72% had developed chronic lung disease (CLD) and 51% were discharged on home oxygen. History of PDA ligation was present in 31% of patients and necrotizing enterocolitis in 23%. Eighty-two percent of patients underwent echocardiography in the neonatal period without diagnosis of PVS. Median age at PVS diagnosis was 6.5 months (1 month–6 years). Evaluation for pulmonary hypertension in 67% of patients led to a diagnosis of PVS. In 23% of patients, PVS was found incidentally. PVS was diagnosed by echocardiography in 56% of patients and by contrast CT–angiography, MRI, or cardiac catheterization in 44%. Unilateral PVS was found in 64% of patients, and 88% of these had a left-side involvement. Management included surgery in 46%, supportive therapies in 44%, and a palliative approach in 10% of patients. Freedom from death or restenosis for all patients was 73% at 1 year and 55% at 2, 5, and 10 years. PVS diagnosed before 6 months was associated with shorter survival. In conclusion, PVS in infants who were born prematurely may be unapparent at birth, associated with pulmonary hypertension, CLD, and O2 dependency, and often overlooked by routine echocardiogram. There is a male predisposition and a predilection for left-sided veins. The occurrence of PVS in one twin suggests that epigenetic factors may be important in the postnatal development or worsening of PVS.
KN Goss,1, RS Tepper,2, T Lahm2
1University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA;
2Indiana University School of Medicine, Indianapolis, Indiana, USA
Premature birth affects 10%–12% of infants, with increasing severity of prematurity associated with an increased risk for development of chronic lung disease, pulmonary hypertension (PH), and right ventricular dysfunction in the neonatal period. Whether these infants remain at risk for persistence of PH into adulthood or whether they are at higher risk for redevelopment of PH later in life remains unknown. Adults aged 18–60 years with a diagnosis of PH were recruited from Indiana University (IU) pulmonary clinics or during attendance at the 2014 Pulmonary Hypertension Association (PHA) Conference and asked to complete a brief survey regarding their personal history of preterm birth. For the IU cohort, baseline characteristics, including demographics, classification of PH, hemodynamics, and functional status, were obtained from their medical records. A total of 225 patients were surveyed (n = 166 from IU and n = 59 from the PHA conference). When asked if born 4 or more weeks premature, 80.8% responded “no” (n = 80), 10.1% responded “unsure” (n = 10), and 9.1% responded “yes” (n = 9). Self-reported gestational age at birth was 32–36 weeks in preterm subjects (mean: 33.9 weeks). Distribution of WHO PH groups was similar among those with and without a history of prematurity, with group I PH accounting for 83% of term subjects and 77.8% of preterm subjects. In the IU cohort, baseline hemodynamics by right heart catheterization, functional status, 6-minute walk distance, and brain natriuretic peptide levels were similar between term- and preterm-born adults. In conclusion, in this medium-sized cohort of PH patients, a history of mild prematurity was encountered at a rate similar to that in the general population, suggesting that mild prematurity does not predispose to PH development later in life. Additional prospective studies are needed to determine the long-term risk for developing PH in adults with a history of moderate or severe prematurity.
Jennifer E. Tingo, Erika B. Rosenzweig, Usha Krishnan
Columbia University Medical Center, New York, New York, USA
Portopulmonary hypertension (PoPH) is defined by the combination of portal hypertension and precapillary pulmonary hypertension (mPAP ≥ 25 mmHg, PCWP < 15 mmHg, and PVR > 3 Wood units). Very little is known about this process in pediatric patients, but the prognosis is generally poor. In order to increase the knowledge of this diagnosis in pediatrics and allow further characterization of presentation, pathophysiology, prognosis, and potential therapeutic measures, we reviewed our institutional experience with PoPH in pediatric patients. We report 5 patients with a diagnosis of PoPH treated at the Pulmonary Hypertension Center at Columbia University Medical Center. A retrospective chart review of these patients was conducted. Data including demographics, clinical characteristics, cardiac and hepatic function indices, and management strategies were collected. Five children, 3 female and 2 male, were identified with PoPH. The median age of diagnosis of portal hypertension was 6 years (8 months–9 years) and that of pulmonary hypertension was 1.4 years (10 months–8 years). One patient had a history of congenital heart disease. The hepatic diagnoses included portocaval shunts, biliary hypoplasia with cirrhosis, and portal vein thrombosis. Two patients presented with chest pain and syncope. The diagnosis of pulmonary hypertension was made by echocardiogram in all patients, 4 of whom also had cardiac catheterization. The median mean PA pressure was 46 mmHg (range: 45–90), with a median PVRi of 9 WU m2 (range: 6–56). All were AVT nonresponsive. All patients received targeted therapies, with 2 on IV prostanoids. Of the 3 patients who died, timing from the diagnosis of PoPH to death ranged from 3 days to 3 years. In conclusion, PoPH is a disorder with significant mortality in childhood. Based on our limited experience, disease progression can be rapid. Clinical symptoms are subtle, and the majority of patients had severe disease at diagnosis with variable response to treatment. There is no widely accepted screening for pulmonary hypertension in children with portal hypertension. In pediatric patients with liver disease and unexplained cardiorespiratory symptoms, screening for pulmonary hypertension should be performed. Further study of these patients is warranted to determine whether routine screening should be performed.
Rebecca Johnson Kameny, Michael Johengen, Gary W. Raff, Sanjeev Datar, Jeffrey Fineman
Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, USA
MicroRNAs (miR/miRNA) are small, noncoding, single-stranded RNAs that pair with mRNA to negatively regulate gene expression through degradation or suppression of translation. The role of miRNA in cardiovascular disease is increasingly appreciated, including cardiac development, remodeling, and hypertrophy and heart failure. In our ovine model of congenital heart disease with a fetally implanted aortopulmonary shunt and increased pulmonary blood flow, we have demonstrated a novel adaptive right ventricular (RV) response to increased afterload, along with global cardiac hypertrophy, which may be due to preservation of the fetal phenotype. We hypothesized that shunt RV would have an miRNA expression pattern distinct from control but similar to fetal RV and that miRNA gene regulation contributes to the adaptive shunt RV phenotype. Late-gestation fetal lambs (n = 5) underwent placement of an aortopulmonary vascular graft (shunt). Four weeks after delivery, RV tissue was harvested from shunt and twin controls. Fetal RV tissue was obtained from late-gestation lambs. The miRNA expression levels were determined by quantitative PCR, and screening for downstream targets used RNA sequencing (n = 3 for RNA seq.). Of the 93 miRNA targets analyzed in control, shunt, and fetal RV tissue, 57 miRs were significantly different from control in either shunt or fetal RV or both. Of these 57, 14 targets were similarly up- or downregulated in shunt and fetal RV, compared to control. Eleven were upregulated in both: miRs 18a-5p, 25-3p, 30a-5p, 99b-5p, 106b-5p, 127-3p, 210-3p, 379-5p, 382-5p, 543, and 664-3p. Three were downregulated in both: miRs 199b-5p, 208a-3p, and 378a-3p. For these 14 miRs, we then utilized RNA sequencing as a screen for known downstream targets of miR regulation. There were significant changes in mRNA targets of miR 18a-5p, 25-3p, 30a-5p, 106b-5p, 210-3p, 199b-5p, 208a-3p, and 378a-3p in shunt RV, compared to control. Further, these downstream genes are potentially involved in adaptive hypertrophy mechanisms, as they target physiologic hypertrophy, angiogenesis, cardiac fibrosis, and ROS scavenging. In conclusion, the molecular and biochemical mechanisms underlying adaptive RV hypertrophy, as distinct from pathologic hypertrophy and failure, are incompletely elucidated. These preliminary data suggest that miRNA expression patterns in the RV of fetal and shunt lambs may confer an adaptive phenotype through downstream gene regulation. If validated, pharmacologic targeting of miRNA is a tantalizing potential target for therapeutic intervention in congenital heart disease and pulmonary hypertension.
S Kumar,1, P Bobhate,1, L Guo,1, J Trines,1, M Elgendi,2, T Kaddoura,2, S Jain,1, B Goot,1, T Colen,1, N Khoo,1, I Adatia1
1Stollery Children's Hospital, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada;
2Department of Computing Science, University of Alberta, Edmonton, Alberta, Canada
We sought to investigate the influence of right atrial (RA) active emptying fraction (RA EaF) on survival in childhood pulmonary arterial hypertension (PAH). Children with PAH (mean PA pressure [mPAp] ≥ 25 mmHg, wedge pressure < 15 mmHg) undergoing cardiac catheterization between 2009 and 2014 were studied. RA and right ventricular (RV) endocardial areas indexed to BSA were traced in the apical 4-chamber view. We measured RA area at end-systole (RAA max), at the onset of the P wave (RAA p), and at end-diastole (RAA min). We calculated the following: right atrial fractional area change (RAFAC) from [(RAA max – RAA min)/RAA max] × 100, active RA emptying area (RA Ea) from RAA p – RAA min, and RA EaF from (RA Ea/RAFAC) × 100. Time to clinical worsening was calculated from diagnosis to initiation of prostanoid therapy, transplant, or death. We studied 31 children (16 females), with mean age 6.7 ± 5.6 years and mean BSA 0.83 ± 0.45 m2. Median follow-up was 1.9 years (range: 0.1–6.1). Median event-free survival was 1.2 years (range: 0.01–5.5), with 12 events due to worsening of PAH (10 patients started on prostanoid, 3 deaths, 1 transplant). RA EaF ≥ 56% predicted worse diagnostic hemodynamics (mPAp: 65 ± 22 vs. 42 ± 18 mmHg [P = 0.004], PVRI: 16.8 ± 8 vs. 9.9 ± 6.3 WU · m2 [P = 0.01]) and significant clinical worsening in 10 of 19 patients (53%), compared to RA EaF < 56% (2/12 [17%], P = 0.03). A higher dependency on RA EaF at diagnosis predicted 5-year clinical worsening (sensitivity: 83%, specificity: 53%). RVFAC < 25% predicted 5-year clinical worsening with 67% sensitivity and 68% specificity, and combining the variables predicted clinical worsening with 80% sensitivity and 91% specificity. In conclusion, increased reliance on active RA emptying is associated with clinical worsening in childhood PAH. RA EaF supplements RVFAC in predicting clinical worsening.
Presentation of this work at the 8th International Conference on Neonatal and Childhood Pulmonary Vascular Disease was made possible through the generous support of Ikaria Canada's Ambassador Program.
Mohamed Elgendi, Shine Kumar, Prashant Bobhate, Shreepal Jain, Long Guo, Jennifer Rutledge, Yashu Coe, Roger Zemp, Dale Schuurmans, Ian Adatia
Departments of Pediatrics, Computing Science, and Biomedical Engineering, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
We hypothesized that vibrations created by the pulmonary circulation would create sound, like the vocal cords during speech, and that subjects with pulmonary artery hypertension (PAH) might have a unique sound signature. We recorded heart sounds at the cardiac apex and second left intercostal space (LICS), using a digital stethoscope, from 27 subjects (12 males) with a median age of 7 years (range: 3 months–19 years) undergoing simultaneous cardiac catheterization. Thirteen subjects had a mean pulmonary artery pressure (mPAP) < 25 mmHg (range: 8–24 mmHg). Fourteen subjects had mPAP ≥ 25 mmHg (range: 25–97 mmHg). We extracted the relative power of the frequency band, the entropy, and the energy of the sinusoid formants from the heart sounds. We applied linear discriminant analysis with leave-one-out cross validation to differentiate children with and without PAH. The significance of the results was determined using a t test and a rank-sum test. The entropy of the first sinusoid formant contained within an optimized window length of 2 seconds of the heart sounds recorded at the second LICS was decreased significantly in subjects with mPAP ≥ 25 mmHg versus subjects with mPAP < 25 mmHg, with a sensitivity of 93% and a specificity of 92%. In conclusion, the reduced entropy of the first sinusoid formant of the heart sounds in children with PAH suggested the existence of an organized pattern. The analysis of this pattern revealed a unique sound signature that could be applied to a noninvasive method to diagnose PAH.
Presentation of this work at the 8th International Conference on Neonatal and Childhood Pulmonary Vascular Disease was made possible through the generous support of Ikaria Canada's Ambassador Program.
T Kaddoura,1, S Kumar,2, L Guo,2, D Kim,3, D Taylor,3, W Tymchak,3, D Schuurmans,4, R Zemp,1, I Adatia2
1Department of Electrical and Computer Engineering, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada;
2Stollery Children's Hospital, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada;
3Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada;
4Department of Computing Science, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
We sought to use speech recognition algorithms to distinguish between S2 in subjects with and without pulmonary hypertension (PH). We recorded simultaneously the heart sounds, electrocardiogram (EKG), and pulmonary artery (PA) pressure, using the Zargis Signal X system (Princeton, NJ). PH was defined by a mean pulmonary artery pressure (mPAp) ≥ 25 mmHg. We identified S2 by locating the loudest signal in a window (composed of 30% of the cardiac cycle) around the T wave on the simultaneously recorded EKG. We used the Matlab (2014b, Mathworks, Natick, MA) programming environment for signal analysis, optimization, and training of an acoustic model for PH and non-PH based on Mel-frequency cepstral coefficients. The developed acoustic models were tested against the remaining subjects using negative log-likelihood classification. One hundred twenty-nine patients (68 female) with a median age of 47 years (range: 0.27–86) and median body surface area 1.73 m2 met inclusion criteria. Of these, 125 subjects had recordings of sufficient quality for analysis. Sixty-eight of the 125 subjects had PH (mPAp: 37 mmHg, range: 25–66), and 57/125 had normal mPAp (16 mmHg; range: 9–24 [P < 0.001]). There was no difference in mPAp between the training and testing groups with PH (n = 34, mPAp: 38 mmHg, range: 25–66 vs. n = 34, mPAp: 41 mmHg, range: 25–63 [P = 0.1]) and without PH (n = 30, mPAp: 16 mmHg, range: 9–24 vs. n = 31, mPAp: 16 mmHg, range: 9–24 [P = 0.4]). The speech recognition algorithm correctly classified 78% of patients as PH or non-PH, with a false-negative rate of 18% and a false-positive rate of 24%. In conclusion, the results suggest that speech recognition algorithms based on S2 may differentiate subjects with and without PH. The false-negative rate is concerning, but we hope to further improve it with a bigger sample size.
Presentation of this work at the 8th International Conference on Neonatal and Childhood Pulmonary Vascular Disease was made possible through the generous support of Ikaria Canada's Ambassador Program.