EASL-ERN position paper on liver involvement in patients with Fontan-type circulation.

Fontan-type surgery is the final step in the sequential palliative surgical treatment of infants born with a univentricular heart. The resulting long-term haemodynamic changes promote liver damage, leading to Fontan-associated liver disease (FALD), in virtually all patients with Fontan circulation. Owing to the lack of a uniform definition of FALD and the competitive risk of other complications developed by Fontan patients, the impact of FALD on the prognosis of these patients is currently debatable. However, based on the increasing number of adult Fontan patients and recent research interest, the European Association for The Study of the Liver and the European Reference Network on Rare Liver Diseases thought a position paper timely. The aims of the current paper are: (1) to provide a clear definition and description of FALD, including clinical, analytical, radiological, haemodynamic, and histological features; (2) to facilitate guidance for staging the liver disease; and (3) to provide evidence- and experience-based recommendations for the management of different clinical scenarios.

Fontan protein-losing enteropathy is associated with advanced liver disease and a proinflammatory intestinal and systemic state.

BACKGROUND AND AIMS: Protein-losing enteropathy (PLE) after Fontan surgery carries significant morbimortality. Its pathophysiology and association with other Fontan complications are poorly understood. Our aims were to examine whether Fontan-PLE is associated with greater liver damage and to assess the presence of systemic and intestinal inflammation. METHODS: Fontan patients with PLE and Fontan controls without PLE matched for age and Fontan surgery procedure were included. Data were prospectively compiled on blood and stool tests, liver imaging, elastography, cardiac-MRI and cardiac catheterization. RESULTS: Twenty-nine Fontan patients were enrolled (14 with PLE and 15 controls without PLE). Patients with PLE had more advanced liver disease estimated by non-invasive methods: blunt liver margins on ultrasonography (71.4% vs 26.7%, P = .027), greater median liver stiffness (25.4 vs 14.5 kPa, P = .003) and higher FIB-4 (P = .016). Portal hypertension-related signs were more common in patients with PLE including ascites (P = .035), larger spleen size (P = .005), oesophageal varices/splanchnic collateral shunts (P = .03), higher liver stiffness-spleen size-to-platelet ratio risk score (P < .001) and lower platelet count (P = .01). Systemic proinflammatory cytokines (TNF-α, interleukin-6), biomarkers of intestinal permeability (intestinal fatty-acid binding protein) and faecal calprotectin concentrations were also significantly increased in Fontan-PLE (P < .05). Faecal calprotectin directly correlated with alpha-1 antitrypsin clearance and inversely with cardiac index, total serum proteins and body mass index. CONCLUSION: Fontan-PLE is associated with advanced liver disease and increased markers of systemic inflammation and intestinal permeability. Faecal calprotectin is elevated and correlates with Fontan-PLE severity. Liver assessment is mandatory in all Fontan patients, and especially in those with PLE.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

Exploring clinical, echocardiographic and molecular biomarkers to predict bronchopulmonary dysplasia.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in childhood, related to prematurity, and the most common cause of pulmonary hypertension (PH) secondary to pulmonary disease in children. Moderate and severe BPD have a worse outcome and relate more frequently with PH. The prediction of moderate or severe BPD development in extremely premature newborns is vital to implement preventive strategies. Starting with the hypothesis that molecular biomarkers were better than clinical and echocardiographic factors, this study aims to explore the ability of clinical, echocardiographic and analytical variables to predict moderate or severe BPD in a cohort of extremely preterm infants. PATIENTS AND METHODS: We designed a prospective longitudinal study, in which we followed a cohort of preterm newborns (gestational age <28 weeks and weight ≤ 1250 grams). In these newborns we recorded weekly clinical and echocardiographic variables as well as blood and tracheal aspirate samples, to analyze molecular biomarkers (IL-6, IL-1, IP10, uric acid, HGF, endothelin-1, VEGF, CCL5). Variables and samples were collected since birth up to week 36 (postmenstrual age), time-point at which the diagnosis of BPD is established. RESULTS: We included 50 patients with a median gestational age of 26 weeks (IQR 25-27) and weight of 871 g (SD 161,0) (range 590-1200g). Three patients were excluded due to an early death. Thirty-five patients (74.5%) developed BPD (mild n = 14, moderate n = 15, severe n = 6). We performed a logistic regression in order to identify risk factors for moderate or severe BPD. We compared two predictive models, one with two variables (mechanical ventilation and inter-ventricular septum flattening), and another-one with an additional molecular biomarker (ET-1). CONCLUSIONS: The combination of clinical and echocardiographic variables is a valuable tool for determining the risk of BPD. We find the two variable model (mechanical ventilation and echocardiographic signs of PH) more practical for clinical and research purposes. Future research on BPD prediction should be oriented to explore the potential role of ET-1.

Preventing bronchopulmonary dysplasia: new tools for an old challenge.

Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease in infants and presents as a consequence of preterm birth. Due to the lack of effective preventive and treatment strategies, BPD currently represents a major therapeutic challenge that requires continued research efforts at the basic, translational, and clinical levels. However, not all very low birth weight premature babies develop BPD, which suggests that in addition to known gestational age and intrauterine and extrauterine risk factors, other unknown factors must be involved in this disease's development. One of the main goals in BPD research is the early prediction of very low birth weight infants who are at risk of developing BPD in order to initiate the adequate preventive strategies. Other benefits of determining the risk of BPD include providing prognostic information and stratifying infants for clinical trial enrollment. In this article, we describe new opportunities to address BPD's complex pathophysiology by identifying prognostic biomarkers and develop novel, complex in vitro human lung models in order to develop effective therapies. These therapies for protecting the immature lung from injury can be developed by taking advantage of recent scientific progress in -omics, 3D organoids, and regenerative medicine.

Pediatrics Spanish Registry of Percutaneous Melody Pulmonary Valve Implantation in Patients Younger Than 18 Years.

INTRODUCTION AND OBJECTIVES: A decade has passed since the first Spanish percutaneous pulmonary Melody valve implant (PPVI) in March 2007. Our objective was to analyze its results in terms of valvular function and possible mid-term follow-up complications. METHODS: Spanish retrospective descriptive multicenter analysis of Melody PPVI in patients < 18 years from the first implant in March 2007 until January 1, 2016. RESULTS: Nine centers were recruited with a total of 81 PPVI in 77 pediatric patients, whose median age and weight were 13.3 years (interquartile range [IQR], 9.9-15.4) and 46kg (IQR, 27-63). The predominant cardiac malformation was tetralogy of Fallot (n = 27). Most of the valves were implanted on conduits, especially bovine xenografts (n = 31). The incidence of intraprocedure and acute complications was 6% and 8%, respectively (there were no periprocedural deaths). The median follow-up time was 2.4 years (IQR, 1.1-4.9). Infective endocarditis (IE) was diagnosed in 4 patients (5.6%), of which 3 required surgical valve explant. During follow-up, the EI-related mortality rate was 1.3%. At 5 years of follow-up, 80% ± 6.9% and 83% ± 6.1% of the patients were free from reintervention and pulmonary valve replacement. CONCLUSIONS: Melody PPVI was safe and effective in pediatric patients with good short- and mid-term follow-up hemodynamic results. The incidence of IE during follow-up was relatively low but was still the main complication.

The economic impact of prematurity and bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is one of the most serious chronic lung diseases in infancy and one of the most important sequels of premature birth (prevalence of 15-50%). Our objective was to estimate the cost of BPD of one preterm baby, with no other major prematurity-related complications, during the first 2 years of life in Spain. Data from the Spanish Ministry of Health regarding costs of diagnosis-related group of preterm birth, hospital admissions and visits, palivizumab administration, and oxygen therapy in the year 2013 were analyzed. In 2013, 2628 preterm babies were born with a weight under 1500 g; 50.9% were males. The need for respiratory support was 2.5% needed only oxygen therapy, 39.5% required conventional mechanical ventilation, and 14.9% required high-frequency ventilation. The incidence of BPD was of 34.9%. The cost of the first 2 years of life of a preterm baby with BPD and no other major prematurity-related complications ranged between 45,049.81 € and 118,760.43 €, in Spain, depending on birth weight and gestational age. If the baby required home oxygen therapy or developed pulmonary hypertension, this cost could add up to 181,742.43 €. CONCLUSION: Prematurity and BPD have an elevated cost, even for public health care systems. This cost will probably increase in the coming years if the incidence and survival of preterm babies keeps rising. The development of new therapies and preventive strategies to decrease the incidence of BPD and other morbidities associated with prematurity should be a priority. What is known: • Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease related with premature birth. • BPD is an increasing disease due to the up-rise in the number of premature births. What is new: • The economic cost of preterm birth and BPD has never before been estimated in Spain nor published with European data. • Preterm babies with BPD and a good clinical outcome carry also an important economic and social burden.

Edwards valve-in-valve implantation in tricuspid position.

We present two cases of percutaneous Sapien XT valve-in-valve implantation in the tricuspid position: a 20-year-old man with severe congenital pulmonary stenosis and percutaneous valvuloplasty, who required surgical implantation of two protheses, pulmonary and tricuspid, and a 12-year-old boy with CHD and a degenerated tricuspid prosthesis. We implanted three Sapien XT valve-in-valves, two in the tricuspid position and one in the pulmonic position. Sapien XT valve-in-valve implantation in the tricuspid position is feasible and can decrease the number of surgeries in CHD patients.

Pulmonary vein stenosis of ex-premature infants with pulmonary hypertension and bronchopulmonary dysplasia, epidemiology, and survival from a multicenter cohort.

BACKGROUND: Pulmonary vein stenosis is emerging as an important clinical problem in ex-premature infants. METHODS: We sought to describe the epidemiology of pulmonary vein stenosis affecting ex-premature infants by a multicenter retrospective cohort study of patients from seven children's hospitals diagnosed between 2000-2014. RESULTS: We identified 39 ex-premature patients (26 males, median gestational age 28 weeks range 22-36 weeks, birth weight 1.1 kg range 433-2645-g) with pulmonary vein stenosis. Median age at diagnosis was 6.5 months (1 month-6 years). Presentation with pulmonary hypertension occurred in 26/39 (67%) and 29/39 (74%) had bronchopulmonary dysplasia, 15 (39%) were born of twin pregnancies with unaffected twin siblings. A median of 5 (range 1-25) echocardiograms was performed prior to diagnosis. The diagnosis was made using echocardiography in 22/39 (56%), by multi-detector contrast computed tomography scan (CT) in 8/39 (21%), cardiac catheterization in 6/39 (15%) patients, magnetic resonance imaging in 3/39 (8%). Freedom from death or re-stenosis was 73% at 1-year, 55% at 2, 5, and 10 years. Factors associated with shorter survival or re-stenosis were stenosis of ≥3 pulmonary veins (P < 0.01), bilateral pulmonary vein stenosis (P < 0.01) small for gestational age (P = 0.05), aged <6 months at diagnosis (P < 0.01). CONCLUSION: Pulmonary vein stenosis of ex-premature infants is a complex problem with poor survival, delayed diagnosis, and unsatisfactory treatment. The lack of concordance in twins suggests epigenetic or environmental factors may play a role in the development of pulmonary vein stenosis. In ex-premature infants with pulmonary hypertension and bronchopulmonary dysplasia a focused echocardiographic assessment of the pulmonary veins is required with further imaging if the echocardiogram is inconclusive.

Repair of congenital heart disease with associated pulmonary hypertension in children: what are the minimal investigative procedures? Consensus statement from the Congenital Heart Disease and Pediatric Task Forces, Pulmonary Vascular Research Institute (PVRI).

Standardization of the diagnostic routine for children with congenital heart disease associated with pulmonary arterial hypertension (PAH-CHD) is crucial, in particular since inappropriate assignment to repair of the cardiac lesions (e.g., surgical repair in patients with elevated pulmonary vascular resistance) may be detrimental and associated with poor outcomes. Thus, members of the Congenital Heart Disease and Pediatric Task Forces of the Pulmonary Vascular Research Institute decided to conduct a survey aimed at collecting expert opinion from different institutions in several countries, covering many aspects of the management of PAH-CHD, from clinical recognition to noninvasive and invasive diagnostic procedures and immediate postoperative support. In privileged communities, the vast majority of children with congenital cardiac shunts are now treated early in life, on the basis of noninvasive diagnostic evaluation, and have an uneventful postoperative course, with no residual PAH. However, a small percentage of patients (older at presentation, with extracardiac syndromes or absence of clinical features of increased pulmonary blood flow, thus suggesting elevated pulmonary vascular resistance) remain at a higher risk of complications and unfavorable outcomes. These patients need a more sophisticated diagnostic approach, including invasive procedures. The authors emphasize that decision making regarding operability is based not only on cardiac catheterization data but also on the complete diagnostic picture, which includes the clinical history, physical examination, and all aspects of noninvasive evaluation.

Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes.

OBJECTIVE: Pulmonary hypertension (PH) worsens the prognosis of bronchopulmonary dysplasia (BPD). The following items have not been fully established for PH in BPD: clinical characterization, incidence of cardiovascular anomalies (CVAs), response to PH treatment, and outcome. STUDY DESIGN: A review of clinical records, computed tomography (CT) images and catheterization data of 36 patients with PH-BPD referred to our PH Unit (March 2006 to December 2011) was performed. Twenty-nine patients without major congenital heart defects and with complete follow-up data were included. RESULTS: The diagnosis of PH was made at a median age of 4.5 months (IQR 2.4-7.8), with an echocardiography estimated median right ventricular pressure/systemic pressure ratio of 70% (IQR 60-80%). CT scanning was performed in 21 patients and catheterization in 14 patients. CVAs were found in 19 patients (65.5%): aortopulmonary collaterals (n = 9), pulmonary vein stenosis (n = 7), ASD (n = 4), and PDA (n = 9). Hemodynamic data: PVRI 4.3 UW m(2) (2.7-7); PVRI/SVRI 0.44 (0.32-0.8); and transpulmonary gradient 28 mmHg (19-40). At a median follow-up of 35 months (IQR 21-91), 6 patients had undergone shunts closure, 22 received specific PH drugs, 3 spontaneously improved of their PH, and 8 (26%) had died. CONCLUSION: PH in BPD is not always a transient condition; it can be diagnosed at later stages and can have a protracted course. The incidence of associated CVAs is high. Prompt diagnosis, detection, and treatment of CVAs, and specific drug therapy can improve the outcome in these patients, although the mortality rate remains high.

Inhaled iloprost as a rescue therapy for transposition of the great arteries with persistent pulmonary hypertension of the newborn.

Transposition of the great arteries (TGA) in the newborn combined with persistent pulmonary hypertension was reported previously to occur in 3-12 % of full-term neonates with TGA. Right-to-left shunting at the ductal level causes severe hypoxemia despite prostaglandin infusion and balloon atrial septostomy. Although the introduction of inhaled nitric oxide (iNO) has improved the prognosis, this condition still is associated with high preoperative mortality. This report describes the case of a newborn with TGA and persistent pulmonary hypertension, which was managed successfully with oral sildenafil, iNO, and inhaled iloprost during life-threatening acute pulmonary hypertension, thus preventing the use of extracorporeal membrane oxygenation.

Clasificación funcional de la hipertensión pulmonar en niños: informe del task force pediátrico del Pulmonary Vascular Research Institute (PVRI), Panamá 2011 / Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011

Los miembros del Task Force pediátrico del Pulmonary Vascular Research Institute (PVRI, su sigla en Inglés) fueron conscientes de la necesidad de desarrollar una clasificación funcional de la hipertensión pulmonar en niños. La clasificación que se propone sigue el mismo patrón y utiliza los mismos criterios de la clasificación de la hipertensión pulmonar específica para adultos de Dana Point. Fue necesario incluir modificaciones para los niños, teniendo en cuenta que la edad, el crecimiento físico y la madurez influyen en la expresión funcional de la enfermedad. Es necesario definir el estado clínico del niño, pues ello facilita revisar la evolución del mismo en una forma consistente y objetiva a medida que él/ella crecen. Particularmente en los niños más jóvenes, se trató de incluir indicadores objetivos como el crecimiento, la necesidad de alimentos suplementarios y los registros de asistencia al colegio y a la guardería. Esto ayuda a monitorear la evolución clínica y la respuesta al tratamiento a través de los años y facilita el desarrollo de algoritmos de tratamiento en estos pacientes. Se presenta un artículo de consenso sobre una clasificación aplicable a los niños con hipertensión pulmonar que se discutió en la reunión anual del PVRI que se llevó a cabo en Panamá en febrero de 2011.

The members of the Pediatric Task Force of the Pulmonary Vascular Research Institute (PVRI) were aware of the need to develop a functional classification of pulmonary hypertension in children. The proposed classification follows the same pattern and uses the same criteria as the Dana Point pulmonary hypertension specific classification for adults. Modifications were necessary for children, since age, physical growth and maturation influences the way in which the functional effects of a disease are expressed. It is essential to encapsulate a child's clinical status, to make it possible to review progress with time as he/she grows up, as consistently and as objectively as possible. Particularly in younger children we sought to include objective indicators such as thriving, need for supplemental feeds and the record of school or nursery attendance. This helps monitor the clinical course of events and response to treatment over the years. It also facilitates the development of treatment algorithms for children. We present a consensus paper on a functional classification system for children with pulmonary hypertension, discussed at the Annual Meeting of the PVRI in Panama City, February 2011.

Consenso sobre la clasificación de la enfermedad vascular pulmonar hipertensiva en niños: reporte del task force pediátrico del Pulmonary Vascular Research Institute (PVRI) Panamá 2011 / A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011

Las clasificaciones actuales de la hipertensión pulmonar han contribuido significativamente al conocimiento de la enfermedad vascular pulmonar, han facilitado ensayos farmacológicos y han mejorado nuestro conocimiento de las cardiopatías congénitas del adulto; sin embargo estas clasificaciones no son aplicables completamente a la enfermedad en el niño. La clasificación que aquí se propone se basa principalmente en la práctica clínica. Los objetivos específicos de esta nueva clasificación son mejorar las estrategias diagnósticas, promover la investigación clínica, mejorar nuestro conocimiento de la patogénesis, de la fisiología y de la epidemiología de la enfermedad y orientar el desarrollo de modelos de la enfermedad humana en el laboratorio y estudios en animales; también puede servir como un recurso docente. Se hace énfasis en los conceptos de maladaptación perinatal, alteraciones del desarrollo e hipoplasia pulmonar como factores causantes de la hipertensión pulmonar pediátrica; así mismo, en la importancia de los múltiples síndromes malformativos congénitos, genéticos y cromosómicos en la presentación de la hipertensión pulmonar pediátrica. La enfermedad vascular pulmonar hipertensiva en niños se divide en diez grandes categorías.

Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories.

[Update on pediatric cardiology and congenital heart disease: imaging techniques, pulmonary arterial hypertension, hybrid treatment, and surgical treatment]. / Actualización en cardiología pediátrica y cardiopatías congénitas: técnicas de imagen, hipertensión arterial pulmonar, tratamientos híbridos y quirúrgicos.

This article contains a review of the most significant contributions to pediatric cardiology and congenital heart disease reported in publications between September 2009 and August 2010. The review focuses on imaging techniques, new treatment for pulmonary arterial hypertension in pediatric patients, and therapy in general (e.g. hybrid treatment and surgical treatment). With regard to imaging techniques, the review highlights the increasing application of congenital heart disease diagnosis during fetal life, the introduction of new echocardiographic techniques (e.g. tissue Doppler imaging, two-dimensional speckle-tracking imaging and three-dimensional echocardiography) into routine clinical practice, and the growing use of cardiac CT and magnetic resonance imaging in diagnosis and the assessment of cardiac function, respectively. The role played by cardiac interventions continues to increase and cardiac surgery is becoming more advanced and has, in some cases, been combined with hybrid techniques. However, there are still a number of controversial issues in cardiac surgery that have not yet been resolved, such as whether or not fenestration should be used with Fontan surgery, the optimum type of correction for hypoplastic left heart syndrome, and the best conduit for pulmonary artery replacement.