The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking. METHODS AND ANALYSIS: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses. ETHICS AND DISSEMINATION: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained. TRIAL REGISTRATION NUMBER: NTR6982; Pre-results

Recirculation during veno-venous extra-corporeal membrane oxygenation - a simulation study

Purpose: Veno-venous ECMO is indicated in reversible life-threatening respiratory failure without life-threatening circulatory failure. Recirculation of oxygenated blood in the ECMO circuit decreases efficiency of patient oxygen delivery but is difficult to measure. We seek to identify and quantify some of the factors responsible for recirculation in a simulation model and compare with clinical data. Methods: A closed-loop real-time simulation model of the cardiovascular system has been developed. ECMO is simulated with a fixed flow pump 0 to 5 l/min with various cannulation sites -1) right atrium to inferior vena cava, 2) inferior vena cava to right atrium, and 3) superior+ inferior vena cava to right atrium. Simulations are compared to data from a retrospective cohort of 11 consecutive adult veno-venous ECMO patients in our department. Results: Recirculation increases with increasing ECMO-flow, decreases with increasing cardiac output, and is highly dependent on choice of cannulation sites. A more peripheral drainage site decreases recirculation substantially. Conclusions: Simulations suggest that recirculation is a significant clinical problem in veno-venous ECMO in agreement with clinical data. Due to the difficulties in measuring recirculation and interpretation of the venous oxygen saturation in the ECMO drainage blood, flow settings and cannula positioning should rather be optimized with help of arterial oxygenation parameters. Simulation may be useful in quantification and understanding of recirculation in VV-ECMO

Identification of protein biomarkers associated with congenital diaphragmatic hernia in human amniotic fluid

Abstract Congenital diaphragmatic hernia (CDH) is a severe birth defect frequently associated with pulmonary hypoplasia, pulmonary hypertension, and heart failure. Since amniotic fluid comprises proteins of both fetal and maternal origin, its analysis could provide insights on mechanisms underlying CDH and provide biomarkers for early diagnosis, severity of pulmonary changes and treatment response. The study objective was to identify proteomic changes in amniotic fluid consistently associated with CDH. Amniotic fluid was obtained at term (37–39 weeks) from women with normal pregnancies (n = 5) or carrying fetuses with CDH (n = 5). After immuno-depletion of the highest abundance proteins, off-line fractionation and high-resolution tandem mass spectrometry were performed and quantitative differences between the proteomes of the groups were determined. Of 1036 proteins identified, 218 were differentially abundant. Bioinformatics analysis showed significant changes in GP6 signaling, in the MSP–RON signaling in macrophages pathway and in networks associated with cardiovascular system development and function, connective tissue disorders and dermatological conditions. Differences in selected proteins, namely pulmonary surfactant protein B, osteopontin, kallikrein 5 and galectin-3 were validated by orthogonal testing using ELISA in larger cohorts and showed statistically significant differences aiding in the diagnosis and prediction of CDH. The findings provide potential tools for clinical management of CDH

Ready for Transfer to Adult Care? A Triadic Evaluation of Transition Readiness in Adolescents With Congenital Heart Disease and Their Parents

Transfer to adult care for adolescents with chronic conditions ought to be determined by transition readiness. The aims of this study were (a) to describe the level of readiness for transition in adolescents with congenital heart disease, (b) to compare adolescents' assessment of transition readiness with their parents' assessments, and (c) to study potential correlates of transition readiness. A total of 157 triads of adolescents aged 14 to 18 years and their parents completed the Readiness for Transition Questionnaire. Adolescents scored higher on overall readiness than their parents. Multivariable analyses revealed that higher levels of adolescents' overall readiness were associated with a less threatening view of the illness, a higher level of empowerment, and with higher mothers' and fathers' overall readiness scores. Adolescents' responsibility scores were positively associated with age and parental adolescent responsibility scores. Parental involvement scores were negatively associated with adolescents' age and positively with the mothers' parental involvement scores. By using a triadic evaluation, the results of the present study significantly extend what is currently known about this population.status: publishe

Parental uncertainty about transferring their adolescent with congenital heart disease to adult care

AIMS: To study parent's levels of uncertainty related to the transfer from pediatric to adult care in adolescents with congenital heart disease (CHD) and to identify potentially correlating factors. BACKGROUND: Parents acknowledge that during transition they struggle with finding ways of feeling secure in handing over the responsibility and letting go of control. Well-prepared and informed parents who feel secure are most likely better skilled to support their adolescent and to hand over the responsibility. DESIGN: A cross-sectional study. METHODS: Overall, 351 parents were included (35% response rate). Parental uncertainty was assessed using a Linear Analogue Scale (0-100). Data were collected between January - August 2016. Potential correlates were assessed using the readiness for transition questionnaire and sociodemographic data. RESULTS: The mean parental uncertainty score was 42.5. Twenty-four percent of the parents had a very low level of uncertainty (score 0-10) and 7% had a very high level (score 91-100). Overall, 26% of the mothers and 36% of the fathers indicated that they had not started thinking of the transfer yet. The level of uncertainty was negatively associated with the level of perceived overall readiness. Adolescents' age, sex, CHD complexity, and parental age were not related to uncertainty. CONCLUSION: A wide range in the levels of uncertainty was found. Parents who were less involved in the care, or perceived their adolescent as readier for the transition, felt less uncertain. Still, thirty percent of the parents had not started to think about the transfer to adult care.status: publishe

Congenital diaphragmatic hernia in Scandinavia from 1995 to 1998: Predictors of mortality.

BACKGROUND/PURPOSE: There is a lack of large contemporary studies on the management of congenital diaphragmatic hernia (CDH), and the prediction of mortality remains difficult. The aim of this study was to investigate the influence of perinatal factors on mortality rate in a contemporary multicenter study. METHODS: The authors conducted a retrospective multicenter cohort study. Twelve of 13 Scandinavian pediatric surgical centers participated in the study. During a 4-year period (1995 through 1998) 195 children with CDH were included. The main endpoints were hospital mortality rate and total mortality rate (before 2001). Bivariate and multivariate survival analyses were performed using Kaplan-Meier plots, Log-rank test, and Cox regression. RESULTS: Overall hospital mortality rate was 30%. Among 168 neonates with symptoms within 24 hours (early presenters) 35% died before discharge. All 61 deaths occurred in 157 neonates with symptoms within the first 2 hours of life. Among early presenters, 27% had prenatal ultrasound diagnosis, 26% were delivered by cesarean section, and 21% had associated major malformations. Bivariate analysis of early presenters showed increased risk of death in neonates with prenatal diagnosis, associated anomalies, right-sided diaphragmatic hernia (RCDH), low 1-minute and 5-minute Apgar scores, low birth weight, short gestational age, and cesarean delivery. Neonates with prenatal diagnosis were characterized by significantly lower Apgar scores, lower birth weight, and increased frequency of associated anomalies than those diagnosed after birth. Multivariate analysis found that prenatal diagnosis (P =.004), 1-minute Apgar (P =.001), and RCDH (P =.042) were independent predictors of total mortality rate. CONCLUSIONS: In a series of 195 CDH patients, all 61 deaths occurred in the 157 neonates presenting with symptoms within the first 2 hours of life. Prenatal diagnosis, 1-minute Apgar score, and RCDH were significant independent predictors of total mortality. J Pediatr Surg 37:1269-1275. Copyright 2002, Elsevier Science (USA). All rights reserved

In-Hospital Neurologic Complications in Adult Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation

Objevtives: To elucidate the epidemiology, complication profiles, hospital outcome, and predisposing factors of CNS complications occurring during venoarterial extracorporeal membrane oxygenation in adults. Design: Retrospective analysis of the Extracorporeal Life Support Organization registry. Setting: Data reported to Extracorporeal Life Support Organization by 230 extracorporeal membrane oxygenation centers from 1992 to 2013. Patients: Patients more than 16 years old supported with a singlerun of venoarterial extracorporeal membrane oxygenation. Interventions: None. Measurements and Main Results: We examined 4,522 adult patients supported with venoarterial extracorporeal membrane oxygenation and included in the Extracorporeal Life Support Organization registry. Venoarterial extracorporeal membrane oxygenation was used for cardiac dysfunction in 3,005 patients (66.5%), cardiopulmonary resuscitation in 877 patients (19.4%), and respiratory failure in 640 patients (14.1%), respectively. Multivariate logistic regression was performed to identify factors independently associated with CNS injury. Neurologic complications occurred in 682 patients (15.1%), and included brain death in 358 patients (7.9%), cerebral infarction in 161 patients (3.6%), seizures in 83 patients (1.8%), and cerebral hemorrhage in 80 patients (1.8%). Multiple CNS complications in the same patient occurred in 70 cases. Hospital mortality in patients with CNS complications was 89%, compared with 57% in patients without (p < 0.001). In a multivariable model, age, pre-extracorporeal membrane oxygenation cardiac arrest, the use of inotropes on extracorporeal membrane oxygenation, and post-extracorporeal membrane oxygenation hypoglycemia were shown to be associated with CNS complications. Conclusions: Neurologic complications in adult patients on venoarterial extracorporeal membrane oxygenation support are common and associated with poor survival. Further research should focus on better understanding and management of brain/extracorporeal membrane oxygenation interaction to avoid such catastrophic complications

Neurologic injury in adults supported with veno-venous extracorporeal membrane oxygenation for respiratory failure: Findings from the extracorporeal life support organization database

Objectives: To assess in-hospital neurologic (CNS) complications in adult patients undergoing veno-venous extracorporeal membrane oxygenation for respiratory failure. Design: Retrospective analysis of the Extracorporeal Life Support Organization's data registry. Setting: Data reported to Extracorporeal Life Support Organization from 350 international extracorporeal membrane oxygenation centers during 1992-2015. Patients: Adults (>= 18 yr old) supported with veno-venous extracorporeal membrane oxygenation for respiratory failure. Interventions: None. Measurements and Main Results: We included 4,988 adults supported with veno-venous extracorporeal membrane oxygenation for respiratory failure. Neurologic injury was defined as brain death, seizures, stroke, and intracranial hemorrhage occurring during extracorporeal membrane oxygenation support. We used multivariable logistic regression to explore patient and extracorporeal membrane oxygenation factors associated with neurologic injury. Median age of the study cohort was 46 (interquartile range, 32-58). Four hundred twenty-six neurologic complications were reported in 356 patients (7.1%), and included 181 intracranial hemorrhage (42.5%), 100 brain deaths (23.5%), 85 stroke (19.9%), and 60 seizure events (14.1%). In-hospital mortality was significantly higher for those with CNS complications (75.8% vs 37.8%; p < 0.001) and varied by type of CNS injury; mortality was 79.6% in patients with intracranial hemorrhage, 68.2% in patients with stroke, and 50% in patients with seizures. Pre-extracorporeal membrane oxygenation cardiac arrest, continuous veno-venous hemofiltration, and hyperbilirubinemia during extracorporeal membrane oxygenation were associated with increased odds of neurologic injury. Conclusions: Approximately 7% of adults supported with veno-venous extracorporeal membrane oxygenation for respiratory failure had neurologic injury. Intracranial hemorrhage was the most frequent type, and survival for patients with neurologic injury was poor. Future investigations should evaluate anticoagulation management as well as brain/extracorporeal membrane oxygenation interaction to reduce these life-threatening events

The CoDiNOS trial protocol: an international randomised controlled trial of intravenous sildenafil versus inhaled nitric oxide for the treatment of pulmonary hypertension in neonates with congenital diaphragmatic hernia

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that impairs normal lung development, causing pulmonary hypertension (PH). PH in CDH newborns is the main determinant for morbidity and mortality. Different therapies are still mainly based on 'trial and error'. Inhaled nitric oxide (iNO) is often the drug of first choice. However, iNO does not seem to improve mortality. Intravenous sildenafil has reduced mortality in newborns with PH without CDH, but prospective data in CDH patients are lacking. METHODS AND ANALYSIS: In an open label, multicentre, international randomised controlled trial in Europe, Canada and Australia, 330 newborns with CDH and PH are recruited over a 4-year period (2018-2022). Patients are randomised for intravenous sildenafil or iNO. Sildenafil is given in a loading dose of 0.4 mg/kg in 3 hours; followed by continuous infusion of 1.6 mg/kg/day, iNO is dosed at 20 ppm. Primary outcome is absence of PH on day 14 without pulmonary vasodilator therapy and/or absence of death within the first 28 days of life. Secondary outcome measures include clinical and echocardiographic markers of PH in the first year of life. We hypothesise that sildenafil gives a 25% reduction in the primary outcome from 68% to 48% on day 14, for which a sample size of 330 patients is needed. An intention-to-treat analysis will be performed. A p-value (two-sided) <0.05 is considered significant in all analyses. ETHICS AND DISSEMINATION: Ethics approval has been granted by the ethics committee in Rotterdam (MEC-2017-324) and the central Committee on Research Involving Human Subjects (NL60229.078.17) in the Netherlands. The principles of the Declaration of Helsinki, the Medical Research Involving Human Subjects Act and the national rules and regulations on personal data protection will be used. Parental informed consent will be obtained. TRIAL REGISTRATION NUMBER: NTR6982; Pre-results.status: publishe