Congenital Diaphragmatic Hernia: 10-Year Evaluation of Survival, Extracorporeal Membrane Oxygenation, and Foetoscopic Endotracheal Occlusion in Four High-Volume Centres

Background: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly with significant mortality. Objectives: The aim of this study was to determine if there were trends in survival over the last decade and to compare patient populations, treatment options, and survival rates between 4 high-volume centres, and hence determine which factors were associated with survival. Methods: In 4 high-volume CDH centres from the CDH EURO Consortium, data from all CDH patients born between 2004 and 2013 were analysed. The predictive value of variables known at birth and the influence of centre-specific treatments (extracorporeal membrane oxygenation, ECMO, and foetoscopic endotracheal occlusion, FETO) on survival were evaluated in multivariable logistic regression analyses. Results: Nine hundred and seventy-five patients were included in the analysis, of whom 274 (28.1%) died. ECMO was performed in 259 patients, of whom 81 (31.3%) died. One hundred and forty-five patients (14.9%) underwent FETO, and from those 76 patients (52.4%) survived. Survival differed significantly between years (p = 0.006) and between the 4 centres (p < 0.001). In the multivariable logistic regression analysis, lung-to-head ratio, gestational age at birth, ECMO, centre of birth, and year of birth were significantly associated with survival, whereas FETO was not. Conclusions: The patient populations were different between centres, which influenced outcomes. There was a significant variability in survival over time and between centres, which should be taken into consideration in the planning of future trials

Neurodevelopmental Outcome in High-Risk Congenital Diaphragmatic Hernia Patients: An Appeal for International Standardization

BACKGROUND: Since mortality in congenital diaphragmatic hernia (CDH) is decreasing, morbidity such as neurodevelopmental outcome is becoming increasingly important. OBJECTIVES: We evaluated neurodevelopmental outcome in high-risk CDH patients treated according to the CDH EURO Consortium standardized treatment protocol. METHODS: This observational, prospective cohort study was conducted in two European centers. Neurodevelopment of 88 patients (Rotterdam n = 49; Rome n = 39) was assessed at 12 and 24 months with the Bayley Scales of Infant Development (BSID)-II-NL (Rotterdam) or BSID-III (Rome). Data of the centers were analyzed separately. RESULTS: Cognition was normal in 77.8% of children from Rotterdam and in 94.8% from Rome at 12 months, and in 70.7 and 97.4%, respectively, at 24 months. Motor function was normal in 64.3% from Rotterdam and in 81.6% from Rome at 12 months and in 45.7 and 89.8%, respectively, at 24 months. Longer length of hospital stay (LoS) was associated with worse cognitive outcome and motor function; LoS, low socioeconomic status, and ethnicity were associated with lower cognition. CONCLUSIONS: At 2 years, most CDH patients have normal cognition, but are at risk for motor function delay. Due to differences in outcomes between centers, careful interpretation is needed before conclusions can be drawn for other centers. Future multicenter collaboration should not only focus on standardization of postnatal care, but also on international standardization of follow-up to identify risk factors and thereby reduce morbidity

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

Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update

In 2010, the congenital diaphragmatic hernia (CDH) EURO Consortium published a standardized neonatal treatment protocol. Five years later, the number of participating centers has been raised from 13 to 22. In this article the relevant literature is updated, and consensus has been reached between the members of the CDH EURO Consortium. Key updated recommendations are: (1) planned delivery after a gestational age of 39 weeks in a high-volume tertiary center; (2) neuromuscular blocking agents to be avoided during initial treatment in the delivery room; (3) adapt treatment to reach a preductal saturation of between 80 and 95% and postductal saturation >70%; (4) target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy, and (6) intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension. This article represents the current opinion of all consortium members in Europe for the optimal neonatal treatment of CDH

Congenital Diaphragmatic Hernia: 10-Year Evaluation of Survival, Extracorporeal Membrane Oxygenation, and Foetoscopic Endotracheal Occlusion in Four High-Volume Centres

Background: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly with significant mortality. Objectives: The aim of this study was to determine if there were trends in survival over the last decade and to compare patient populations, treatment options, and survival rates between 4 high-volume centres, and hence determine which factors were associated with survival. Methods: In 4 high-volume CDH centres from the CDH EURO Consortium, data from all CDH patients born between 2004 and 2013 were analysed. The predictive value of variables known at birth and the influence of centre-specific treatments (extracorporeal membrane oxygenation, ECMO, and foetoscopic endotracheal occlusion, FETO) on survival were evaluated in multivariable logistic regression analyses. Results: Nine hundred and seventy-five patients were included in the analysis, of whom 274 (28.1%) died. ECMO was performed in 259 patients, of whom 81 (31.3%) died. One hundred and forty-five patients (14.9%) underwent FETO, and from those 76 patients (52.4%) survived. Survival differed significantly between years (p = 0.006) and between the 4 centres (p < 0.001). In the multivariable logistic regression analysis, lung-to-head ratio, gestational age at birth, ECMO, centre of birth, and year of birth were significantly associated with survival, whereas FETO was not. Conclusions: The patient populations were different between centres, which influenced outcomes. There was a significant variability in survival over time and between centres, which should be taken into consideration in the planning of future trials

Score for Neonatal Acute Physiology-II Predicts Outcome in Congenital Diaphragmatic Hernia Patients.

OBJECTIVE: Accurate and validated predictors of outcome for infants with congenital diaphragmatic hernia are needed. Score for Neonatal Acute Physiology-II has been validated to predict mortality in newborns. We investigated whether Score for Neonatal Acute Physiology-II scores in congenital diaphragmatic hernia could predict mortality, need for extracorporeal membrane oxygenation (in patients born in a center with extracorporeal membrane oxygenation availability), and development of bronchopulmonary dysplasia (oxygen dependency beyond 28 d after birth) in survivors. DESIGN: Data were obtained from a prospective, multicenter randomized controlled trial of initial ventilation strategy carried out by the Congenital Diaphragmatic Hernia EURO Consortium (NTR 1310). SETTING: ICUs of level III university children's hospitals. PATIENTS: Congenital diaphragmatic hernia infants without severe chromosomal anomalies or severe cardiac anomalies born between November 2008 and December 2013. INTERVENTIONS: Randomization for initial ventilation strategy (high-frequency oscillation/ conventional mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Logistic regression analyses were used to evaluate associations between Score for Neonatal Acute Physiology-II and outcome parameters. Of the 171 included patients, 46 died (26.9%), 40 of 108 (37.0%) underwent extracorporeal membrane oxygenation, and 39 of 125 survivors (31.2%) developed bronchopulmonary dysplasia. In nonsurvivors, the median Score for Neonatal Acute Physiology-II was 42.5 (interquartile range, 33.5-53.8) and 16.5 (interquartile range, 9.0-27.5) in survivors (p < 0.001). Score for Neonatal Acute Physiology-II also significantly differed between extracorporeal membrane oxygenation and non-extracorporeal membrane oxygenation-treated patients (p < 0.001), and survivors with and without bronchopulmonary dysplasia (p < 0.001). Multivariable logistic regression analyses adjusted for hernia side, liver position, ventilation mode, gestational age, center and observed-to-expected lung-to-head-ratio showed that Score for Neonatal Acute Physiology-II was associated with mortality (odds ratio, 1.16 [1.09-1.23]; p < 0.001) and need for extracorporeal membrane oxygenation support (odds ratio, 1.07 [1.02-1.13]; p = 0.01), but not for the development of bronchopulmonary dysplasia (odds ratio, 1.04 [0.99-1.09]; p = 0.14). CONCLUSIONS: The Score for Neonatal Acute Physiology-II predicts not only mortality but also need for extracorporeal membrane oxygenation in congenital diaphragmatic hernia patients. We, therefore, recommend to implement this simple and rapid scoring system in the evaluation of severity of illness in patients with congenital diaphragmatic hernia and thereby have insight into the prognosis within 1 day after birth.status: publishe

Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial).

OBJECTIVES: To determine the optimal initial ventilation mode in congenital diaphragmatic hernia. BACKGROUND: Congenital diaphragmatic hernia is a life-threatening anomaly with significant mortality and morbidity. The maldeveloped lungs have a high susceptibility for oxygen and ventilation damage resulting in a high incidence of bronchopulmonary dysplasia (BPD) and chronic respiratory morbidity. METHODS: An international, multicenter study (NTR 1310), the VICI-trial was performed in prenatally diagnosed congenital diaphragmatic hernia infants (n = 171) born between November 2008 and December 2013, who were randomized for initial ventilation strategy. RESULTS: Ninety-one (53.2%) patients initially received conventional mechanical ventilation and 80 (46.8%) high-frequency oscillation. Forty-one patients (45.1%) randomized to conventional mechanical ventilation died/ had BPD compared with 43 patients (53.8%) in the high-frequency oscillation group. An odds ratio of 0.62 [95% confidence interval (95% CI) 0.25-1.55] (P = 0.31) for death/BPD for conventional mechanical ventilation vs high-frequency oscillation was demonstrated, after adjustment for center, head-lung ratio, side of the defect, and liver position. Patients initially ventilated by conventional mechanical ventilation were ventilated for fewer days (P = 0.03), less often needed extracorporeal membrane oxygenation support (P = 0.007), inhaled nitric oxide (P = 0.045), sildenafil (P = 0.004), had a shorter duration of vasoactive drugs (P = 0.02), and less often failed treatment (P = 0.01) as compared with infants initially ventilated by high-frequency oscillation. CONCLUSIONS: Our results show no statistically significant difference in the combined outcome of mortality or BPD between the 2 ventilation groups in prenatally diagnosed congenital diaphragmatic hernia infants. Other outcomes, including shorter ventilation time and lesser need of extracorporeal membrane oxygenation, favored conventional ventilation.status: publishe

High-sensitivity troponin T and N-terminal pro-brain natriuretic peptide in prediction of outcome in congenital diaphragmatic hernia: Results from a Multicenter, Randomized controlled trial

Biomarkers may be helpful in prediction of outcomes of infants with congenital diaphragmatic hernia. The predictive value of high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide was investigated in 128 infants with congenital diaphragmatic hernia. After correction for multiple testing, those biomarkers did not predict severe pulmonary hypertension, death, need of extracorporeal membrane oxygenation, or bronchopulmonary dysplasia. Trial registration Netherlands Trial Registry: 1310