The VICI-trial: high frequency oscillation versus conventional mechanical ventilation in newborns with congenital diaphragmatic hernia: an international multicentre randomized controlled trial

Background: Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly of the diaphragm resulting in pulmonary hypoplasia and pulmonary hypertension. It is associated with a high risk of mortality and pulmonary morbidity. Previous retrospective studies have reported high frequency oscillatory ventilation (HFO) to reduce pulmonary morbidity in infants with CDH, while others indicated HFO to be associated with worse outcome. We therefore aimed to develop a randomized controlled trial to compare initial ventilatory treatment with high-frequency oscillation and conventional ventilation in infants with CDH.Methods/design: This trial is designed as a multicentre trial in which 400 infants (200 in each arm) will be included. Primary outcome measures are BPD, described as oxygen dependency by day 28 according to the definition of Jobe and Bancalari, and/or mortality by day 28. All liveborn infants with CDH born at a gestational age of over 34 weeks and no other severe congenital anomalies are eligible for inclusion. Parental informed consent is asked antenatally and the allocated ventilation mode starts within two hours after birth. Laboratory samples of blood, urine and tracheal aspirate are taken at the first day of life, day 3, day 7, day 14 and day 28 to evaluate laboratory markers for ventilator-induced lung injury and pulmonary hypertension.Discussion: To date, randomized clinical trials are lacking in the field of CDH. The VICI-trial, as the first randomized clinical trial in the field of CDH, may provide further insight in ventilation strategies in CDH patient. This may hopefully prevent mortality and morbidity.Trial registration: Netherlands Trial Register (NTR): NTR1310

Congenital Diaphragmatic hernia – a review

Congenital Diaphragmatic hernia (CDH) is a condition characterized by a defect in the diaphragm leading to protrusion of abdominal contents into the thoracic cavity interfering with normal development of the lungs. The defect may range from a small aperture in the posterior muscle rim to complete absence of diaphragm. The pathophysiology of CDH is a combination of lung hypoplasia and immaturity associated with persistent pulmonary hypertension of newborn (PPHN) and cardiac dysfunction. Prenatal assessment of lung to head ratio (LHR) and position of the liver by ultrasound are used to diagnose and predict outcomes. Delivery of infants with CDH is recommended close to term gestation. Immediate management at birth includes bowel decompression, avoidance of mask ventilation and endotracheal tube placement if required. The main focus of management includes gentle ventilation, hemodynamic monitoring and treatment of pulmonary hypertension followed by surgery. Although inhaled nitric oxide is not approved by FDA for the treatment of PPHN induced by CDH, it is commonly used. Extracorporeal membrane oxygenation (ECMO) is typically considered after failure of conventional medical management for infants ≥ 34 weeks’ gestation or with weight >2 kg with CDH and no associated major lethal anomalies. Multiple factors such as prematurity, associated abnormalities, severity of PPHN, type of repair and need for ECMO can affect the survival of an infant with CDH. With advances in the management of CDH, the overall survival has improved and has been reported to be 70-90% in non-ECMO infants and up to 50% in infants who undergo ECMO

Antenatal maternally-administered phosphodiesterase type 5 inhibitors normalize eNOS expression in the fetal lamb model of congenital diaphragmatic hernia

PURPOSE: Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. METHODS: CDH were created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. RESULTS: Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82±12% in Normal-Placebo, 61±5% in CDH-Placebo, 116±6% in Normal-Tadalafil, and 86±8% in CDH-Tadalafil lambs. Normalized expression of β-sGC was 105±15% in Normal-Placebo, 82±3% in CDH-Placebo, 158±16% in Normal-Tadalafil, and 86±8% in CDH-Tadalafil lambs. Endothelial NOS and β-sGC were significantly decreased in CDH (p = 0.0007 and 0.01 for eNOS and β-sGC, respectively), and tadalafil significantly increased eNOS expression (p = 0.0002). CONCLUSIONS: PDE5 inhibitors can cross the placental barrier. β-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH

Lung hypoplasia in newborn rabbits with a diaphragmatic hernia affects pulmonary ventilation but not perfusion

BackgroundA congenital diaphragmatic hernia (DH) can result in severe lung hypoplasia that increases the risk of morbidity and mortality after birth; however, little is known about the cardiorespiratory transition at birth.MethodsUsing phase-contrast X-ray imaging and angiography, we examined the cardiorespiratory transition at birth in rabbit kittens with DHs. Surgery was performed on pregnant New Zealand white rabbits (n=18) at 25 days' gestation to induce a left-sided DH. Kittens were delivered at 30 days' gestation, intubated, and ventilated to achieve a tidal volume (V t) of 8 ml/kg in control and 4 ml/kg in DH kittens while they were imaged.ResultsFunctional residual capacity (FRC) recruitment and V t in the hypoplastic left lung were markedly reduced, resulting in a disproportionate distribution of FRC into the right lung. Following lung aeration, relative pulmonary blood flow (PBF) increased equally in both lungs, and the increase in pulmonary venous return was similar in both control and DH kittens.ConclusionThese findings indicate that nonuniform lung hypoplasia caused by DH alters the distribution of ventilation away from hypoplastic and into normally grown lung regions. During transition, the increase in PBF and pulmonary venous return, which is vital for maintaining cardiac output, is not affected by lung hypoplasia.SCOPUS: ar.jinfo:eu-repo/semantics/publishe