A Trial of Phosphodiesterase-5 Inhibitor in Neonatal Congenital Diaphragmatic Hernia (TOP-CDH)

Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 3000 US live births, similar to the incidence seen within the Utah Birth Defects cohort. The diaphragmatic defect compromises lung growth and alters pulmonary vascular development. This is reflected postnatally as respiratory failure, pulmonary hypertension (PH) and overall cardiopulmonary dysfunction, particularly post-repair. Currently, optimal management of post-repair PH remains poorly investigated. Sildenafil citrate is a highly selective phosphodiesterase-5 inhibitor that increases cGMP levels, leading to smooth muscle relaxation and an anti-proliferative effect within the pulmonary vasculature. It is used off-label for many neonatal PH disorders, including PH associated with bronchopulmonary dysplasia and idiopathic persistent PH. Most neonates with CDH born within the Mountain West referral basin are managed at a quaternary care center, Primary Children's Hospital (PCH). Of these neonates with PH, approximately 25% have been treated with off-label sildenafil. However, neither the PCH clinical care group nor others have developed/published a standardized approach for either initiating or discontinuing sildenafil therapy in this group of patients. Thus, the aim of this study is to assess the safety and effectiveness of sildenafil therapy for PH in neonates with CDH within the Utah cohort. Given the relatively short-term outcome and small sample size for this trial, the plan is to use this data to support a larger multicenter randomized trial targeting long-term cardiopulmonary outcomes of infants with CDH and post-repair PH.

Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 3000 US live births, similar to the incidence seen within the Utah Birth Defects cohort. An early developmental diaphragmatic defect leads to herniation of abdominal contents into the thoracic cavity. Such visceral herniation compromises lung growth and alters pulmonary vascular development. This is reflected postnatally as respiratory failure, pulmonary hypertension (PH) and overall cardiopulmonary dysfunction, particularly post-repair. Survival among all liveborn infants is approximately 70% and has not changed in the past 20 years. A major contributor to morbidity and mortality of this neonatal cohort is persistent PH.

CDH-related PH is related to 1) arteriolar remodeling with increased vascular smooth muscularization leading to smaller diameters of the distal arterioles; 2) a hypodense vascular bed related to compromised lung growth; and 3) endothelial dysfunction resulting in increased vasoreactivity. Given this multifactorial nature of CDH-related PH, post-natal treatment is often challenging. Moreover, there is an increased risk of PH crises with post-operative inflammatory cascades and fluid shifts. Currently, optimal management of post-repair PH remains poorly investigated.

An important pulmonary vasodilatory cascade includes the nitric oxide pathway, which acts via increases in cyclic guanosine monophosphate (cGMP). Sildenafil citrate is a highly selective phosphodiesterase-5 inhibitor that increases cGMP levels, leading to smooth muscle relaxation and an anti-proliferative effect within the pulmonary vasculature. It is used off-label for many neonatal PH disorders, including PH associated with bronchopulmonary dysplasia and idiopathic persistent PH. A multi-center trial evaluating the use of sildenafil in premature infants with bronchopulmonary dysplasia (NCT04447989) is currently underway. Pharmacokinetics of sildenafil in infants have previously been studied with a dosing range of 1mg/kg every 6-8 hours. In addition, sildenafil administration in the neonatal cohort appears safe and well-tolerated. Off-label use of sildenafil to treat CDH-related PH is increasing, despite limited evidence of efficacy in neonates with CDH. Use is based on the hypothesis that administering sildenafil post-hernia repair at a time when physiological changes are rapidly shifting may assist with pulmonary vascular relaxation to alleviate PH. Improvement in PH may ultimately benefit post-operative cardiorespiratory stability. Left ventricular eccentricity index (LVEI) is a non-invasive echocardiographic measure of such PH. LVEI is an objective measure that reflects the more subjective measure of left ventricular septal flattening. Its use decreases inter-observer variability and is a reliable assessment of neonatal PH. Elevated values of LVEI ≥ 1.4 are associated with right ventricular suprasystemic pressures. Normative values of LVEI in neonates without PH are ≤1.

Most neonates with CDH born within the Mountain West referral basin are managed at a quaternary care center, Primary Children's Hospital (PCH). PCH neonatal intensive care unit (NICU) averages 19 infants of CDH per year (range 12-24). Preliminary data shows that between 2007 and 2020, 60-85% of neonates with CDH managed at PCH manifest post-operative PH with LVEI values averaging between 1.4 to 2 on the post-repair echocardiogram. Of these neonates with PH, approximately 25% have been treated with off-label sildenafil. However, neither the PCH clinical care group nor others have developed/published a standardized approach for either initiating or discontinuing sildenafil therapy in this group of patients. Equipoise exists within the PCH clinical care group as the effectiveness of sildenafil use in neonates with CDH has not been well studied. Thus, the aim of this study is to assess the safety and effectiveness of sildenafil therapy for PH in neonates with CDH within the Utah cohort. Given the relatively short-term outcome and small sample size for this trial, this data can be used to support a larger multicenter randomized trial targeting long-term cardiopulmonary outcomes of infants with CDH and post-repair PH.

Eligibility Criteria:
Inclusion Criteria:

* Infants admitted to PCH NICU
* Diagnosis of congenital diaphragmatic hernia (CDH)
* Status post-surgical repair of diaphragmatic defect
* Has an echocardiogram 48-72 hours after repair with left ventricular eccentricity index (LVEI) ≥ 1.4
* Parental consent obtained within 24 hours after the above echocardiogram

Exclusion Criteria:

* Infants with CDH who do not undergo surgical repair
* Does not have an echocardiogram 48-72 hours post-repair
* Has LVEI \< 1.4 on above echocardiogram
* Has concurrent severe congenital heart defect that requires neonatal cardiac repair
* Has a documented sildenafil allergy
* Concurrent therapy with fluconazole at time of study drug initiation
* Inability to obtain parental consent within 24 hours of the echocardiogram
* Receiving extracorporeal membrane oxygenation (ECMO) at the time of the study