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.