Newborns with Congenital Diaphragmatic hernia: inhaled Nitric Oxide versus intravenous Sildenafil: ;an international randomized controlled trial

Congenital diaphragmatic hernia (CDH) is a developmental defect of the
diaphragm and both lungs that allows the abdominal content to herniate into the
chest. Lung development is impaired in both lungs resulting in pulmonary
hypoplasia and abnormal pulmonary vasculature growth, resulting in a variable
degree of pulmonary hypertension (PH). CDH occurs in approximately one in 2500
live births and is associated with a reported mortality of approximately 27% in
live-born patients. Most children with CDH develop severe cardiorespiratory
distress after birth. Initial therapy is focused on *gentle* mechanical
ventilation and cardiorespiratory stabilization. Thereafter, surgical repair of
the diaphragmatic defect is indicated. PH, severe lung hypoplasia and
ventilator-induced lung injury are the most important risk factors for poor
outcome in children with CDH.
PH is the cause of considerable morbidity and mortality in 65-75% of newborns
with CDH. Elevated pulmonary vascular resistance and abnormal vascular
reactivity is due to excessive muscularisation and pulmonary vascular
remodeling. PH causes right ventricular dilatation, hypertrophy and
dysfunction, which contribute to illness severity including mortality.
Three known cytokine pathways mediate pulmonary artery smooth muscle tone to
control PVR: the nitric oxide-cGMP pathway, the endothelin pathway, and the
prostacyclin pathway. Pharmacological therapies that target these pathways have
been proposed, and are currently used, to treat PH in CDH. However, no
prospective studies have resolved the utility, timing and dosage of these
therapies while a number are not available in IV form either. As a result there
is very limited evidence for the optimal choice of individual drugs in the PH
treatment in CDH patients.
At present studies investigating therapies that target endothelin- and
prostacyclin pathways are not possible due to the absence of non-enteral forms
of these drugs and the lack of data in infants less than three months of age.
Inhaled nitric oxide, iNO, is at present the most commonly administered drug to
treat PH in CDH. In non-CDH patients with persistent pulmonary hypertension of
the newborn (PPHN) iNO decreases the median duration of mechanical ventilation
and the need for extracorporeal membrane oxygenation (ECMO). However, in the
one available RCT in patients with CDH INO did not improve, and may even have
worsened outcome.
Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor
that theoretically acts in concert with NO to increase cGMP-mediated pulmonary
vasodilatation. Sildenafil may also augment NO-mediated vasoproliferation. A
Cochrane analysis investigated the efficacy and safety of sildenafil in
neonates with PPHN without CDH. Three randomized single-center trials were
included, in which iNO and ECMO were initially not available. Although the
patient numbers are small and not all outcome measures are adequately reported,
the meta-analysis showed a significant reduction in mortality in the treated
group (20% versus 54% in the placebo group). A RCT comparing sildenafil and
placebo in PPHN patients without CDH receiving iNO is currently recruiting
patients (NCT01720524).
For CDH patients, only retrospective data are available. A decrease in
pulmonary vascular resistance (PVR) and an increase in cardiac output were
found in a small group of oral sildenafil-treated infants with CDH refractory
to iNO. Intravenous sildenafil in CDH patients was associated with improved
oxygenation index (OI) and reversal of the right-to-left shunt over the patent
ductus arteriosus (PDA). As no prospective randomized controlled trials have
been carried out to compare iNO and intravenous sildenafil in infants with CDH
and PH, a trial to evaluate the effect of these treatment strategies in
children with CDH is urgently needed to reach evidence based practice and
subsequently implement this in a worldwide standardized postnatal treatment
strategy.

To determine the most effective drug (iNO or IV sildenafil) for the treatment
of PH in newborns with CDH and to reach evidence based dosing of this drug.
Subsequently this drug will be added to the international guidelines for the
treatment of newborns with CDH to increase survival rate and reduce morbidity
including chronic lung disease, and the hospital length of stay. The hypothesis
to be tested is: IV sildenafil is superior to iNO for the treatment of PH in
CDH newborns and should be considered as the drug of first choice in the
future.

This study is designed as an open label prospective, multicenter, international
randomized controlled trial. In this trial, 330 newborns with CDH and pulmonary
hypertension will be recruited in a 3-year period, using the established
international collaboration within the framework of the CDH EURO CONSORTIUM, an
assembly of high volume centers for CDH within Europe.

Postnatally, all newborns will be treated according to the standard protocol
for patients with CDH, which is implemented in all participating centers
according to the revised CDH consortium guidelines (published April 2016).
Strict guidelines for cardiovascular support will be used. After
echocardiographic evaluation on the first day of life, the infant will be
randomized to receive either iNO or intravenous sildenafil if clinical
significant PH is present. The patient can also be randomized after new
echocardiographic evaluation revealing PH within the first seven days of life
if PH was not present on day one. The randomization will take place by a web
based system using a center specific block randomization. Inhaled NO will be
given with a starting dose of 20 ppm. Inhaled nitric oxide will be provided by
a tank connected to a neonatal ventilator. Some centers use integrated systems,
making it impossible to disconnect the iNO tank and replace it with another gas
to facilitate a blinded intervention. Therefore, the study will be open label.
Sildenafil will be given intravenously, using a loading dose of 0.4mg/kg in 3
hours, followed by continuous infusion of 1.6mg/kg/day. Echocardiography will
be performed to determine eligibility of entry into the study at day 1,and
subsequently before and after study drug administration, day 7,day 14, day 28
(or discharge whichever is sooner) and at follow up at 3,6 and 12 months.
Additional echocardiographic images will be collected for centralized, blinded
analysis of pulmonary artery pressure and cardiac function by 2 investigators.
Demographic and neonatal characteristics as well as data on the clinical course
and treatment of all patients will be collected in a central database in
Rotterdam. Because all patients will be analyzed on the basis of
intention-to-treat, data after treatment failure will be collected in a similar
way for all included patients. All centers will keep a log book of the number
of eligible non-participants, including the reasons for non- participating.

The risks involved in the trail are the side effects of both drugs and are
expected to be mild. Sildenafil can cause a temporary decrease in blood
pressure. This often recovers spontaneously, but can also be treated with
medication. Inhaled nitrix oxide can cause methemoglobinemia, which decreases
oxygen transport capacity of erythrocytes. This is very rare in the low dose we
will be using in our trail. MetHb can be measured in the blood.
At the moment, there is no evidence based treatment of PH in children with CDH,
an anomaly with a high morbidity and mortality. Comparing the treatment of
first choice with sildenafil, a drug that seems promising in small series,
could result in a break trough in the treatment of this severe illness. The
side effect of both drugs are limited.
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