Basic & Clinical Pharmacology & Toxicology, 2018, 123, 392–406 Doi: 10.1111/bcpt.

13051

MiniReview

Current and Future Treatments for Persistent Pulmonary

Hypertension in the Newborn
Jonas Pedersen1, Elise R. Hedegaard1, Ulf Simonsen1, Marcus Kr€
uger2, Manfred Infanger2 and Daniela Grimm1,2
1
Department of Biomedicine, Pharmacology, Aarhus University, Aarhus, Denmark and 2Clinic for Plastic, Aesthetic and Hand Surgery,
Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
(Received 20 March 2018; Accepted 27 May 2018)

Abstract: Persistent pulmonary hypertension in newborn (PPHN) is a serious and possibly fatal syndrome characterized by sus-
tained foetal elevation of pulmonary vascular resistance at birth. PPHN may manifest secondary to other conditions as meconium
aspiration syndrome, infection and congenital diaphragmatic hernia. This MiniReview provides the reader with an overview of
current and future treatment options for patients with PPHN without congenital diaphragmatic hernia. The study is based on sys-
tematic searches in the databases PubMed and Cochrane Library and registered studies on Clinicaltrials.gov investigating PPHN.
Inhaled nitric oxide (iNO) is well documented for treatment of PPHN, but 30% fail to respond to iNO. Other current treatment
options could be sildenafil, milrinone, prostaglandin analogues and bosentan. There are several ongoing trials with sildenafil, but
evidence is lacking for the other treatments and/or for the combination with iNO. Currently, there is no evidence for effect in
PPHN of other treatments, for example tadalafil, macitentan, ambrisentan, riociguat and selexipag used for pulmonary arterial
hypertension in adults. Experimental studies in animal models for PPHN suggest effect of a series of approaches including
recombinant human superoxide dismutase, L-citrulline, Rho-kinase inhibitors and peroxisome proliferator-activated receptor-c
agonists. We conclude that iNO is the most investigated and the only approved pulmonary vasodilator for infants with PPHN. In
the iNO non-responders, sildenafil currently seems to be the best alternative either alone or in combination with iNO. Systematic
and larger clinical studies are required for testing the other potential treatments of PPHN.

Persistent pulmonary hypertension of the newborn (PPHN) is
a serious syndrome characterized by sustained foetal elevation
of pulmonary vascular resistance at birth. The syndrome is
seen in two of 1000 live-born infants and is associated with a
normal or low systemic vascular resistance [1]. Newborns with
PPHN are at risk of severe complications as asphyxia, chronic
lung disease, neurodevelopmental sequelae and death [2].
The pulmonary transition at birth relies on an immediate
drop in pulmonary vascular resistance and an eight to 10 times
increase in pulmonary blood flow. Stimuli known to con-
tribute to the pulmonary vasodilation and hence the drop in
pulmonary vascular resistance are increased PO2, rhythmic
distension of the lungs, drainage and absorption of foetal lung
liquid, and increased production of different vasoactive media-
tors. The effects of especially increased PO2, increased blood
flow or shear stress and ventilation are partly dependent on
the activation of endothelial nitric oxide synthase. The activa-
tion of endothelial nitric oxide synthase resulting in the pro-
duction of the vasoactive mediator nitric oxide is responsible
for nearly 50% of the fall in pulmonary vascular resistance.
Phosphodiesterase type 5 (PDE 5) is an enzyme that hydroly-
ses cyclic GMP and hence inhibits the vasodilatation induced
Author for correspondence: Daniela Grimm, Department of Biomedi-
cine, Pharmacology, Aarhus University, Wilhelm Meyers Alle 4,
DK-8000 Aarhus C, Denmark (e-mail dgg@biomed.au.dk).
by nitric oxide. Thus, PDE 5 limits the drop in pulmonary
vascular resistance. PDE 5 is highly expressed in lung tissue
during foetal life and a key regulator of perinatal pulmonary
circulation along with nitric oxide [3].
The pathophysiology of PPHN is based on changes in pul-
monary vascular structure and function. An elevated pul-
monary vascular resistance may result from pulmonary
vasoconstriction, structural remodelling of the pulmonary mus-
culature, intravascular obstruction and lung hypoplasia [1]. It
may be secondary to other diseases as meconium aspiration
syndrome, infection and congenital diaphragmatic hernia. Pre-
term and birth by Caesarean versus natural delivery increase
the risk of PPHN [3]. Antenatal exposure to selective sero-
tonin-reuptake inhibitors used to treat maternal depression has
been associated with the development of PPHN [4]. Another
known risk factor is antenatal exposure to smoke. The use of
non-steroidal anti-inflammatory drugs, especially ibuprofen,
naproxen and aspirin during pregnancy is associated with
PPHN [5]. This is problematic because of the easy access to
over-the-counter non-steroidal anti-inflammatory drugs. Fur-
thermore, stress or pain, perinatal malnutrition and hyperoxia
may impair the pulmonary vascular adaptation at birth [3].
Infants with PPHN secondary to congenital diaphragmatic her-
nia may respond differently to treatment and should be anal-
ysed separately [6].

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview PERSISTENT NEWBORN PULMONARY HYPERTENSION
Clinically, PPHN shows varying degrees of hypoxemic
respiratory failure. PPHN is characterized by labile hypox-
aemia and pre–post ductal saturation gradient which mani-
fests itself as differential cyanosis [7]. Hypoxaemia is due to
intrapulmonary shunting secondary to V/Q mismatch and/or
extrapulmonary right-to-left shunting across persistent foetal
channels because of the increased pulmonary vascular resis-
tance/systemic vascular resistance ratio [1]. Echocardiography
is the gold standard investigation for the diagnosis of PPHN
[8]. The echocardiographic findings are right ventricular
hypertrophy, deviation of the interventricular septum to the
left, tricuspid regurgitation and right-to-left or bidirectional
shunting across patent foramen ovale, and patent ductus arte-
riosus [7].
Inhaled nitric oxide (iNO) is the only approved specific pul-
monary vasodilator for infants in the USA [9]. No literature
describing other approved vasodilators has been found; how-
ever, literature describing clinical use of other treatments than
iNO has been found. It is a costly intervention, and approxi-
mately 30% of neonates with PPHN fail to respond to iNO.
Some may even experience a rebound pulmonary hypertension
due to suppression of endogenous nitric oxide production
[9,10]. Therefore, knowledge about the effects and the clinical
use of other treatments than iNO may be important for the
survival of the infant [7–9]. Some treatment options for PPHN
have previously been described [9], but without a description
of the quality of evidence or implications for future research
for each treatment. This MiniReview provides the reader with
an updated systematic overview of current available treat-
ments. Furthermore, implications for future research for each
treatment will be discussed. Adverse events of each drug
choice will be reviewed. This is important information in situa-
tions where non-responders to iNO may be fatally challenged
by adverse events of the treatment.
The objective of this MiniReview was to examine the cur-
rent available and emerging future treatment options for per-
sistent pulmonary hypertension of the newborn without
congenital diaphragmatic hernia.
Methods
Eligibility criteria: Following the Oxford Centre for Evidence-Based
Medicine 2011 Levels of Evidence, all studies rated levels 1–5 were
considered eligible. As far as possible, eligible studies should be from
2008 or newer, but if the available data were limited due to the low
prevalence of PPHN, older studies would be considered eligible, too.
Information sources: PubMed – by the National Center for Biotech-
nology Information, U.S. National Library of Medicine. The Cochrane
Library – a collection of six databases that contain different types of
high-quality, independent evidence to inform healthcare decision-mak-
ing, and a seventh database that provides information about Cochrane
groups. Clinicaltrials.gov is a database of privately and publicly
funded clinical studies conducted around the world, run by U.S
National Library of Medicine. Pro.medicin.dk is a website and data-
base containing information about drugs and therapeutic instructions.
It is issued by DLI A/S (Dansk Lægemiddel Information A/S). Pub-
Chem is an open chemistry database at the National Institutes of
Health, collecting information on chemical structures, identifiers,
chemical and physical properties, biological activities, patents, health,
safety, toxicity data and many others.
© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
393
The last literature search was performed on 14 February 2018. On
PubMed, the search strategy was ‘Persistent Pulmonary Hypertension
of the Newborn’. This resulted in 2130 items. With a ‘Clinical Trial’
filter, 111 items were found. With no filter and the addition of MeSH
Term ‘Animals, Newborn’, 153 items were collected. For finding in-
depth literature describing each treatment, a search for ‘*Drug Name*
AND Persistent Pulmonary Hypertension of the Newborn’ was carried
out, for example ‘Treprostinil AND Persistent Pulmonary Hyperten-
sion of the Newborn’. Searching for ‘Persistent Pulmonary Hyperten-
sion of the Newborn’ in Cochrane Library gave nine items and using
the same search on Clinicaltrials.gov resulted in 31 items.
Study selection: Cf. the objective of this MiniReview, only studies
investigating treatments for PPHN without congenital diaphragmatic
hernia were included. To be included, the individual study should
clearly state the diagnosis of PPHN without congenital diaphragmatic
hernia in the patient group investigated. Systemic reviews and meta-
analysis found on The Cochrane Library were excluded if no eligible
study had been found. Studies from Clinicaltrials.gov with the status
of ‘withdrawn’ or with an objective different from investigating a
treatment were excluded.
Therapy of PPHN
General management.
The general management of PPHN comprises the treatment of
hypoxaemia with oxygen supplementation and the underlying
condition besides maintaining haemoglobin, glucose, intravas-
cular volume, temperature and electrolytes at normal levels
[2,8]. High-frequency ventilation allows ventilation with small
tidal volumes. Combined with iNO in a randomized multi-cen-
tre trial, high-frequency ventilation was shown to be more suc-
cessful than treatment with high-frequency ventilation or iNO
alone [11]. This management may be considered in neonates
with PPHN before advancing to extra corporeal membrane
oxygenation (ECMO). ECMO is an extremely complex and
invasive technique providing life support in severe, but poten-
tially reversible respiratory failure. The technique oxygenates
blood outside the body. Infants with PPHN are well suited to
ECMO as the improved oxygenation and physiological stabil-
ity improves pulmonary blood flow without risking further
barotrauma [12]. When compared to conventional ventilation
support as presented in a Cochrane review by Mugford
et al.[12], ECMO was shown to reduce mortality without an
increased risk of severe disability in infants with PPHN.
Inhaled nitric oxide.
Nitric oxide (NO) is produced from the nitrogen of L-arginine
and molecular oxygen by the endothelial nitric oxide synthase
enzyme (eNOS) in vascular endothelial cells. NO diffuses
through the endothelium to the vascular smooth muscle and
activates soluble guanylyl cyclase (sGC) leading to the pro-
duction of cyclic guanyl monophosphate (cGMP), which acti-
vates the cGMP-dependent protein kinase or protein kinase G
(PKG). PKG stimulates myosin phosphatase associated with
dephosphorylation of myosin light chain and activates potas-
sium channels followed by hyperpolarization, and reduction of
the influx of calcium. This leads to vasodilation. iNO acts
locally as pulmonary vasodilator (fig. 1). Thus, iNO is an
obvious choice in the treatment of PPHN.
394 JONAS PEDERSEN ET AL. MiniReview

Barrington et al.[6] compared iNO with control in neonates
with PPHN by meta-analysing 17 randomized controlled trials
(RCTs). Participants were newborn infants (<1 month of age)
with hypoxaemia suspected to be due to lung disease, pul-
monary hypertension with right-to-left shunting or both. The
inclusion criterion was studies in term and near-term infants
(>34 weeks of gestational age). Exclusions were infants with
intracardiac shunting due to structural congenital heart disease.
They reported no significant difference in death before hospi-
tal discharge between the groups. A significant reduction in
the use of ECMO before hospital discharge was found, indi-
cating that the number needed to treat with iNO for an addi-
tional beneficial outcome to prevent 1 neonate from requiring
ECMO was 5. Oxygenation was significantly improved in
infants treated with iNO, and the oxygenation index 30–
60 min. after the start of treatment was significantly lower in
the iNO group. PaO2 30–60 min. after treatment was signifi-
cantly higher when treated with iNO. Furthermore, neonates
who received iNO were not at increased risk of neurodevelop-
mental sequelae and did not experience increased post-dis-
charge pulmonary complications. The meta-analysis reported
that clinical or echocardiographic evidence of PPHN was not
present in all the included studies. Therefore, it was concluded
that iNO should be considered for near-term infants with
hypoxic respiratory failure with or without clear evidence of
PPHN. The quality of evidence was rated moderate to high.
To the author’s knowledge, iNO is the most investigated treat-
ment for PPHN.
Currently, iNO is not believed to have systemic adverse
events due to systemic inactivation by interactions with hae-
moglobin [6] (table 1). That said, an interaction between iNO
and haemoglobin may result in the creation of methaemoglo-
bin. Methaemoglobin levels should be carefully monitored as
it is toxic and causes a left shift in the O2-Haemoglobin disso-
ciation curve resulting in worsening of hypoxia [13]. Signifi-
cant methaemoglobinaemia has been reported in a case of an
overdose of iNO in a neonate [14]. Increased toxicity has not
been shown after long-term treatment iNO. A reaction
between a superoxide and nitric oxide creates peroxynitrite,
which may result in membrane lipid peroxidation. The forma-
tion of the end product nitrite may induce bronchoconstriction
and cough. Furthermore, NO inhibits platelet aggregation and
adhesion influencing the hemostasis.
Phosphodiesterase inhibitors.
PDE 5 is responsible for breaking down cGMP in the smooth
muscle cell. Inhibiting PDE 5 extends the duration of activity
of cGMP resulting in relaxation of the smooth vascular muscle.
Thus, the inhibition of PDE 5 leads to vasodilation. Dipyri-
damole is a PDE 5 inhibitor but has shown significant systemic
adverse effects in newborn lamb models with persistent pul-
monary hypertension [15]. Sildenafil (fig. 2A) is also a PDE 5
inhibitor and has been studied in neonatal pig models of pul-
monary hypertension secondary to meconium aspiration, show-
ing no adverse systemic effects and a vasodilating efficiency at

Fig. 1. Pharmacodynamics of current and emerging treatments. PDE5, phosphodiesterase-5; PDE3, phosphodiesterase-3; GMP, guanylyl monophos-
phate; AMP, adenosine monophosphate; cGMP, cyclic guanylyl monophosphate; cAMP, cyclic adenosine monophosphate; sGC, soluble guanylyl
cyclase; AC, adenylyl cyclase; IP, PGI2-receptor; EP, PGE1-receptor; PGIS, prostacyclin synthase; COX, cyclooxygenase; eNOS, nitric oxide
synthase; ET-1, endothelin; rETB, relaxant endothelin receptor; cETB, contractile endothelin receptor and ETA, endothelin receptor; rhSOD,
recombinant human superoxide dismutase; L-arg., L-arginine; SNAT1, sodium-coupled neutral amino acid transporter.

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview PERSISTENT NEWBORN PULMONARY HYPERTENSION 395

least as good as iNO [16]. Sildenafil has become a common
agent in the chronic management of pulmonary hypertension in
adults [17] and is the most common enteral pulmonary
vasodilator for children with pulmonary arterial hypertension
[9]. Therefore, sildenafil may be a promising choice of treat-
ment for PPHN when iNO is not available (fig. 1).
Kelly et al.[10], a Cochrane review, investigated the efficacy
and safety of sildenafil for treatment of PPHN. They included
term and near-term neonates (postnatal age <28 days after
reaching gestational age of 40 weeks) with either primary or
secondary PPHN. The included studies based the diagnosis on
clinical findings with or without echocardiographic confirma-
tion. Exclusion criteria were infants with structural genital heart
disease with exception of patent foramen ovale and patent duc-
tus arteriosus. Sildenafil was compared to either placebo or no
treatment, versus another pulmonary vasodilator, and sildenafil
and another pulmonary vasodilator versus another pulmonary
vasodilator and placebo. This resulted in five included studies.
When compared to placebo, a significant reduction in mortality
in the sildenafil group was found based on three studies. No tri-
als reported significant difference in mortality upon comparison
of the sildenafil group versus the active control group, or when
iNO was administered to both groups. Oxygenation index and
PaO2 suggested steady improvement after the first sildenafil
dose, but without statistical significance. No adverse events
were reported. In a small open-label study testing the pharma-
cokinetics of sildenafil in infants with PPHN, the following
adverse events were reported: hypotension, development of
patent ductus arteriosus with left-to-right shunting, pneumotho-
rax, total anomalous pulmonary venous return, hypotension
associated with trisomy 21 and adrenal insufficiency [18]
(table 1). Other known adverse events of PDE 5 inhibitors are
visual, musculoskeletal, hearing and vestibular disorders [19].
The available literature regarding sildenafil as treatment of
PPHN is limited and low-rated regarding quality of evidence
due to the imprecision of small studies and lack of methodologi-
cal features. Despite the lack of literature, sildenafil is currently
used as acute adjuvant to iNO in NO-resistant PPHN and as an
acute primary treatment of PPHN when iNO is not available or
contraindicated [9]. Further RCTs investigating sildenafil should
be performed to increase the quality of evidence. Sildenafil
could either be investigated versus placebo or iNO. Double-
blinding of future studies would be preferred to raise the evi-
dence, and the studies should be conducted in such manner that
follow-up will be possible for investigating long-term effects.
Tadalafil is also a PDE-5 inhibitor approved for use in
adults with pulmonary arterial hypertension and has larger
selectivity for PDE5 and longer half-life. One animal study,
investigating tadalafil in seven piglets with induced acute pul-
monary hypertension, showed a reduction in PVR and lung
shunt fraction as well as an increase in cardiac output and
arterial oxygenation, when oral tadalafil was administered
[20]. No human study investigating tadalafil for use in PPHN
has been found. One open-label study investigating tadalafil
for use in 25 children with pulmonary arterial hypertension
has been found. Nineteen patients were administered tadalafil
and six patients had been on sildenafil for longer than
6 months. A transition from sildenafil to tadalafil showed a
significant clinical improvement. This study found that tadala-
fil may be more effective than sildenafil. The most frequent
reported adverse event was nausea (table 1) [21]. Even though
tadalafil has a low affinity for phosphodiesterase-6 in

Table 1.
Adverse event profiles.
Endothelin receptor
Modulation of NO/cGMP pathway Modulation of cAMP pathway antagonists Rho-kinase inhibitors
iNO: PDE 3 inhibitor:
• Cough • Hypotension
• Hepatotoxicity • Systemic hypotension
• Bronchoconstriction • Thrombocytopenia
• Nasopharyngitis
• Methaemoglobinaemia • Arrhythmias
• Headache
• Tolerance development Prostaglandin analogues:
• Flushing
• Change in haemostasis • Hypotension
• Peripheral oedema
PDE 5 inhibitor: • Drug tolerance
• Nausea • Nausea/vomiting
• Hypotension • Headache
• Hearing, visual, musculoskeletal, • Cough
and vestibular disorders • Jaw pain
• Adrenal insufficiency • Diarrhoea
• Pneumothorax • Catheter-related infections
• Patent ductus arteriosus • Fatigue
with right-to-left shunting • Skin symptoms
• Total anomalous pulmonary venous return • Thrombosis
• Hypotension associated • Flushing
with trisomy 21 • Infusion-site erythema and pain
sGC stimulator: • Pain in extremity
• Hypotension
• Headache
• Nasopharyngitis
• Peripheral oedema
• Musculoskeletal, gastrointestinal, vestibular
and haemorrhagic disorders

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
396 JONAS PEDERSEN ET AL. MiniReview

O CH3
A B H
N N O
O O N
N
S
N N
H N
N N
H3C O CH3

CH3
C D
O O O
S
OH NH O
O
H H N
N
N O

OH OH N OH

E
N
N
N F

N N

H2 N NH2
N O

Fig. 2. The chemical structures of sildenafil (A), milrinone (B), iloprost (C), bosentan (D) and riociguat (E).

photoreceptors, visual disturbances have been reported, too.
Musculoskeletal, hearing and vestibular disorders have been
reported, but these are suggested to be less likely associated
with tadalafil than sildenafil [19]. To investigate tadalafil in
PPHN, future studies must be conducted.
Phosphodiesterase-3 (PDE 3) is responsible for the break-
down of cyclic adenosine monophosphate (cAMP) in vascular
smooth muscle cells and myocardium. By inhibiting PDE 3,
the intracellular cAMP level increases leading to vasodilation
and may increase cardiac contractility. Milrinone (fig. 2B) is a
PDE 3 inhibitor and vasodilator (fig. 1). In rat models of pul-
monary hypertension, milrinone has shown to have an additive
pulmonary vasodilating effect when administered with iNO
[22]. In lamb models with PPHN, milrinone exhibited an
enhancing effect of the vasodilation induced by prostacyclin.
Thus, a combination therapy of milrinone and prostacyclin
may be a new option of treatment for PPHN [23,24]. An
open-label study [25] investigated milrinone in neonates with
PPHN and suboptimal response to iNO. Inclusion criteria were
neonates with a gestational age larger than 34 weeks and <10
postnatal days of life, echocardiographic diagnosis of PPHN,
indwelling arterial line for obtaining blood samples, and
absence of a congenital heart defect excluding small atrial sep-
tal defects and ventricular septal defects. A total of 11 neo-
nates were included. The study showed that the administration
of milrinone was associated with improvement in pulmonary
arterial hypertension and blood flow. Previously, adverse
events of hypotension, thrombocytopenia and arrhythmia have
been reported after the use of milrinone, but these were not
confirmed due to no reports of adverse events in the study
(table 1) [25]. Based on these data, milrinone should not be
interpreted as an alternative to iNO due to the lack of a con-
trol group. Future RCTs should be conducted to investigate
mortality, oxygenation index improvement or requirement for
ECMO. Double-blinding would be preferred as well as a long-
term follow-up for investigating sequelae.
Prostaglandin analogues.
The arachidonic acid-prostacyclin pathway plays an important
role in vascular pulmonary muscle tonus. By activating adenylyl
cyclase prostaglandins increase the intracellular cAMP concen-
tration in vascular smooth muscle cells and lead to vasodilation
(fig. 1). Prostacyclin derivates (e.g. Iloprost; fig. 2C) are used
to treat pulmonary arterial hypertension in adults.
Janjindamai et al.[26] conducted a retrospective medical
records review of 33 infants diagnosed with PPHN by echocar-
diography. They found that intravenous iloprost significantly
reduced the oxygenation index. They showed that the need of
inotropic support increased. When administered in adult patients
with pulmonary arterial hypertension in an open-label study, the
most common adverse events were headache and cough
(table 1). One patient experienced hypotension [27]. The use of
aerosolised iloprost has shown a subsequent rapid tolerance
development to the vasodilatory effect [28].

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview PERSISTENT NEWBORN PULMONARY HYPERTENSION
In another retrospective study of 47 infants with PPHN
[29], iloprost seemed to be more effective than sildenafil in
terms of time to and duration of a clinical response.
A retrospective cohort study [30] of 142 infants between
≤10 days and ≥34 weeks of gestation revealed the use of pros-
taglandin E1 in infants with PPHN is significantly associated
with a shortened length of hospitalization. No statistically sig-
nificant difference in mortality between PGE1-treated and non-
PGE1-treated infants was found. The final diagnosis of PPHN
was based on echocardiography.
In a small phase I/II open-label clinical trial [31], 21 infants
with PPHN born at >34 weeks of gestation at an age of
<2 weeks were administered inhaled alprostadil, which is a
PGE1 analogue. Echocardiography was not a required diagno-
sis for enrolment, and all infants were treated with surfactant
prior to enrolment. Alprostadil treatment revealed an improve-
ment in PaO2 without toxic adverse events. No serious adverse
events associated to alprostadil were reported. A RCT tried to
investigate this further but failed to include enough patients
[32]. In bovine coronary artery smooth muscle cells, prosta-
glandin E2 has shown not to develop tolerance to antimito-
genic actions within 24 hr, as it was shown for iloprost
[33,34]. When administered to patients with impaired renal
function, alprostadil has shown adverse events as hypotension,
nausea, vomiting, fatigue and skin symptoms (table 1) [35].
Epoprostenol is a prostacyclin analogue used for treatment
of pulmonary arterial hypertension in adults. The found data
regarding the use of epoprostenol in neonates with PPHN are
limited to two old and small studies and case reports. The two
studies were consistent in reporting beneficial outcome of the
use of epoprostenol in neonates with PPHN [36,37]. When
administered in healthy adults, the most common adverse
event of epoprostenol was headache [38]. When administered
intravenously in adults with pulmonary arterial hypertension,
adverse events of jaw pain, diarrhoea, catheter-related infec-
tions and thrombosis have been reported (table 1) [39]. Drug
tolerance was reported for continuous intravenous treatment
with epoprostenol in pulmonary hypertension [40].
Treprostinil is a known prostacyclin analogue. The data on
the use of treprostinil are limited. Two case reports described
the administration of treprostinil in two neonates with early
onset sepsis and PPHN who did not respond to iNO. Within
6–12 hr after the treatment with treprostinil, both patients
showed clinical improvement. No systemic adverse events
were observed [41]. When administered intravenously in
adults with pulmonary arterial hypertension, the most common
reported adverse events were infusion-site erythema and pain
[42]. When administered orally in adults, adverse events were
headache, diarrhoea, nausea, flushing and jaw pain (table 1)
[43].
Selexipag, a prostacyclin receptor agonist, is an orally avail-
able prodrug which has shown significantly improvements in
the treatment of pulmonary arterial hypertension in adults
[44,45]. Thus, selexipag may have a future potential in the
treatment of PPHN [46–49]. No animal studies investigating
selexipag in PPHN have been found. In a large double-blinded
and randomized global study testing selexipag used in
© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
397
pulmonary arterial hypertension, the most frequently reported
adverse events leading to treatment interruption were head-
ache, diarrhoea, nausea, vomiting and pain in extremity
(table 1) [50].
Although prostaglandins are well-known pulmonary
vasodilators, sufficient literature regarding treatment of PPHN
is non-existent.
Endothelin receptor antagonists.
Endothelin-1 (ET-1) is a physiological potent vasoconstrictor
produced by vascular endothelial cells. Endothelin-1 activates
smooth muscle ETA receptors and smooth muscle ETB recep-
tors. The smooth muscle ETB receptor is well known as con-
tractile ETB receptor. The activation of both the ETA and
contractile ETB receptor leads to vasoconstriction. Further-
more, endothelin-1 activates an endothelial ETB receptor well
known as relaxant ETB receptor. The activation of the
endothelial relaxant ETB receptors in large pulmonary arteries
is associated with release of NO and vasodilatation. Bosentan
(fig. 2D) is an ET-1 antagonist acting at both receptors
(fig. 1). It has proven to be efficient in adults with pulmonary
hypertension [51]. In newborn lamb models, PPHN was asso-
ciated with increased ETA-mediated vasoconstriction and a
loss of ETB-mediated vasodilation [52,53]. Furthermore, ele-
vated plasma levels of ET-1 had been reported in newborn
infants with pulmonary hypertension [54,55]. Therefore, the
use of bosentan or other endothelin receptor antagonists to
treat PPHN may be an effective alternative to iNO.
More et al.[56] identified in a systematic review of random-
ized, cluster-randomized or quasi-randomized controlled trials
two studies that evaluated the efficacy and safety of endothelin
receptor antagonists in term and late pre-term infants with
PPHN. Both studies reported that bosentan was well tolerated
and that there were no major adverse events. The problem
with the studies investigating PPHN is the low amounts of
patients. Thus, more rare and serious adverse events are not
detected. In adults, treatment with bosentan for pulmonary
arterial hypertension has shown to cause an abnormal liver
function and elevations of alanine aminotransferase and aspar-
tate aminotransferase, indicating hepatotoxicity [57–59].
Adverse events of nasopharyngitis have also been reported in
patient groups treated with bosentan [59]. Other reported
adverse events are headache, flushing and peripheral oedema
(table 1) [60].
In the first study, bosentan was used as the sole pulmonary
vasodilator. iNO and ECMO were not available in the setting.
Mohamed et al.[61] reported no significant difference in death
from any cause prior to hospital discharge or prior to 28 days
of life between bosentan-treated infants and a placebo control
group. The infants treated with bosentan showed a significant
benefit when comparing at least 20% improvement in oxy-
genation index within 72 hr of treatment to the placebo con-
trol group. Furthermore, the bosentan group showed a
significant benefit in improved oxygenation index by at least
20% at the end of the treatment. The total duration of mechan-
ical ventilation was significantly lower in the bosentan group.
398 JONAS PEDERSEN ET AL.
There was no difference in development of cerebral palsy or
hearing impairment between the groups. However, a trend to a
higher incidence of other adverse neurodevelopmental seque-
lae was found in the placebo group. They did not report the
length of hospitalization, other adverse events or other infor-
mation on cognitive and neurodevelopmental disability at 18–
24 months. This study had no available iNO for treatment. No
hepatotoxicity was reported.
In the FUTURE-4 trial, a multi-centre study where iNO and
ECMO were available, bosentan was used as an adjunct ther-
apy to iNO. Steinhorn et al.[62] reported no significant differ-
ence in the requirement for ECMO prior to hospital discharge
between the groups. There was no significant difference in
duration of iNO therapy or total duration of mechanical venti-
lation. The authors reported that bosentan did not affect sys-
temic blood pressure adversely, but no details were given. No
hepatotoxicity was reported.
However, for both studies, the overall quality rating of evi-
dence was low due to small sample size of the included stud-
ies, the numerical imbalance between the groups due to
randomization and attrition, and unclear risk of bias on some
of the important domains [56]. More RCTs regarding the effi-
cacy and safety of bosentan as alternative to iNO in the treat-
ment for PPHN should be conducted.
Macitentan is a new dual ETRA showing potential in the
treatment of pulmonary arterial hypertension. Macitentan has
been reported to have less adverse effects e.g. hepatotoxicity
compared to bosentan (table 1); therefore, macitentan may
have a future potential in the treatment of PPHN [63–65].
That said, one case report describing serious liver injury after
macitentan treatment for adult pulmonary arterial hypertension
has been found [66], indicating the importance of registering
adverse events of ETRAs in future studies.
Ambrisentan is an ETRA used in the treatment of pul-
monary arterial hypertension in functional WHO class II–III
[67,68]. No studies investigating ambrisentan in neonates with
PPHN have been found. In an ongoing study (NCT01406327)
of 702 patients with pulmonary arterial hypertension treated
with ambrisentan, interim results have shown that common
adverse events are anaemia, peripheral oedema, headache, face
oedema, abnormal hepatic function and epistaxis [69].
Soluble guanylyl cyclase activators/stimulators.
As previously described, iNO acts on sGC, but resistance to
NO and tolerance may limit the vasodilation. Thus, by activat-
ing sGC directly with an activator, a relaxation of vascular
smooth muscle cells may occur independently of NO (fig. 1).
The sGC stimulator riociguat (fig. 2E) (BAY 63-2521 [70]) is
used for pulmonary arterial hypertension as monotherapy or in
combination with ETRA or prostanoids [71]. Information
regarding the use of riociguat in children with pulmonary arte-
rial hypertension is missing [71,72]. No studies investigating
sGC activators/stimulators as treatment of PPHN in neonates
were found. Spreemann et al.[73] reported positive results in a
case using oral riociguat in combination with bosentan in a
child with supra-systemic pulmonary hypertension at the age
© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview
of 3 years. In adult patients with chronic thromboembolic pul-
monary hypertension, the most common adverse events of
treatment with riociguat were hypotension, headache,
nasopharyngitis and peripheral oedema [74,75]. Other reported
adverse events of riociguat are musculoskeletal, gastrointesti-
nal, vestibular and haemorrhagic disorders (table 1) [19].
Other known compounds that simulate sGC are YC-1, BAY
41-2272, BAY 41-8543, CFM-1571 and A-350619. Known
compounds that activate sGC are BAY 58-2667 and HMR-
1766 (related derivative: S-3448) [76]. In neonatal lamb mod-
els with PPHN, sGC activators has been shown to cause a sig-
nificantly greater fall in PVR than either 100% O2 or iNO
[77,78]. Furthermore, a study in foetal lambs has indicated an
impaired sGC activity as a contributing factor in the pathogen-
esis of PPHN [77].
These findings suggest that sGC stimulators and activators
may have a therapeutic potential as alternative or adjuvant
therapy for infants with PPHN who are non-responsive to iNO
and O2. By conducting a double-blinded RCT in the future,
the efficacy of riociguat in the treatment of PPHN without
CDH could be enlightened. A subsequent follow-up would be
necessary to evaluate long-term effects.
Rho-kinase inhibitors.
RhoA is a small GTPase increasing Rho-kinase activity lead-
ing to phosphorylation of myosin light chain and vasoconstric-
tion in vascular smooth muscle (fig. 1). Rho-kinase activity
has shown to modulate contraction of vascular smooth muscle
cells in the systemic and pulmonary circulation [79]. In foetal
lambs, Rho-kinase activity has been shown to maintain the
high PVR [80].
The RhoA-Rho-kinase pathway is involved in vasoconstric-
tion, when eNOS is inhibited which may indicate Rho-kinase
inhibitors as a future treatment [80]. Furthermore, increased
Rho-kinase activity was found to lead to impaired angiogene-
sis in foetal lambs [79]. Therefore, the activity of the Rho-
kinase may be a potential future target for treatment of PPHN.
A newer animal study using foetal lambs with PPHN has sug-
gested interactions between the Rho-kinase activity and perox-
isome proliferator-activated receptor-c (PPAR-c). By
inhibiting the Rho-kinase in foetal lambs with decreased
PPAR-c activity, the PPAR-c activity was restored to normal.
These findings suggest that an inhibition of the Rho-kinase
combined with activation of PPAR-c results in a restored
growth of pulmonary arterial smooth muscle cells [81]. Com-
pounds inhibiting the Rho-kinase are Y-27632 and fasudil
(HA-1077) [80]. Fasudil is registered for the treatment of pul-
monary arterial hypertension in Japan. Infused fasudil has
shown to improve pulmonary hemodynamics without signifi-
cant toxicity [82]. Inhaled fasudil has shown to be at least as
effective as iNO [83]. Administered in a double-blinded, pla-
cebo-controlled clinical trial, fasudil hydrochloride (AT-
877ER) was shown to improve hemodynamics in adult
patients with pulmonary arterial hypertension [84]. No studies
investigating fasudil in PPHN have been found. Fasudil is also
used for preventing cerebral vasospasms in patients
MiniReview PERSISTENT NEWBORN PULMONARY HYPERTENSION
undergoing surgery for subarachnoid haemorrhage and when
investigated versus placebo in these patients, no significant
difference in adverse events was found [85]. Some studies
report no clinical significant systemic hypotension caused by
fasudil [82,86,87] whereas a newer animal study has con-
cluded fasudil is not a useful targeting drug due to a signifi-
cant systemic hypotension (table 1) [88]. No larger clinical
trial investigating fasudil has been found. Future studies of
fasudil could determine the profile of adverse events. Fasudil
has a potential in the treatment of pulmonary arterial hyperten-
sion, and future research should address the effect of fasudil
versus placebo or iNO in PPHN in a large double-blinded
RCT.
Clinical trials.
Clinical trials concerning the pharmaceutical treatment on PPHN
can be found on Clinicaltrials.gov. Details regarding studies reg-
istered on Clinicaltrials.gov are presented in table 2 for sildenafil,
bosentan, prostaglandins, milrinone and for iNO. Most of these
studies aim to assess the safety and treatment effect of the drugs
in infants with PPHN to find optimal starting doses as well as
therapy timescales. Further, some trials in adults have investi-
gated an additive effect of combining prostacyclins with silde-
nafil or bosentan. First results seem to be promising with
improvement in hemodynamic parameters [43]. Emerging targets
and therapies for PPHN are currently under investigation.
Table 3 summarizes implications of future research.
Future Treatments
This section will describe possible future treatments based on
findings in animal studies. These compounds could be
researched in future phase 0–1 studies. Some drugs are used
in other treatments, for example rosiglitazone in diabetes mel-
litus type II meaning that some adverse events and pharma-
cokinetics already are known.
Antioxidants.
Mechanical ventilation as treatment option for PPHN may
result in formation of reactive oxygen species which can inac-
tivate NO and cause further vasoconstriction (fig. 1). In foetal
lamb models with PPHN, intratracheal recombinant human
superoxide dismutase (rhSOD) has shown to improve oxy-
genation and reduce oxidation and vasoconstriction [89]. In
another study, inhaled rhSOD was shown to enhance the
effect of iNO in foetal lambs with PPHN [90]. In foetal lambs,
rhSOD has also been shown to restore eNOS coupling [91].
These findings indicate that rhSOD could be a future therapy
adjuvant to iNO for PPHN.
L-citrulline.
L-citrulline is a L-arginine-NO precursor. Through a two-step
enzymatic process, L-citrulline is converted to L-arginine
which is directly channelled to eNOS for efficient NO produc-
tion [92,93] (fig. 1). Furthermore, L-citrulline stimulates the
© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
399
recoupling of eNOS which improves NO production [94]. In
piglet models, L-citrulline is transported into pulmonary arte-
rial endothelial cells (PAEC) by a sodium-coupled neutral
amino acid transporter (SNAT1). The activity of SNAT1 mod-
ulates the L-citrulline-induced NO production, which increases
in hypoxic PAEC due to an increased expression of SNAT1
within 24, 48 and 72 hr of hypoxic conditions in piglets
[95,96]. Furthermore, it has been demonstrated that an
impaired L-citrulline-L-arginine-NO pathway is involved in
the pathogenesis of pulmonary hypertension [97]. Another
study in piglet models has shown that rescue treatment with
L-citrulline improves pulmonary hypertension induced by
hypoxia [94]. These findings suggest that by increasing NO
production, supplemental L-citrulline and modulators of
SNAT1 may be emerging alternate therapies for infants with
PPHN. In 25 adult patients with idiopathic pulmonary hyper-
tension or Eisenmenger syndrome, oral L-citrulline has shown
a reduction in PVR [98]. No clinical trials regarding L-citrul-
line use in infants had been performed until today.
PPAR-c agonists.
PPAR-c regulates smooth muscle cell proliferation and inhi-
bits vascular remodelling (fig. 1). In a mouse model, it has
been shown that a selective deletion of the PPAR-c gene
results in spontaneously developed pulmonary arterial hyper-
tension [99]. Furthermore, activation of PPAR-c resulted in a
decreased proliferation of pulmonary arterial smooth muscle
cells in vitro [99]. In foetal lamb models with PPHN, ET-1
has shown to decrease PPAR-c signalling which contributes to
dysfunction of pulmonary arterial endothelial cells [100]. In
the same study, PPAR-c agonists increased eNOS activity in
normal PAEC and in PAEC from lambs with PPHN. These
findings may indicate that a combination of PPAR-c agonists
and bosentan could be a future treatment option for PPHN.
Currently, no studies involving human beings had been con-
ducted. As described in the section above, PPAR-c agonists
may be a future treatment combined with Rho-kinase inhibi-
tors. Compounds that act as PPAR-c agonists are rosiglitazone
and 15D-prostaglandin-J2 [100].
Discussion
According to the literature, sildenafil is the most investigated
drug together with iNO in the treatment of PPHN. Some clini-
cal trials investigating the treatment of PPHN can be found on
Clinicaltrials.gov [101] (table 2). Six studies investigated the
use of sildenafil either as monotherapy compared to placebo,
or as adjuvant therapy to iNO. But sildenafil has the disadvan-
tage of requiring endogenous NO or natriuretic peptides to
work in the pulmonary circulation.
The development of increased pulmonary vascular resis-
tance may rely on malfunctioning intracellular pathways due
to genetic variations, for example a malfunction of eNOS.
Therefore, other treatments instead of sildenafil should be
investigated. For instance, sGC activators may be promising
drugs, because they are potentially better than sildenafil when
400 JONAS PEDERSEN ET AL.
An overview of clinical trials registered at Clinicaltrials.gov investigating sildenafil, bosentan, prostaglandins, milrinone or iNO in PPHN.
Drug Title
Sildenafil A multi-centre, randomized, placebo-
controlled, double-blind, two-armed,
parallel group study to evaluate efficacy
and safety of iv sildenafil in the treatment
of neonates with PPHN or hypoxic
respiratory failure and at risk for PPHN,
with a long-term follow-up investigation
of developmental progress 12 and
24 months after completion of study
treatment.
ID: NCT01720524
Oral Sildenafil in Persistent Pulmonary
Hypertension Secondary to Meconium
Aspiration Syndrome in Newborns: A
Randomized Placebo Controlled Trial.
ID: NCT01757782 [102]
Pharmacokinetics of Sildenafil in Premature
Infants
ID: NCT01670136
A Single Arm Single Centre Study To
Investigate Safety And Efficacy Of
Sildenafil In Near Term and Term
Newborns With Persistent Pulmonary
Hypertension Of The Newborn
ID: NCT01069861
Phase II Trial of Sildenafil in Newborns
With Persistent Pulmonary Hypertension
ID: NCT01409031
A Follow-Up Investigation For Patients
Completing Study A1481276 To
Investigate Developmental Progress 12
and 24 Months Following Completion Of
Sildenafil Treatment
ID: NCT01801982
Bosentan Multi-centre, Double-Blind, Placebo-
Controlled, Randomized, Prospective
Study of Bosentan as Adjunctive Therapy
to Inhaled Nitric Oxide in the
Management of Persistent Pulmonary
Hypertension of the Newborn (PPHN)
(FUTURE 4)
ID: NCT01389856 [62]
Prostaglandins Intravenous Remodulin (Treprostinil) as
Add-on Therapy for the Treatment of
Persistent Pulmonary Hypertension of the
Newborn: A Randomized, Placebo-
Controlled, Safety and Efficacy Study.
ID: NCT02261883
Pilot Study: The Effect of Inhaled Iloprost
on Oxygenation in Term and Near Term
infants With Pulmonary Hypertension.
Testing Two Doses.
ID: NCT00409526
© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
Table 2.
Design
Interventional, estimated
enrolment: 64, randomized,
masking: double, phase III
Interventional, actual
enrolment: 96, randomized,
parallel assignment, masking:
single, phase IV
Interventional actual
enrolment: 34 non-
randomized single group
assignment open label phase 1
Interventional, actual
enrolment: 4, single group
assignment, open label, phase
II
Interventional, actual
enrolment: 4, randomized,
parallel assignment, masking:
triple, phase II
Observational, actual
enrolment: 1, prospective,
phase II
Interventional, actual
enrolment: 23, randomized,
parallel assignment, m
asking: quadruple, phase III
Interventional, estimated
enrolment: 70, randomized,
parallel assignment, masking:
quadruple, phase II
Interventional, actual
enrolment: 1, single group
assignment, open label, phase
IV
MiniReview
Objective Status
This study will evaluate whether Recruiting
IV sildenafil can reduce the
time on iNO treatment and
reduce the failure rate of
available treatments for PPHN
The purpose of this study was to Recruitment
study the role of oral sildenafil completed
in PPHN secondary to
meconium aspiration syndrome
(MAS) in newborns and to
study risk factors of MAS
developing into PPHN
The purpose of this study was to Recruitment
learn more about the safety and completed
dosing of sildenafil in infants
The purpose of this study was to Terminated
learn more about the safety and
dosing of sildenafil in infants
The purpose of this study was to Terminated
determine whether intravenous
sildenafil reduces pulmonary
artery pressure and improves
oxygenation in near-term and
term infants with PPHN
This study would monitor Completed
developmental progress of
PPHN patients for 2 years
following study treatment,
using Bayley III and
Hammersmith tools
The study was a phase 3 study Terminated
to investigate whether adding
bosentan to iNO in newborns
with PPHN was a supporting
and safe therapy and to
evaluate pharmacokinetics of
bosentan and its metabolites
This study aims to assess the Recruiting
safety and treatment effect of
acute dosing with IV remodulin
in neonates with PPHN
The purpose of this study was to Terminated
test safety and efficacy of
inhaled iloprost in reducing
pulmonary artery pressure in
near-term infants with PPHN
(continued)
MiniReview PERSISTENT NEWBORN PULMONARY HYPERTENSION
Table 2. (continued)
Drug Title
Milrinone Milrinone in Congenital Diaphragmatic
Hernia
ID: NCT02951130 [103]
Milrinone Pharmacokinetics and
Pharmacodynamics in Newborns with
Persistent Pulmonary Hypertension of the
Newborn – a Pilot Study to Enable a
Randomized Trial of Intervention
ID: NCT01088997
iNO Effect of Early iNO on Oxidative Stress,
Vascular Tone and Inflammation in Term
and Late-Preterm Infants With Hypoxic
Respiratory Failure
ID: NCT01891500
Early Inhaled Nitric Oxide Therapy in Term
and Near Term Infants With Respiratory
Failure
ID: NCT00005773 [104]
The Randomized Inhaled Nitric Oxide
Study (NINOS) in Full-Term and Nearly
Full-Term Infants With Hypoxic
Respiratory Failure
ID: NCT00005776 [105]
NO Need to Ventilate: A Trial of Non-
invasive iNO in Persistent Pulmonary
Hypertension of the Newborn
ID: NCT00139217
Inhaled Nitric Oxide in Neonates With
Elevated A-aDO2 Gradients Not Requiring
Mechanical Ventilation
ID: NCT00732537 [106]
eNOS is malfunctional. No studies on Clinicaltrials.gov cur-
rently have investigated sGC activators. One study on Clini-
caltrials.gov investigated a specific PTGS1 genetic variation
and the risk of developing PPHN. Future research should
© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
Design
Interventional, estimated
enrolment: 66, randomized,
parallel assignment, masking:
quadruple, phase II
Interventional, actual
enrolment: 12, randomized,
parallel assignment, masking:
single
Interventional, estimated
enrolment: 34, randomized,
parallel assignment, masking:
triple, phase IV
Interventional, actual
enrolment: 302, randomized,
parallel assignment, masking:
quadruple, phase III
Interventional, actual
enrolment: 235, randomized,
parallel assignment, masking:
quadruple, phase III
Interventional, estimated
enrolment: 400, randomized,
single group assignment,
open label
Interventional, actual
enrolment: 8, randomized,
masking: triple, phase IV
investigate genetic variations which may contribute to devel-
opment of targeted treatment for PPHN. The other drugs that
are currently studied on Clinicaltrials.gov are bosentan, milri-
none, iNO and prostaglandins. No other treatments under
401
Objective Status
This pilot trial determines Recruiting
whether milrinone infusion in
neonates with CDH would lead
to an increase in PaO2 with a
corresponding decrease in OI
by itself or in conjunction with
other pulmonary vasodilators
24 hr post-infusion
The purpose of this pilot study Terminated
was to determine a safe dose of
milrinone to use in a larger
study of babies with PPHN
The purpose of this study is to Recruiting
evaluate if giving the inhaled
nitric oxide earlier in the
course of disease improves the
effectiveness of the drug,
reduces the amount of cellular
injury from oxygen exposure,
and decreases the total amount
of time a patient requires
supplemental oxygen
This study tested whether Terminated
initiating iNO therapy earlier
would reduce death and reduce
the use of ECMO compared to
standard recommendation
threshold
The primary objective is to Terminated
determine whether inhaled
nitric oxide would reduce
mortality or the initiation of
extracorporeal membrane
oxygenation in infants with
hypoxic respiratory failure
The primary objective of the Completed
trials is to determine the
feasibility and clinical safety
and efficacy of non-invasive
inhaled iNO in infants with
PPHN without significant
pulmonary parenchymal disease
who would normally receive
iNO only after placement of a
tracheal tube and the institution
of mechanical ventilation
This study was to determine of Completed
iNO given into an oxygen
hood is effective in improving
oxygenation in term and near-
term infants who have poor
oxygenation but who are not
yet mechanically ventilated
402 JONAS PEDERSEN ET AL. MiniReview

Table 3.
Treatments in need of research and implications for future research regarding PPHN.
Treatments Implications for future research
Sildenafil
Milrinone • Mortality compared to placebo or iNO
Prostaglandins • Requirement for ECMO compared to placebo or iNO
Bosentan • OI Improvements within, for example 24, 48 and 72 hr of administration compared to placebo or iNO
sGC activators/stimulators • Adverse effects compared to placebo or iNO
rhSOD • Long-term sequelae
• Methodological information to increase quality of evidence
L-citrulline
• Information about whether infants have received surfactant or supportive care affecting primary outcome.
Rho-kinase inhibitors
PPAR-c agonists
• PPHN with CDH should be investigated separately

investigation have been found. This MiniReview and the find-
ings on Clinicaltrials.gov are consistent in pointing out that
implications for future research are to investigate every aspect
of each described current and future treatment for PPHN
except iNO (fig. 1 and table 3). More double-blinded RCTs
should be conducted, focusing on mortality, requirement for
ECMO, frequently measured oxygenation index improvements
compared to iNO within the first days of administration,
adverse events and long-term sequelae especially neurodevel-
opmental. The overall problem with describing adverse effects
in the treatment of PPHN is the low prevalence, which may
result in an underestimation of adverse effects due to a small
sample size. Nevertheless, some adverse events to the treat-
ments have been reported. The adverse event profiles are sum-
marized in table 1. These adverse event profiles indicate that
some drugs may be superior to others in terms of adverse
events when treating an infant with PPHN, who is a non-
responder to iNO. Hypotension is the common adverse event
of each drug; thus, blood pressure should be monitored to pre-
vent development of shock and hypoperfusion in the hypoxic
infant. Future studies with sufficient sample sizes should
ensure to investigate adverse event profiles as secondary aim
of the intervention drugs, as this is important knowledge for
choosing a treatment alternative to iNO. To investigate the
adverse events of drugs used in the treatment of PHHN, we
suggest making a systematic database for registering the
adverse events of treatments in PPHN. This would be an
opportunity to investigate PPHN properly even though the
prevalence is low. Methodological information should be
detailed to raise the quality of evidence if the RCTs are
included in future systematic reviews and meta-analyses.
Researchers should mention whether infants have received sur-
factant or not and be aware that PPHN with CDH should be
investigated separately (table 3). To evaluate long-term effects,
for example neurodevelopment, follow-up is required.
Conclusions
Nowadays, the general management of PPHN relies on treat-
ing hypoxaemia and the underlying condition besides main-
taining haemoglobin, glucose, intravascular volume,
temperature and electrolytes. Infants with PPHN have shown
to respond positively to the treatment of high-frequency venti-
lation combined with iNO. ECMO is a complex and invasive
technique which has shown to reduce mortality when used for
treating PPHN. iNO is the most investigated choice of treat-
ment and the only approved specific pulmonary vasodilator
for newborns. iNO should be considered for infants with
hypoxaemic respiratory failure with or without PPHN; 30% of
the patients are non-responsive to iNO. Literature reports the
use of sildenafil, prostaglandins, milrinone and bosentan as
alternative treatment to iNO. These drug choices have different
profiles of adverse events (table 3). A common adverse event
for each drug is hypotension, which may be unwanted in a
hypoxic infant with PPHN due to the risk of developing shock
and hypoperfusion. On Clinicaltrials.gov, sildenafil is the most
investigated non-iNO treatment. Animal studies have proven
that other treatments of PPHN may emerge in the future.
These promising choices consist of sGC activators and stimu-
lators, rhSOD, L-citrulline, Rho-kinase inhibitors and PPAR-c
agonists. sGC activators and stimulators and Rho-kinase inhi-
bitors are known in the treatment of pulmonary hypertension
in adults. This MiniReview and the findings on Clinicaltrials.-
gov are consistent in pointing out that implications for future
research are to investigate every aspect of each one of the pre-
viously described current and future treatment options for
PPHN, except from iNO (fig. 1). The treatments and sug-
gested implications for future research are summarized in
table 3. We suggest making a multi-centre global database for
registering adverse events of treatments for PPHN to avoid
underestimations due to the low prevalence.
Outlook
There are many small studies, and we lack a systematic and
prioritized effort to perform larger clinical studies in this area.
One problem future researchers may encounter will be the
long period of recruitment for a sufficient power due to the
low incidence of PPHN. The use of sildenafil, prostaglandins,
milrinone and bosentan for PPHN as treatment alternate to
iNO is commonly reported. Current literature lacks sufficiently
conducted double-blinded RCTs investigating these choices
with a sufficient sample size and long-term follow-up. If
future RCTs testing these drugs are conducted, new beneficial
or adverse effects may be reported in the treatment of PPHN.
These drugs could be tested either versus placebo or iNO.
This will improve the possible choices of treatment when neo-
nates with PPHN are non-responders to iNO. sGC activators

© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview PERSISTENT NEWBORN PULMONARY HYPERTENSION
and stimulators, rhSOD, L-citrulline, Rho-kinase inhibitors
and PPAR-c agonists all seem promising future choices based
on known use in pulmonary arterial hypertension and animal
models with PPHN. These treatments are summarized in
table 3 with implications of future research.
sGC stimulators as riociguat are already used as either
monotherapy or in combination with ETRA in the treatment
of arterial pulmonary hypertension in adults [76]. No paedi-
atric studies using riociguat in the treatment of PPHN were
performed.
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