Review
Neonatology 2016;109:334344
DOI: 10.1159/000444895
Advances in Neonatal Pulmonary
Hypertension
Robin H. Steinhorn
Childrens National Health System, George Washington University, Washington, D.C., USA
Key Words
Inhaled nitric oxide Persistent pulmonary hypertension of
the newborn Pulmonary vascular resistance
Abstract
Persistent pulmonary hypertension of the newborn (PPHN)
is a surprisingly common event in the neonatal intensive
care unit, and affects both term and preterm infants. Recent
studies have begun to elucidate the maternal, fetal and ge-
netic risk factors that trigger PPHN. There have been numer-
ous therapeutic advances over the last decade. It is now ap-
preciated that oxygen supplementation, particularly for the
goal of pulmonary vasodilation, needs to be approached as
a therapy that has risks and benefits. Administration of sur-
factant or inhaled nitric oxide (iNO) therapy at a lower acuity
of illness can decrease the risk of extracorporeal membrane
oxygenation/death, progression of disease and duration of
hospital stay. Milrinone may have specific benefits as an ino-
dilator, as prolonged exposure to iNO plus oxygen may ac-
tivate phosphodiesterase (PDE) 3A. Additionally, sildenafil
and hydrocortisone may benefit infants exposed to hyper-
oxia and oxidative stress. Continued investigation is likely to
reveal new therapies such as citrulline and cinaciguat that
will enhance NO synthase and soluble guanylate cyclase
function. Continued laboratory and clinical investigation will
be needed to optimize treatment and improve outcomes.
2016 S. Karger AG, Basel
2016 S. Karger AG, Basel
16617800/16/10940334$39.50/0
E-Mail karger@karger.com
www.karger.com/neo
Published online: June 3, 2016
Introduction
The lung must establish itself as the organ of gas ex-
change within the first few minutes of life. This amazing
feat is accomplished via a rapid decrease in pulmonary
vascular resistance (PVR) and increase in pulmonary
blood flow. Subsequently, pulmonary artery pressure and
vascular resistance progressively decrease through the
first few weeks of life. The vasoconstrictive response to
hypoxia is retained into adulthood, and pulmonary hy-
pertension (PH) can be easily triggered in the newborn
period by hypoxic lung disease, apnea or other causes.
Abnormalities of vascular development or function dur-
ing this critical developmental window can result in per-
sistent pulmonary hypertension of the newborn (PPHN),
a syndrome of failed circulatory adaptation at birth.
The PPHN syndrome is defined by sustained elevation
of PVR and is often associated with myocardial dysfunc-
tion and normal or low systemic vascular resistance. In
term and near-term infants, clinically significant PPHN
occurs in about 2/1,000 live born infants [1]. The term
PPHN is commonly used interchangeably with hypox-
emic respiratory failure, although the latter refers only to
respiratory failure associated with hypoxemia, with or
without PH. PPHN is also recognized in up to 2% of pre-
term infants presenting with early respiratory distress [2,
UFRJ Universidade Federal do Rio de Janeiro
3]. In term and near-term infants, PPHN can occur idio-
146.164.3.22 - 6/18/2016 7:15:25 PM
Robin H. Steinhorn, MD
Childrens National Medical Center
111 Michigan Avenue NW
Downloaded by:
Washington, DC 20010 (USA)
E-Mail rsteinhorn@childrensnational.org
pathically but is more commonly associated with diverse
lung pathologies including meconium aspiration syn-
drome (MAS), perinatal asphyxia, congenital diaphrag-
matic hernia (CDH), pneumonia and respiratory distress
syndrome. PH is now recognized as a frequent comorbid-
ity of bronchopulmonary dysplasia (BPD) and CDH, and
is a common complication of congenital heart disease.
Timely recognition and therapy for neonatal PH are
important because of high associated rates of mortality
and short- and long-term morbidities, including signifi-
cant neurodevelopmental impairment. Since PPHN is a
common complication of respiratory failure, the clinician
should maintain a high index of suspicion particularly
when hypoxemia is out of proportion to the parenchymal
lung disease.

a
Classification, Epidemiology and Pathogenesis of
PPHN

In clinical practice PPHN is typically classified accord-

ing to its etiology. Idiopathic or primary PPHN is the least
common and implies intrauterine pulmonary vascular
remodeling. Primary PPHN should be suspected when
there is an absence of parenchymal lung disease to explain
elevated pulmonary arterial pressure, and can occur in
term or preterm infants. Maladaptive or secondary PPHN
is much more common and is associated with other acute
respiratory conditions such as MAS, respiratory distress
syndrome or pneumonia. The third common cause of
PPHN is pulmonary vascular hypoplasia which is usually
associated with lung hypoplastic disorders such as CDH.
In preterm infants, prolonged rupture of membranes
with oligohydramnios is a common precursor to PPHN
[4]. While this etiologic classification approach is helpful,
it can be quite difficult to differentiate chronic intrauter-
ine vascular remodeling from acute pulmonary vasocon-
b
striction due to parenchymal lung disease or lung hypo-
plasia. For example, in addition to their lung findings,
Fig. 1. Representative histology of pulmonary vessels from infants
neonates with severe, lethal MAS typically have excessive who died with severe PH. a Small pulmonary vessel from an infant
muscularization at autopsy, consistent with antenatal with asphyxia, meconium aspiration and PPHN demonstrating
vascular remodeling (fig.1). dramatic smooth muscle cell thickening around pulmonary arter-
The developing lung is subject to genetic, pathological ies (arrow). b Lung photomicrograph with elastin staining from an
and/or environmental influences during fetal and neona- infant with BPD-associated PH and organizing pneumonia. A
thickened medial layer, double elastic lamina and modest prolif-
tal life that affect lung adaptation, development and eration of the adventitia are noted (arrow). Both examples indicate
growth. As a result, it is not surprising that the causes and a lack of the intimal proliferation that characterizes adult PH.
treatment of PH are strikingly different in neonates ver-
sus older children and adults [5]. The 2013 Nice Classifi-
cation of Pulmonary Hypertension incorporates these as-
UFRJ Universidade Federal do Rio de Janeiro

pects of pediatric disease [6]. Due to its unique anatomic

146.164.3.22 - 6/18/2016 7:15:25 PM

Advances in Neonatal PH Neonatology 2016;109:334344 335

DOI: 10.1159/000444895
Downloaded by:
and functional differences, PPHN is now classified as a
separate subcategory in group 1 (pulmonary arterial hy-
pertension). Developmental lung diseases such as BPD
and CDH are included in group 3 (PH due to lung dis-
eases and/or hypoxia) due to the growing recognition that
abnormal lung structural growth is often accompanied by
disordered pulmonary vascular growth and PH.
Fetal pulmonary development can be disrupted by en-
vironmental, toxic or other influences. A recent case-con-
trol surveillance study reported that maternal risk factors
of black or Asian maternal race, elevated BMI (>27), dia-
betes, and asthma are associated with a higher risk of
PPHN. Neonatal risk factors included male gender, large
for gestational age infants, delivery by cesarean section
and delivery before 37 weeks or after 41 weeks gestation
[7].
Recent animal and epidemiologic studies also suggest
that maternal therapy can alter fetal pulmonary vascular
development and function. Two classes of maternal med-
ications, selective serotonin receptor inhibitors (SSRIs)
and nonsteroidal anti-inflammatory drugs (NSAIDs),
have been of particular interest. SSRI use during the last
half of pregnancy is associated with an increased inci-
dence of PPHN in several population studies, although
the severity of PPHN has not been well described and
other studies have not found this association [810]. It is
speculated that higher SSRI-induced circulating sero-
tonin levels result in pulmonary vasoconstriction [11,
12], although a recent report found no differences in right
pulmonary artery Doppler PI in fetuses of mothers ex-
posed to SSRI antidepressants [13]. At present, maternal
physical and psychological well-being remain the prima-
ry factors guiding antidepressant therapy during preg-
nancy and the postpartum period. The use of NSAIDs
such as aspirin during late gestation may be associated
with closure of the fetal ductus arteriosus and PPHN.
Based on a recent epidemiologic study, the NSAID asso-
ciation appears to be dependent on the specific agent and
timing of exposure [14], although aspirin use during late
pregnancy remains a risk factor for PPHN.
Unlike PH in older patients, few genetic risk factors for
PPHN have been identified. Children with Down syn-
drome (trisomy 21) commonly develop PH in association
with structural heart defects, but the risk for idiopathic
PPHN is also increased by nearly tenfold. In a Dutch co-
hort with excellent early ascertainment, PPHN was docu-
mented in 5.2% of Down syndrome infants [15] and oth-
er studies have shown that Down syndrome infants are
overrepresented in neonates requiring ECMO support
[16]. A recent single-center study reported the results of
336 Neonatology 2016;109:334344
DOI: 10.1159/000444895
rigorous genotype analysis of 88 neonates with docu-
mented PPHN [17]. No differences were noted in most
candidate genes, including BMPR2 and nitric oxide (NO)
synthase. However, PPHN was significantly associated
with genetic variants for cortisol signaling [corticotropin-
releasing hormone receptor-1 (CRHR1) and CRH-bind-
ing protein] and increased levels of 17-hydroxyprogester-
one were observed in PPHN infants. These findings are
supported by animal studies indicating that antenatal or
postnatal steroids normalize NO synthase function and
improve pulmonary vascular function in experimental
PPHN [18, 19].
Multiple events can disrupt the timing and overall suc-
cess of pulmonary vascular adaptation at birth. In par-
ticular perinatal asphyxia is a major risk factor for PPHN
[20]. Many mechanisms associated with asphyxia will
cause respiratory failure and affect the transitional pul-
monary circulation, including fetal hypoxemia, ischemia,
meconium aspiration, ventricular dysfunction and acido-
sis. Acute asphyxia is associated with reversible pulmo-
nary vasoconstriction, but chronic in utero asphyxia with
or without MAS may be associated with more significant
vasoconstriction and vascular remodeling [21].
Preclinical studies generated concern that therapeutic
hypothermia would increase the risk and severity of
PPHN in asphyxiated infants. However, randomized tri-
als of selective head cooling and whole body cooling in-
dicate that moderate therapeutic hypothermia (33.5 C)
does not increase the incidence of PPHN (rates of 25 vs.
20%) [22, 23]. On the other hand, deeper whole body hy-
pothermia (32 C) compared with conventional hypo-
thermia at 33.5 C increased the rate of PPHN (34 vs. 25%,
p = n.s.), the need for iNO therapy (34 vs. 24%, p < 0.05)
and ECMO (9 vs. 4%, p < 0.05) [24]. Thus, while standard
hypothermia at 33.5 C does not worsen PPHN, deeper
hypothermia appears to be significant risk factor and
should be avoided.
New Therapeutic Insights
General management principles for PPHN have not
changed much in the last decade and include mainte-
nance of normal body temperature, electrolytes (particu-
larly calcium), glucose and intravascular volume. Polycy-
themia should be corrected with a partial exchange trans-
fusion. Other general principles include optimization of
lung function and support of cardiac function and oxygen
delivery including maintaining sufficient hemoglobin
UFRJ Universidade Federal do Rio de Janeiro
levels to optimize blood oxygen carrying capacity.
146.164.3.22 - 6/18/2016 7:15:25 PM
Steinhorn
Downloaded by:
 Pulmonary Management
Neonates with clinically significant PPHN almost al-
ways require mechanical respiratory support, although
few guidelines exist to standardize ventilator manage-
ment. Some advocate a gentle ventilation approach with
avoidance of paralysis and blood gas goals consisting of a
PaO2 5070 mm Hg (6.59.2 kPa) and PaCO2 4060 mm temic pressure and low cardiac output, in part because of
Hg (5.37.9 kPa). This strategy has never been rigorously
tested [25], but may be the optimal strategy for infants in
the early phases of disease. When significant parenchy-
mal lung disease is present, high-frequency ventilation
improves lung expansion and amplifies the oxygenation
response to iNO [26].
Surfactant deficiency (respiratory distress syndrome)
or inactivation (e.g. from MAS or pneumonia) is common-
ly associated with PPHN, and surfactant therapy can be
useful when significant parenchymal disease exists. A small
randomized study in 40 neonates with MAS reported that
3 doses of surfactant improved oxygenation and reduced
the need for ECMO, duration of oxygen therapy and length
of hospitalization (p < 0.05 for each) [27]. A subsequent
large prospective multicenter trial found that surfactant
therapy reduced the need for ECMO by 30% relative to a
control group [28]. However, neonates enrolled late in the
course of disease [oxygenation index (OI): 3139] experi-
enced no benefit while those with less severe or early dis-
ease (OI: 1522) had a threefold reduction in the need for
ECMO (p = 0.013). More recently, a retrospective analysis
of a large group of infants with moderate PPHN found that
use of surfactant was significantly associated with de-
creased risk of ECMO/death [29]. Similar to high-frequen-
cy ventilation, improving lung expansion by surfactant ad-
ministration may be important in optimizing the effect of
iNO. However, neither of these strategies is effective for
idiopathic PPHN because the lungs are already well ex-
panded and without airspace disease.
Acidosis is a pulmonary vasoconstrictor and enhances
hypoxic vasoconstriction, and should be avoided. Its con-
verse, alkalosis induced by hyperventilation or infusion of
sodium bicarbonate, produces transient pulmonary vaso-
dilation and was frequently employed prior to the avail-
ability of specific pulmonary vasodilators such as iNO [1].
However, no long-term benefit has ever been documented
and prolonged alkalosis may paradoxically worsen pul-
monary vascular tone, reactivity and permeability edema
[30]. Even more importantly, alkalosis produces cerebral
vasoconstriction and reduced cerebral blood flow, and is
associated with neurodevelopmental impairment, includ-
ing sensorineural hearing loss [31, 32].
Advances in Neonatal PH
Cardiac Support
Systemic blood pressure should be maintained at nor-
mal levels for age with volume and cardiotonic therapy
with a primary goal of optimizing both left and right ven-
tricular dysfunction and enhancing systemic oxygen
transport. PPHN is frequently associated with low sys-
increased right ventricular afterload, bowing of the intra-
ventricular septum and restriction of left side filling, and
myocardial dysfunction. Infants with PPHN typically
have right-to-left shunting at the atrial and ductal level.
Because this extrapulmonary shunting can produce se-
vere hypoxemia, it can be tempting to elevate systemic
vascular resistance to reverse the ductal shunt and im-
prove pulmonary blood flow and oxygenation. While this
approach may temporarily improve oxygenation, the
neonatal right ventricle is poorly adapted to handle an
acute elevation in afterload [33] and using pressors to
raise systemic blood pressure may induce right ventricu-
lar failure if PVR does not also fall. It is also important to
remember that an open ductus can also protect the right
ventricle by providing a pop-off that relieves some of the
right ventricular afterload.
Some infants may develop the worrisome finding of
left-to-right shunt at the foramen ovale despite predomi-
nant right-to-left shunting at the ductus. When this oc-
curs, left ventricular dysfunction is contributing to the
underlying pathophysiology which increases left atrial
and pulmonary venous pressure, elevates pulmonary ar-
terial pressure and causes right-to-left shunting with little
vasoconstriction. In such cases pulmonary vasodilators
will not improve oxygenation and may cause or aggravate
pulmonary edema; therefore, they must be accompanied
by therapies targeted to increase cardiac performance and
decrease left ventricular afterload.
Dopamine remains the most commonly used first-line
agent: it stimulates dopaminergic, 1-, 2- and 1-receptors,
and reliably increases systemic blood pressure in neonates.
However, some animal studies have shown that high doses
of dopamine will elevate both systemic and pulmonary
vascular resistances, particularly if pulmonary vascular re-
modeling is present [34]. Milrinone, which inhibits phos-
phodiesterase (PDE) 3 (cAMP PDE) activity in cardiomy-
ocytes and pulmonary arterial smooth muscle, is viewed as
an inodilator that may be especially useful in the context
of left ventricular dysfunction and pulmonary venous hy-
pertension [35]. Since iNO inhibits PDE3 activity both in
vitro and in vivo, milrinone may also be particularly effec-
UFRJ Universidade Federal do Rio de Janeiro
tive as adjunctive therapy for iNO [36, 37]. Arginine vaso-
146.164.3.22 - 6/18/2016 7:15:25 PM
Neonatology 2016;109:334344 337
DOI: 10.1159/000444895
Downloaded by:
pressin was recently reported to improve both oxygenation
and systemic hypotension in infants with PPHN and con-
genital heart disease [38]; more studies are needed to de-
termine its mechanism of action and safety.
Pulmonary Vasodilation
Oxygen
Oxygen is a mainstay of PPHN therapy to maintain
oxygen delivery to the brain and other tissues, and to
facilitate pulmonary vasodilation. Alveolar hypoxia and
hypoxemia are pulmonary vasoconstrictors and contrib-
ute to the pathophysiology of PPHN and should be avoid-
ed. On the other hand, the degree of hyperoxic ventilation
needed for pulmonary vasodilation has recently come un-
der scrutiny (fig.2). While oxygen is a pulmonary vaso-
dilator, the use of concentrations >50% has not been
shown to provide any additional benefit in pulmonary
vasodilation. Moreover, hyperoxic ventilation increases
oxidant stress and lung injury and may paradoxically im-
pair the vasodilator response to iNO. Therefore, the oxy-
gen concentration and PaO2 should be titrated to maxi-
mize pulmonary vasodilation. Studies in newborn lambs
suggest that the lowest PVR can be maintained with a
preductal SpO2 in the 9097% range with preductal PaO2
between 60 and 80 mm (7.910.5 kPa) [39, 40]. Overall,
oxygen should be used like any other drug, taking into
account its potential benefits and side effects.
Inhaled Nitric Oxide
NO production is diminished in PPHN, so the thera-
peutic use of inhaled nitric oxide (iNO) was a logical ad-
vance. iNO reduces PVR and extrapulmonary right-to-
left shunting and improves intrapulmonary ventilation
perfusion matching. iNO acutely improves oxygenation
and decreases the need for ECMO support in newborns
with PPHN and an OI >25. However, up to a third of in-
fants fail to achieve a sustained improvement in oxygen-
ation and no studies have demonstrated that iNO reduc-
es mortality or length of hospitalization.
The optimal window for introduction of therapy with
iNO remains uncertain. The initial randomized trials
studied term and near-term infants with severe PPHN
and an OI of 2540 [41, 42]. A subsequent large trial test-
ed earlier use of iNO in infants with moderate respiratory
failure (median OI of 20), but did not report reductions
in ECMO/death relative to controls (16.7 vs. 19.5%, re-
spectively; p = n.s.). However, a post hoc analysis sug-
gested that initiating iNO at an OI <20 was associated
338 Neonatology 2016;109:334344
DOI: 10.1159/000444895
Prostacyclin (inhaled)
Treprostanil (IV, SQ)
Endothelial
NO PGI2 ET-1
cell
Bosentan
ETA
ETB
Guanylate cyclase Adenylate cyclase
Smooth
GTP ATP
5GMP cGMP cAMP AMP muscle
Vasoconstriction cell
PDE5 PDE3
Vasodilation
Sildenafil
Milrinone
Fig. 2. Schematic of the NO, PGI2 and ET-1 signaling pathways,
and therapies taking advantage of the signaling abnormalities. NO
stimulates sGC to increase intracellular cGMP, and PGI2 stimu-
lates adenylate cyclase to increase intracellular cyclic AMP (cAMP).
Both cGMP and cAMP indirectly decrease free cytosolic calcium,
resulting in smooth muscle relaxation. ET-1 produced by endothe-
lial cells binds ETA and ETB receptors on smooth muscle cells.
Sildenafil inhibits PDE5 in vascular smooth muscle, and milrinone
inhibits PDE3 in cardiomyocytes and vascular smooth muscle.
Prostanoids such as Flolan (PGI2) and treprostinil can be given
by inhaled or intravenous routes. The ET-1 receptor antagonist
bosentan blocks ET-1 effects and reduces vasoconstriction.
with decreased use of ECMO compared to initiation at an
OI >20. This early phase of disease could be optimal for
future study of pulmonary vasodilators for PPHN. Pre-
term infants with severe hypoxemic respiratory failure
and PPHN presenting on the first day of life will show
marked improvement in oxygenation after treatment
with iNO, similar to the response typical for the term
newborn with idiopathic PPHN [43]. Recent reports have
indicated that iNO use ranges from 4 to 8% in extremely
preterm infants (fig.3) [44].
iNO has potential risks including methemoglobin-
emia and increased bleeding time, but over the last 15
years it has proven to be an exceptionally safe therapy. As
iNO consistently reduces the need for ECMO, it seemed
logical that it would improve rates of neurodevelopmen-
tal impairment. However, follow-up to the pivotal studies
used for FDA approval found similar rates of neurodevel-
opmental, behavioral or medical abnormalities at 2 years
of age for infants treated with iNO versus placebo [45, 46].
This surprising finding suggests that neurodevelopmen-
tal impairment could be the result of antenatal or other
UFRJ Universidade Federal do Rio de Janeiro
factors prior to iNO initiation.
146.164.3.22 - 6/18/2016 7:15:25 PM
Steinhorn
Downloaded by:

20
18
16
Percent receiving iNO
14
12
10
8
6
4
2
0
20 25
a Gestational age (weeks)
Fig. 3. a iNO use by gestational age; data from neonatal intensive care unit admissions recorded in the California
Perinatal Quality Collective, 20052013 (n = 136,113) [44]. b Chest radiograph of a preterm infant with PPHN.
Phosphodiesterase Inhibitors
PDE5 catalyzes the breakdown of cGMP and is a key
regulator of cGMP levels. Similar to endothelial NO syn-
thase and soluble guanylate cyclase (sGC), expression of
PDE5 in the lungs peaks in the immediate newborn pe-
riod in sheep and rats, indicating its importance in regu-
lating pulmonary vascular tone at the time of transition.
Increased activity of PDE5 is a consistent finding in ex-
perimental models of PPHN [47, 48]. More recently, in
vitro and in vivo studies have shown that even brief peri-
ods of hyperoxia independently increase the activity of
PDE5 by a mechanism that appears to involve reactive
oxygen species (ROS) [4850]. This finding could par-
tially explain why some infants do not respond favorably
to iNO.
Sildenafil is the best studied of the available phospho-
diesterase inhibitors and can be administered by the en-
teral and intravenous routes. A small randomized trial
found that enteral sildenafil improved oxygenation and
survival in term and late preterm neonates with PPHN
[51]. In a subsequent dose-finding study, intravenous
sildenafil improved oxygenation in neonates with and
without concurrent iNO treatment [52], suggesting that
sildenafil may be a useful adjunct in patients with partial
or poorly sustained responses to iNO [53]. Theoretically,
sildenafil may be particularly effective in neonates with
PPHN following prolonged hyperoxic ventilation since
PDE5 expression and activity are increased following
ventilation with high concentrations of oxygen and expo-
sure to ROS. Sildenafil is generally well tolerated, al-
though hypotension can occur particularly if a loading
dose is given rapidly (<60 min) [52]. The availability of
Advances in Neonatal PH
Color version available online
30 35 40 45
b
sildenafil as an enteral preparation also makes it feasible
for long-term therapy for infants with chronic PH associ-
ated with CDH [54], but chronic treatment needs more
study. Long-term follow-up will be important to deter-
mine the efficacy and safety of this approach [55] particu-
larly given the findings of the STARTS-2 trial, which
studied long-term sildenafil in older children (>1 year of
age) with PH that was idiopathic or due to heart disease
[56]. A multicenter, randomized clinical trial to test the
efficacy of sildenafil in iNO-resistant PPHN is nearing
completion (NCT01720524). Other PDE inhibitors in-
clude tadalafil and vardenafil, but their use in PPHN has
not yet been reported.
Other Pulmonary Vasodilators
Prostanoids
A complementary vasodilatory pathway in the perina-
tal lung is mediated by prostacyclin (PGI2), a metabolite
of arachidonic acid that is endogenously produced by the
vascular endothelium. Similar to NO, PGI2 production
increases in late gestation and early postnatal life, indicat-
ing its importance in the pulmonary vascular transition.
Neonatal PH is associated with decreased PGI2 levels ac-
companied by increased synthesis of the vasoconstrictor
thromboxane A2 [57, 58].
PGI2 (epoprostanol) was approved by the FDA in 1995
for treatment of adult pulmonary arterial hypertension.
While intravenous PGI2 remains a mainstay of therapy
for treatment of PH in adults, rapid dosage escalation is
UFRJ Universidade Federal do Rio de Janeiro
often necessary for acute disease and can produce sys-
146.164.3.22 - 6/18/2016 7:15:25 PM
Neonatology 2016;109:334344 339
DOI: 10.1159/000444895
Downloaded by:
Table 1. Neurodevelopmental outcomes for the major iNO clinical trials

Study n Initial Age at NDI, % Bayley Mental Devel- Bayley Psychomotor Cerebral palsy, %
OI follow-up, opment Index Development Index
months
control iNO control iNO control iNO control iNO

NINOS [45] 235 44 18 24 30 35 87 85 93.6 85.7 10.3 11.8

Clark [46] 248 39 12 14 19 95 95 85 92 1.4 4
Lipkin [69] 155 24.7 12 20 18 a a b b 6 8
Konduri [70] 299 19.2 18 24 25 28 86.1 83.3 98 89 6.3 8.2

NDI = Neurodevelopmental impairment. a 71% of control group and 69% of iNO group reported as normal (Mental Development
Index >85). b 82% of control group and 76% of iNO group reported as normal (Psychomotor Development Index >85).

temic hypotension. Its utility in the neonatal intensive
care unit setting is also limited by the need for a dedicated
central venous catheter, the potential to worsen ventila-
tion-perfusion matching and other systemic side effects
including pain.
Aerosolized PGI2 has been widely adopted in adult
critical care units for treatment of PH [59]. While fewer
reports describe its use in infants, case series indicate that
continuous inhaled PGI2 (50100 ng/kg/min) is well tol-
erated and improves oxygenation in infants with severe
PPHN and inadequate response to iNO [60, 61]. Risks
include airway irritation from the alkaline solution need-
ed to maintain drug stability, rebound PH if the drug is
abruptly discontinued and inconsistent drug delivery due
to drug loss into the circuit. New, more stable prepara-
tions are emerging that are specifically designed for inter-
mittent nebulization, such as iloprost or treprostinil.
Treprostinil is particularly promising because it is also
suitable for systemic administration, including by the
subcutaneous route [62]. A randomized study of intrave-
nous remodulin for PPHN and CDH recently began en-
rolling patients (NCT02261883).
Endothelin Receptor Antagonists
Endothelin-1 (ET-1) is a potent vasoconstrictor syn-
thesized by vascular endothelial cells that acts through
two receptors; ETA and ETB. The ETA receptor plays a
critical role in vasoconstriction, and selective blockade of
the ETA receptor causes fetal pulmonary vasodilation
[63]. ET-1 gene expression and levels are increased in the
lungs and pulmonary arterial endothelial cells in the fetal
lamb model of PPHN [64, 65], and chronic intrauterine
ETA receptor blockade following ductal ligation decreas-
of small pulmonary arteries in utero, decreases right ven-
tricular hypertrophy, and increases the fall in PVR at de-
livery in newborn lambs with PPHN [66]. Thus, it is like-
ly that ET-1 acting through the ETA receptor contributes
to the pathogenesis and pathophysiology of PPHN.
Bosentan, a nonspecific ET-1 receptor blocker, is an es-
tablished treatment for PH in adults. Two recent trials
have shown that bosentan is well tolerated in neonates
with PPHN. One single-center trial reported that bosen-
tan led to substantial improvements in oxygenation in an
iNO-nave population of PPHN infants [67], but a subse-
quent multicenter trial (FUTURE-4) found that bosentan
as adjunctive therapy for iNO did not improve PPHN
outcomes, time on iNO or time to extubation, due pos-
sibly in part to inconsistent intestinal absorption [68].
Outcomes of PPHN
Infants with PPHN are among the most critically ill
patients cared for in the neonatal intensive care unit.
They often have a perinatal history that includes low Ap-
gar scores or fetal compromise that place them at high
risk for abnormal outcomes. The treatment of PPHN in-
volves the use of therapies, including high-frequency ven-
tilation, ECMO, hyperoxia and iNO, which may also ad-
versely affect outcome. Long-term outcomes for the larg-
est iNO trials are summarized in table1; these trials also
provide the most comprehensive, standardized assess-
ment for PPHN infants treated with and without iNO.
Overall, these results highlight that neurodevelopmental
impairment is high in this population (1430%) and not
improved by iNO [45, 46, 69, 70]. In each of these trials a
UFRJ Universidade Federal do Rio de Janeiro

es pulmonary arterial pressure and distal muscularization trend towards higher motor impairment was observed in
146.164.3.22 - 6/18/2016 7:15:25 PM

340 Neonatology 2016;109:334344 Steinhorn

DOI: 10.1159/000444895
Downloaded by:
the iNO group, and in the early iNO trial reported by
Konduri et al. [70] the difference in the Bayley PDI was
statistically significant. The NINOS trial reported that the
rate of disability was not affected by the need for ECMO
[45], leading the authors to speculate that timing of in-
jury was most likely before ECMO.
Neurodevelopmental impairment is high even for
those infants presenting with moderate PPHN. Konduri
et al. [70] reported 18- to 24-month outcomes of infants
enrolled in a randomized, multicenter clinical trial of ear-
ly iNO therapy for infants presenting with respiratory
failure at an OI of 1525. Earlier initiation of iNO did not
reduce the combined incidence of ECMO/mortality, but
did limit the progression of respiratory failure to an OI
>25. Overall rates of neurodevelopmental impairment
were similar to other trials that enrolled patients with
more advanced disease and early iNO did not translate
into improved outcomes. The proportion of infants with
medical problems, such as the need for home medica-
tions, oxygen and gastrostomy feedings, also tended to be
higher in the early iNO group, although these differences
were not statistically significant.
Emerging and Novel Treatment Strategies
Glucocorticoids
Glucocorticoids have potent anti-inflammatory prop-
erties and anecdotal evidence suggests that hydrocorti-
sone improves oxygenation in neonates with PPHN lead-
ing to its use in some centers as a rescue strategy prior to
ECMO. Recent studies from animal models suggest a po-
tential role for glucocorticoids in restoring normal peri-
natal pulmonary vascular function. In neonatal lambs
with PPHN, both antenatal betamethasone and postnatal
hydrocortisone significantly improved oxygenation, in
part by increasing superoxide dismutase activity and re-
ducing oxidant stress [18, 19]. Hydrocortisone also in-
creased cGMP by normalizing sGC and PDE5 activity
and by attenuating abnormalities induced by oxidative
stress [18]. Brief courses of glucocorticoids may be ben-
eficial, particularly in severe MAS in the presence of lung
edema, pulmonary vasoconstriction and inflammation
[71]. However, the usual precautions must be exercised
when considering steroids in neonates.
Citrulline
A growing body of evidence suggests that impairments
in the L-citrulline-L-arginine-NO pathway are involved
in the pathogenesis of chronic hypoxia-induced PPHN.
Advances in Neonatal PH
Hypoxia appears to uncouple endothelial NO synthase
in pulmonary endothelial cells, which reduces NO syn-
thesis from L-arginine and increases oxidant stress. Oral
citrulline has been reported as an effective method to in-
crease serum L-arginine concentrations and may repre-
sent a strategy for improving endogenous NO signaling.
In newborn piglets exposed to 310 days of hypoxia, L-
citrulline increased NO production and reduced chronic
hypoxia-induced PH even after the onset of disease [72].
Another in vivo study demonstrated that subcutaneous
L-citrulline reduced vascular remodeling and alveolar
growth arrest in an experimental neonatal rat model of
oxygen-induced BPD [73]. These findings suggest that
supplementation with L-citrulline to restore normal L-ar-
ginine levels is a promising therapeutic approach for
treatment of early PPHN, as well as chronic PH associ-
ated with BPD.
sGC Activators
Decreased activity of sGC reduces NO-cGMP signal-
ing and contributes to severe PPHN [74]. In the presence
of increased ROS and hyperoxia, sGC becomes oxidized,
decreasing the ability to produce cGMP-mediated dila-
tion [75]. Cinaciguat, an sGC activator that is effective in
the setting of oxidized sGC, significantly increased pul-
monary vasodilation in fetal lambs with PPHN, with an
effect greater than that of increased oxygen and iNO
alone [76]. Furthermore, the effects of cinaciguat on
cGMP production were greater under hyperoxic condi-
tions compared to room air. This suggests that cinaciguat
may provide a novel treatment option for severe PPHN,
particularly as sGC is oxidized due to hyperoxic exposure.
Antioxidants
Numerous preclinical studies suggest a potential role
for antioxidant therapy for treatment of PPHN. For in-
stance, intratracheal antioxidants decrease oxidant stress,
increase endothelial NO synthase expression and nor-
malize tetrahydrobiopterin levels in PPHN lambs [77,
78], suggesting that the combination of iNO and antioxi-
dants could be more effective than iNO alone. Intratra-
cheal recombinant human SOD also reduces protein ni-
tration and inactivation, decreases PDE5 activity and in-
creases cGMP in pulmonary arteries of ventilated PPHN
lambs [48], suggesting that antioxidant therapy improves
NO signaling at multiple points in the pathway. Unfortu-
nately, to date there has been very limited success in clin-
ical trials of antioxidant therapy for a wide range of dis-
eases including BPD [79]. Antioxidant therapy may be
UFRJ Universidade Federal do Rio de Janeiro
ineffective once the disease has progressed beyond a crit-
146.164.3.22 - 6/18/2016 7:15:25 PM
Neonatology 2016;109:334344 341
DOI: 10.1159/000444895
Downloaded by:
ical stage, suggesting that early detection strategies may
improve outcomes. ROS scavenging may also interfere
with normal signaling pathways in the developing lung.
Furthermore, oxidant stress may be localized to specific
subcellular compartments in different diseases which
may limit the efficacy of nonspecific antioxidants. Thus,
highly targeted therapies may be needed to maximize the
potential of antioxidants in treatment of hypertensive
diseases.
Conclusions
An increased understanding over the last two decades
of pulmonary pathophysiology and vascular signaling
changes that trigger PPHN has led to improved manage-
ment and a substantial decrease in the number of neo-
nates requiring ECMO. Animal models have contributed
significantly to the understanding of fetal circulation,
pulmonary vascular transition at birth and the hemo-
dynamic and biochemical abnormalities associated with
PPHN. However, continued basic, translational and clin-
ical research into pulmonary vasodilator therapy, reversal
of remodeling in pulmonary vasculature and right ven-
tricular failure will be needed to improve long-term respi-
ratory and neurodevelopmental outcomes. The overall
lack of an iNO effect on neurodevelopmental outcomes
also suggests that a better understanding of the fetal and
placental abnormalities associated with PPHN will be
needed to achieve long-term outcomes. Other ongoing
challenges will be CDH and the preterm infant with
PPHN or PH associated with BPD.
Disclosure Statement
Robin Steinhorn has received honoraria from Scientific Thera-
peutics Information through Mallinckrodt.

References
1 Walsh-Sukys MC, Tyson JE, Wright LL, Bau-
er CR, Korones SB, Stevenson DK, Verter J,
Stoll BJ, Lemons JA, Papile LA, Shankaran S,
Donovan EF, Oh W, Ehrenkranz RA, Fana-
roff AA: Persistent pulmonary hypertension
of the newborn in the era before nitric oxide:
practice variation and outcomes. Pediatrics
2000;105:1420.
2 Kumar VH, Hutchison AA, Lakshminrusim-
ha S, Morin FC 3rd, Wynn RJ, Ryan RM:
Characteristics of pulmonary hypertension in
preterm neonates. J Perinatol 2007; 27: 214
219.
3 Aikio O, Metsola J, Vuolteenaho R, Perhomaa
M, Hallman M: Transient defect in nitric ox-
ide generation after rupture of fetal mem-
branes and responsiveness to inhaled nitric
oxide in very preterm infants with hypoxic
respiratory failure. J Pediatr 2012; 161: 397
403.e1.
4 de Waal K, Kluckow M: Prolonged rupture of
membranes and pulmonary hypoplasia in
very preterm infants: pathophysiology and
guided treatment. J Pediatr 2015; 166: 1113
1120.
5 Cerro MJ, Abman S, Diaz G, Freudenthal AH,
Freudenthal F, Harikrishnan S, Haworth SG,
Ivy D, Lopes AA, Raj JU, Sandoval J, Sten-
mark K, Adatia I: A consensus approach to
the classification of pediatric pulmonary hy-
pertensive vascular disease: report from the
PVRI Pediatric Taskforce, Panama 2011.
Pulm Circ 2011;1:286298.
6 Ivy DD, Abman SH, Barst RJ, Berger RM,
Bonnet D, Fleming TR, Haworth SG, Raj JU,
Rosenzweig EB, Schulze Neick I, Steinhorn
RH, Beghetti M: Pediatric pulmonary hyper-
tension. J Am Coll Cardiol 2013; 62:D117
D126.
7 Hernandez-Diaz S, Van Marter LJ, Werler
MM, Louik C, Mitchell AA: Risk factors for
persistent pulmonary hypertension of the
newborn. Pediatrics 2007;120:e272e282.
8 Huybrechts KF, Bateman BT, Palmsten K,
Desai RJ, Patorno E, Gopalakrishnan C, Levin
R, Mogun H, Hernandez-Diaz S: Antidepres-
sant use late in pregnancy and risk of persis-
tent pulmonary hypertension of the newborn.
JAMA 2015;313:21422151.
9 Kieler H, Artama M, Engeland A, Ericsson O,
Furu K, Gissler M, Nielsen RB, Norgaard M,
Stephansson O, Valdimarsdottir U, Zoega H,
Haglund B: Selective serotonin reuptake in-
hibitors during pregnancy and risk of persis-
tent pulmonary hypertension in the newborn:
population based cohort study from the five
Nordic countries. BMJ 2012;344:d8012.
10 Grigoriadis S, Vonderporten EH, Mamisash-
vili L, Tomlinson G, Dennis CL, Koren G,
Steiner M, Mousmanis P, Cheung A, Ross LE:
Prenatal exposure to antidepressants and per-
sistent pulmonary hypertension of the new-
born: systematic review and meta-analysis.
BMJ 2014;348:f6932.
11 Delaney C, Gien J, Grover TR, Roe G, Abman
SH: Pulmonary vascular effects of serotonin
and selective serotonin reuptake inhibitors in
the late-gestation ovine fetus. Am J Physiol
Lung Cell Mol Physiol 2011;301:L937L944.
12 Delaney C, Gien J, Roe G, Isenberg N, Kailey
J, Abman SH: Serotonin contributes to high
pulmonary vascular tone in a sheep model of
persistent pulmonary hypertension of the
newborn. Am J Physiol Lung Cell Mol Physi-
ol 2013;304:L894L901.
13 Lim K, Sanders A, Brain U, Riggs W, Ober-
lander TF, Rurak D: Third trimester fetal pul-
monary artery Doppler blood flow velocity
characteristics following prenatal selective se-
rotonin reuptake inhibitor (SSRI) exposure.
Early Hum Dev 2012;88:609615.
14 Van Marter LJ, Hernandez-Diaz S, Werler
MM, Louik C, Mitchell AA: Nonsteroidal
antiinflammatory drugs in late pregnancy
and persistent pulmonary hypertension of the
newborn. Pediatrics 2013;131:7987.
15 Weijerman ME, van Furth AM, van der
Mooren MD, van Weissenbruch MM, Ram-
meloo L, Broers CJ, Gemke RJ: Prevalence of
congenital heart defects and persistent pul-
monary hypertension of the neonate with
Down syndrome. Eur J Pediatr 2010; 169:
11951199.
16 Southgate WM, Annibale DJ, Hulsey TC, Pu-
rohit DM: International experience with tri-
somy 21 infants placed on extracorporeal
membrane oxygenation. Pediatrics 2001;107:
UFRJ Universidade Federal do Rio de Janeiro

549552.
146.164.3.22 - 6/18/2016 7:15:25 PM

342 Neonatology 2016;109:334344 Steinhorn

DOI: 10.1159/000444895
Downloaded by:
17 Byers HM, Dagle JM, Klein JM, Ryckman KK,
McDonald EL, Murray JC, Borowski KS:
Variations in CRHR1 are associated with per-
sistent pulmonary hypertension of the new-
born. Pediatr Res 2012;71:162167.
18 Perez M, Lakshminrusimha S, Wedgwood S,
Czech L, Gugino SF, Russell JA, Farrow KN,
Steinhorn RH: Hydrocortisone normalizes
oxygenation and cGMP regulation in lambs
with persistent pulmonary hypertension of
the newborn. Am J Physiol Lung Cell Mol
Physiol 2012;302:L595L603.
19 Chandrasekar I, Eis A, Konduri GG: Beta-
methasone attenuates oxidant stress in endo-
thelial cells from fetal lambs with persistent
pulmonary hypertension. Pediatr Res 2008;
63:6772.
20 Lapointe A, Barrington KJ: Pulmonary hyper-
tension and the asphyxiated newborn. J Pedi-
atr 2011;158:e19e24.
21 Murphy JD, Vawter GF, Reid LM: Pulmonary
vascular disease in fatal meconium aspiration.
J Pediatr 1984;104:758762.
22 Thoresen M: Hypothermia after perinatal as-
phyxia: selection for treatment and cooling
protocol. J Pediatr 2011;158:e45e49.
23 Sarkar S, Barks JD, Bhagat I, Dechert R, Donn
SM: Pulmonary dysfunction and therapeutic
hypothermia in asphyxiated newborns: whole
body versus selective head cooling. Am J
Perinatol 2009;26:265270.
24 Shankaran S, Laptook AR, Pappas A, McDon-
ald SA, Das A, Tyson JE, Poindexter BB,
Schibler K, Bell EF, Heyne RJ, Pedroza C, Bara
R, Van Meurs KP, Grisby C, Huitema CM,
Garg M, Ehrenkranz RA, Shepherd EG, Cha-
lak LF, Hamrick SE, Khan AM, Reynolds AM,
Laughon MM, Truog WE, Dysart KC, Carlo
WA, Walsh MC, Watterberg KL, Higgins RD:
Effect of depth and duration of cooling on
deaths in the NICU among neonates with hy-
poxic ischemic encephalopathy: a random-
ized clinical trial. JAMA 2014;312:26292639.
25 Wung JT, James LS, Kilchevsky E, James E:
Management of infants with severe respira-
tory failure and persistence of the fetal circu-
lation, without hyperventilation. Pediatrics
1985;76:488494.
26 Kinsella JP, Truog WE, Walsh WF, Goldberg
RN, Bancalari E, Maylock DE, Redding GJ,
deLemos RA, Sardesai S, McCurnin DC,
Moreland SG, Cutter GR, Abman SH: Ran-
domized, multicenter trial of inhaled nitric
oxide and high-frequency oscillatory ventila-
tion in severe, persistent pulmonary hyper-
tension of the newborn. J Pediatr 1997; 131:
5562.
27 Findlay RD, Taeusch W, Walther FJ: Surfac-
tant replacement therapy for meconium aspi-
ration syndrome. Pediatrics 1996;97:4852.
28 Lotze A, Mitchell BR, Bulas DI, Zola EM,
Shalwitz RA, Gunkel JH: Multicenter study of
surfactant (beractant) use in the treatment of
term infants with severe respiratory failure.
Survanta in Term Infants Study Group. J Pe-
diatr 1998;132:4047.
Advances in Neonatal PH
29 Konduri GG, Sokol GM, Van Meurs KP,
Singer J, Ambalavanan N, Lee T, Solimano A:
Impact of early surfactant and inhaled nitric
oxide therapies on outcomes in term/late pre-
term neonates with moderate hypoxic respi-
ratory failure. J Perinatol 2013;33:944949.
30 Laffey JG, Engelberts D, Kavanaugh BP: Inju-
rious effects of hypocapnic alkalosis in the
isolated lung. Am J Resp Crit Care Med 2000;
162:399405.
31 Marron MJ, Crisafi MA, Driscoll JM Jr, Wung
JT, Driscoll YT, Fay TH, James LS: Hearing
and neurodevelopmental outcome in survi-
vors of persistent pulmonary hypertension of
the newborn. Pediatrics 1992;90:392396.
32 Hendricks-Munoz KD, Walton JP: Hearing
loss in infants with persistent fetal circulation.
Pediatrics 1988;81:650656.
33 Reller MD, Morton MJ, Reid DL, Thornburg
KL: Fetal lamb ventricles respond differently
to filling and arterial pressures and to in utero
ventilation. Pediatr Res 1987;22:621626.
34 Cheung PY, Barrington KJ: The effects of do-
pamine and epinephrine on hemodynamics
and oxygen metabolism in hypoxic anesthe-
tized piglets. Crit Care 2001;5:158166.
35 James AT, Corcoran JD, McNamara PJ,
Franklin O, El-Khuffash AF: The effect of mil-
rinone on right and left ventricular function
when used as a rescue therapy for term infants
with pulmonary hypertension. Cardiol Young
2016;26:9099.
36 McNamara PJ, Shivananda SP, Sahni M, Free-
man D, Taddio A: Pharmacology of milri-
none in neonates with persistent pulmonary
hypertension of the newborn and suboptimal
response to inhaled nitric oxide. Pediatr Crit
Care Med 2013;14:7484.
37 Chen B, Lakshminrusimha S, Czech L, Groh
BS, Gugino SF, Russell JA, Farrow KN, Stein-
horn RH: Regulation of phosphodiesterase 3
in the pulmonary arteries during the perinatal
period in sheep. Pediatr Res 2009;66:682687.
38 Mohamed A, Nasef N, Shah V, McNamara PJ:
Vasopressin as a rescue therapy for refractory
pulmonary hypertension in neonates: case se-
ries. Pediatr Crit Care Med 2014;15:148154.
39 Lakshminrusimha S, Russell JA, Steinhorn
RH, Swartz DD, Ryan RM, Gugino SF, Wynn
KA, Kumar VH, Mathew B, Kirmani K, Mo-
rin FC 3rd: Pulmonary hemodynamics in
neonatal lambs resuscitated with 21%, 50%,
and 100% oxygen. Pediatr Res 2007; 62: 313
318.
40 Lakshminrusimha S, Swartz DD, Gugino SF,
Ma CX, Wynn KA, Ryan RM, Russell JA,
Steinhorn RH: Oxygen concentration and
pulmonary hemodynamics in newborn lambs
with pulmonary hypertension. Pediatr Res
2009;66:539544.
41 Clark RH, Kueser TJ, Walker MW, Southgate
WM, Huckaby JL, Perez JA, Roy BJ, Keszler
M, Kinsella JP: Low-dose nitric oxide therapy
for persistent pulmonary hypertension of the
newborn. Clinical Inhaled Nitric Oxide Re-
search Group. N Engl J Med 2000; 342: 469
474.
Neonatology 2016;109:334344
DOI: 10.1159/000444895
42 Neonatal Inhaled Nitric Oxide Study Group:
Inhaled nitric oxide in full-term and nearly
full-term infants with hypoxic respiratory
failure. N Engl J Med 1997;336:597604.
43 Kinsella JP, Steinhorn RH, Krishnan US,
Feinstein JA, Adatia I, Austin ED, Rosenzweig
EB, Everett AD, Fineman JR, Hanna BD,
Hopper RK, Humpl T, Ivy DD, Keller RL,
Mullen MP, Raj JU, Wessel DL, Abman SH:
Recommendations for the use of inhaled ni-
tric oxide therapy in premature newborns
with severe pulmonary hypertension. J Pedi-
atr 2016;170:312314.
44 Handley SC, Steinhorn RH, Hopper AO, Go-
vindaswami B, Bhatt DR, Van Meurs KP,
Ariagno RL, Gould JB, Lee HC: Inhaled nitric
oxide use in preterm infants in California
neonatal intensive care units. J Perinatol 2016,
in press.
45 Inhaled nitric oxide in term and near-term in-
fants: neurodevelopmental follow-up of the
neonatal inhaled nitric oxide study group
(NINOS). J Pediatr 2000;136:611617.
46 Clark RH, Huckaby JL, Kueser TJ, Walker
MW, Southgate WM, Perez JA, Roy BJ, Kesz-
ler M: Low-dose nitric oxide therapy for per-
sistent pulmonary hypertension: 1-year fol-
low- up. J Perinatol 2003;23:300303.
47 Hanson KA, Ziegler JW, Rybalkin SD, Miller
JW, Abman SH, Clarke WR: Chronic pulmo-
nary hypertension increases fetal lung cGMP
phosphodiesterase activity. Am J Physiol
1998;275:L931-L941.
48 Farrow KN, Lakshminrusimha S, Czech L,
Groh BS, Gugino SF, Davis JM, Russell JA,
Steinhorn RH: SOD and inhaled nitric oxide
normalize phosphodiesterase 5 expression
and activity in neonatal lambs with persistent
pulmonary hypertension. Am J Physiol Lung
Cell Mol Physiol 2010;299:L109L116.
49 Farrow KN, Groh BS, Schumacker PT, Laksh-
minrusimha S, Czech L, Gugino SF, Russell
JA, Steinhorn RH: Hyperoxia increases phos-
phodiesterase 5 expression and activity in
ovine fetal pulmonary artery smooth muscle
cells. Circ Res 2008;102:226233.
50 Farrow KN, Lee KJ, Perez M, Schriewer JM,
Wedgwood S, Lakshminrusimha S, Smith CL,
Steinhorn RH, Schumacker PT: Brief hyper-
oxia increases mitochondrial oxidation and
increases phosphodiesterase 5 activity in fetal
pulmonary artery smooth muscle cells. Anti-
oxid Redox Signal 2012;17:460470.
51 Baquero H, Soliz A, Neira F, Venegas ME,
Sola A: Oral sildenafil in infants with persis-
tent pulmonary hypertension of the newborn:
a pilot randomized blinded study. Pediatrics
2006;117:10771083.
52 Steinhorn RH, Kinsella JP, Pierce C, Butrous
G, Dilleen M, Oakes M, Wessel DL: Intrave-
nous sildenafil in the treatment of neonates
with persistent pulmonary hypertension. J
Pediatr 2009;155:841847.e1.
UFRJ Universidade Federal do Rio de Janeiro
146.164.3.22 - 6/18/2016 7:15:25 PM
343
Downloaded by:
53 Abman SH, Hansmann G, Archer SL, Ivy DD,
Adatia I, Chung WK, Hanna BD, Rosenzweig
EB, Raj JU, Cornfield D, Stenmark KR, Stein-
horn R, Thebaud B, Fineman JR, Kuehne T,
Feinstein JA, Friedberg MK, Earing M, Barst
RJ, Keller RL, Kinsella JP, Mullen M, Deter-
ding R, Kulik T, Mallory G, Humpl T, Wes-
sel DL: Pediatric pulmonary hypertension:
guidelines from the American Heart Associa-
tion and American Thoracic Society. Circula-
tion 2015;132:20372099.
54 Keller RL, Moore P, Teitel D, Hawgood S, Mc-
Quitty J, Fineman JR: Abnormal vascular tone
in infants and children with lung hypoplasia:
findings from cardiac catheterization and the
response to chronic therapy. Pediatr Crit Care
Med 2006;7:589594.
55 Abman SH, Kinsella JP, Rosenzweig EB,
Krishnan U, Kulik T, Mullen M, Wessel DL,
Steinhorn R, Adatia I, Hanna B, Feinstein J,
Fineman J, Raj U, Humpl T, Pediatric Pulmo-
nary Hypertension Network: Implications of
the US Food and Drug Administration warn-
ing against the use of sildenafil for the treat-
ment of pediatric pulmonary hypertension.
Am J Respir Crit Care Med 2013; 187: 572
575.
56 Barst R, Layton G, Konourina I, Richardson
H, Beghetti M, Ivy D: STARTS-2: long-term
survival with oral sildenafil monotherapy in
treatment-naive patients with pediatric pul-
monary arterial hypertension (abstract). Eur
Heart J 2012;33(suppl 1):979.
57 Christman BW, McPherson CD, Newman
JH, King GA, Bernard GR, Groves BM, Loyd
JE: An imbalance between the excretion of
thromboxane and prostacyclin metabolites in
pulmonary hypertension. N Engl J Med 1992;
327:7075.
58 Lakshminrusimha S, Porta NF, Farrow KN,
Chen B, Gugino SF, Kumar VH, Russell JA,
Steinhorn RH: Milrinone enhances relaxation
to prostacyclin and iloprost in pulmonary ar-
teries isolated from lambs with persistent pul-
monary hypertension of the newborn. Pediatr
Crit Care Med 2009;10:106112.
59 Walmrath D, Schneider T, Schermuly R,
Olschewski H, Grimminger F, Seeger W: Di-
rect comparison of inhaled nitric oxide and
aerosolized prostacyclin in acute respiratory
distress syndrome. Am J Respir Crit Care
Med 1996;153:991996.
60 Kelly LK, Porta NF, Goodman DM, Carroll
CL, Steinhorn RH: Inhaled prostacyclin for
term infants with persistent pulmonary hy-
pertension refractory to inhaled nitric oxide.
J Pediatr 2002;141:830832.
344 Neonatology 2016;109:334344
DOI: 10.1159/000444895
61 Porta NF, Steinhorn RH: Pulmonary vasodi-
lator therapy in the NICU: inhaled nitric ox-
ide, sildenafil, and other pulmonary vasodi-
lating agents. Clin Perinatol 2012; 39: 149
164.
62 Ferdman DJ, Rosenzweig EB, Zuckerman
WA, Krishnan U: Subcutaneous treprostinil
for pulmonary hypertension in chronic lung
disease of infancy. Pediatrics 2014; 134:e274
e278.
63 Ivy DD, Kinsella JP, Abman SH: Physiologic
characterization of endothelin A and B recep-
tor activity in the ovine fetal pulmonary cir-
culation. J Clin Invest 1994;93:21412148.
64 Ivy DD, Le Cras TD, Horan MP, Abman SH:
Chronic intrauterine pulmonary hyperten-
sion increases preproendothelin-1 and de-
creases endothelin B receptor mRNA expres-
sion in the ovine fetal lung. Chest 1998; 114:
65S.
65 Gien J, Tseng N, Seedorf G, Roe G, Abman
SH: Endothelin-1 impairs angiogenesis in
vitro through Rho-kinase activation after
chronic intrauterine pulmonary hyperten-
sion in fetal sheep. Pediatr Res 2013; 73: 252
262.
66 Ivy DD, Parker TA, Ziegler JW, Galan HL,
Kinsella JP, Tuder RM, Abman SH: Pro-
longed endothelin A receptor blockade atten-
uates chronic pulmonary hypertension in the
ovine fetus. J Clin Invest 1997;99:11791186.
67 Mohamed WA, Ismail M: A randomized,
double-blind, placebo-controlled, prospec-
tive study of bosentan for the treatment of
persistent pulmonary hypertension of the
newborn. J Perinatol 2012;32:608613.
68 Steinhorn RH, Fineman J, Kusic-Pajic A, Cor-
nelisse P, Gehin M, et al: Bosentan as adjunc-
tive therapy for persistent pulmonary hyper-
tension of the newborn: results of the FU-
TURE-4 study. Circulation 2014;130:A13503.
69 Lipkin PH, Davidson D, Spivak L, Straube R,
Rhines J, Chang CT: Neurodevelopmental
and medical outcomes of persistent pulmo-
nary hypertension in term newborns treated
with nitric oxide. J Pediatr 2002;140:306310.
70 Konduri GG, Vohr B, Robertson C, Sokol
GM, Solimano A, Singer J, Ehrenkranz RA,
Singhal N, Wright LL, Van Meurs K, Stork E,
Kirpalani H, Peliowski A, Johnson Y: Early in-
haled nitric oxide therapy for term and near-
term newborn infants with hypoxic respira-
tory failure: neurodevelopmental follow-up. J
Pediatr 2007;150:235240, 240.e231.
71 Mokra D, Mokry J: Glucocorticoids in the
treatment of neonatal meconium aspiration
syndrome. Eur J Pediatr 2011;170:14951505.
72 Fike CD, Dikalova A, Kaplowitz MR, Cun-
ningham G, Summar M, Aschner JL: Rescue
treatment with L-citrulline inhibits hypoxia-
induced pulmonary hypertension in newborn
pigs. Am J Respir Cell Mol Biol 2015;53:255
264.
73 Vadivel A, Aschner JL, Rey-Parra GJ, Magarik
J, Zeng H, Summar M, Eaton F, Thebaud B:
L-citrulline attenuates arrested alveolar
growth and pulmonary hypertension in oxy-
gen- induced lung injury in newborn rats. Pe-
diatr Res 2010;68:519525.
74 Steinhorn RH, Russell JA, Morin FC 3rd: Dis-
ruption of cGMP production in pulmonary
arteries isolated from fetal lambs with pulmo-
nary hypertension. Am J Physiol 1995; 268:
H1483H1489.
75 Lee KJ, Berkelhamer SK, Kim GA, Taylor JM,
OShea KM, Steinhorn RH, Farrow KN: Dis-
rupted pulmonary artery cGMP signaling in
mice with hyperoxia-induced pulmonary hy-
pertension. Am J Respir Cell Mol Biol 2014;
50:369378.
76 Chester M, Seedorf G, Tourneux P, Gien J,
Tseng N, Grover T, Wright J, Stasch JP, Ab-
man SH: Cinaciguat, a soluble guanylate cy-
clase activator, augments cGMP after oxida-
tive stress and causes pulmonary vasodilation
in neonatal pulmonary hypertension. Am J
Physiol Lung Cell Mol Physiol 2011;
301:L755L764.
77 Wedgwood S, Lakshminrusimha S, Farrow
KN, Czech L, Gugino SF, Soares F, Russell JA,
Steinhorn RH: Apocynin improves oxygen-
ation and increases eNOS in persistent pul-
monary hypertension of the newborn. Am J
Physiol Lung Cell Mol Physiol 2012;
302:L616L626.
78 Farrow KN, Lakshminrusimha S, Reda WJ,
Wedgwood S, Czech L, Gugino SF, Davis JM,
Russell JA, Steinhorn RH: Superoxide dis-
mutase restores eNOS expression and func-
tion in resistance pulmonary arteries from
neonatal lambs with persistent pulmonary
hypertension. Am J Physiol Lung Cell Mol
Physiol 2008;295:L979L987.
79 Davis JM, Parad RB, Michele T, Allred E,
Price A, Rosenfeld W, North American Re-
combinant Human CuZnSOD Study Group:
Pulmonary outcome at 1 year corrected age in
premature infants treated at birth with re-
combinant human CuZn superoxide dis-
mutase. Pediatrics 2003;111:469476.
UFRJ Universidade Federal do Rio de Janeiro
146.164.3.22 - 6/18/2016 7:15:25 PM
Steinhorn
Downloaded by: