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Neonatology 2016;109:334344 Published online: June 3, 2016

DOI: 10.1159/000444895

Advances in Neonatal Pulmonary

Robin H. Steinhorn
Childrens National Health System, George Washington University, Washington, D.C., USA

Key Words Introduction

Inhaled nitric oxide Persistent pulmonary hypertension of
the newborn Pulmonary vascular resistance 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
Abstract vascular resistance (PVR) and increase in pulmonary
Persistent pulmonary hypertension of the newborn (PPHN) blood flow. Subsequently, pulmonary artery pressure and
is a surprisingly common event in the neonatal intensive vascular resistance progressively decrease through the
care unit, and affects both term and preterm infants. Recent first few weeks of life. The vasoconstrictive response to
studies have begun to elucidate the maternal, fetal and ge- hypoxia is retained into adulthood, and pulmonary hy-
netic risk factors that trigger PPHN. There have been numer- pertension (PH) can be easily triggered in the newborn
ous therapeutic advances over the last decade. It is now ap- period by hypoxic lung disease, apnea or other causes.
preciated that oxygen supplementation, particularly for the Abnormalities of vascular development or function dur-
goal of pulmonary vasodilation, needs to be approached as ing this critical developmental window can result in per-
a therapy that has risks and benefits. Administration of sur- sistent pulmonary hypertension of the newborn (PPHN),
factant or inhaled nitric oxide (iNO) therapy at a lower acuity a syndrome of failed circulatory adaptation at birth.
of illness can decrease the risk of extracorporeal membrane The PPHN syndrome is defined by sustained elevation
oxygenation/death, progression of disease and duration of of PVR and is often associated with myocardial dysfunc-
hospital stay. Milrinone may have specific benefits as an ino- tion and normal or low systemic vascular resistance. In
dilator, as prolonged exposure to iNO plus oxygen may ac- term and near-term infants, clinically significant PPHN
tivate phosphodiesterase (PDE) 3A. Additionally, sildenafil occurs in about 2/1,000 live born infants [1]. The term
and hydrocortisone may benefit infants exposed to hyper- PPHN is commonly used interchangeably with hypox-
oxia and oxidative stress. Continued investigation is likely to emic respiratory failure, although the latter refers only to
reveal new therapies such as citrulline and cinaciguat that respiratory failure associated with hypoxemia, with or
will enhance NO synthase and soluble guanylate cyclase without PH. PPHN is also recognized in up to 2% of pre-
function. Continued laboratory and clinical investigation will term infants presenting with early respiratory distress [2,
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be needed to optimize treatment and improve outcomes. 3]. In term and near-term infants, PPHN can occur idio- - 6/18/2016 7:15:25 PM

2016 S. Karger AG, Basel

2016 S. Karger AG, Basel Robin H. Steinhorn, MD

16617800/16/10940334$39.50/0 Childrens National Medical Center
111 Michigan Avenue NW
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E-Mail karger@karger.com
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.

Classification, Epidemiology and Pathogenesis of

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-
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-
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pects of pediatric disease [6]. Due to its unique anatomic - 6/18/2016 7:15:25 PM

Advances in Neonatal PH Neonatology 2016;109:334344 335

DOI: 10.1159/000444895
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and functional differences, PPHN is now classified as a rigorous genotype analysis of 88 neonates with docu-
separate subcategory in group 1 (pulmonary arterial hy- mented PPHN [17]. No differences were noted in most
pertension). Developmental lung diseases such as BPD candidate genes, including BMPR2 and nitric oxide (NO)
and CDH are included in group 3 (PH due to lung dis- synthase. However, PPHN was significantly associated
eases and/or hypoxia) due to the growing recognition that with genetic variants for cortisol signaling [corticotropin-
abnormal lung structural growth is often accompanied by releasing hormone receptor-1 (CRHR1) and CRH-bind-
disordered pulmonary vascular growth and PH. ing protein] and increased levels of 17-hydroxyprogester-
Fetal pulmonary development can be disrupted by en- one were observed in PPHN infants. These findings are
vironmental, toxic or other influences. A recent case-con- supported by animal studies indicating that antenatal or
trol surveillance study reported that maternal risk factors postnatal steroids normalize NO synthase function and
of black or Asian maternal race, elevated BMI (>27), dia- improve pulmonary vascular function in experimental
betes, and asthma are associated with a higher risk of PPHN [18, 19].
PPHN. Neonatal risk factors included male gender, large Multiple events can disrupt the timing and overall suc-
for gestational age infants, delivery by cesarean section cess of pulmonary vascular adaptation at birth. In par-
and delivery before 37 weeks or after 41 weeks gestation ticular perinatal asphyxia is a major risk factor for PPHN
[7]. [20]. Many mechanisms associated with asphyxia will
Recent animal and epidemiologic studies also suggest cause respiratory failure and affect the transitional pul-
that maternal therapy can alter fetal pulmonary vascular monary circulation, including fetal hypoxemia, ischemia,
development and function. Two classes of maternal med- meconium aspiration, ventricular dysfunction and acido-
ications, selective serotonin receptor inhibitors (SSRIs) sis. Acute asphyxia is associated with reversible pulmo-
and nonsteroidal anti-inflammatory drugs (NSAIDs), nary vasoconstriction, but chronic in utero asphyxia with
have been of particular interest. SSRI use during the last or without MAS may be associated with more significant
half of pregnancy is associated with an increased inci- vasoconstriction and vascular remodeling [21].
dence of PPHN in several population studies, although Preclinical studies generated concern that therapeutic
the severity of PPHN has not been well described and hypothermia would increase the risk and severity of
other studies have not found this association [810]. It is PPHN in asphyxiated infants. However, randomized tri-
speculated that higher SSRI-induced circulating sero- als of selective head cooling and whole body cooling in-
tonin levels result in pulmonary vasoconstriction [11, dicate that moderate therapeutic hypothermia (33.5 C)

12], although a recent report found no differences in right does not increase the incidence of PPHN (rates of 25 vs.
pulmonary artery Doppler PI in fetuses of mothers ex- 20%) [22, 23]. On the other hand, deeper whole body hy-
posed to SSRI antidepressants [13]. At present, maternal pothermia (32 C) compared with conventional hypo-

physical and psychological well-being remain the prima- thermia at 33.5 C increased the rate of PPHN (34 vs. 25%,

ry factors guiding antidepressant therapy during preg- p = n.s.), the need for iNO therapy (34 vs. 24%, p < 0.05)
nancy and the postpartum period. The use of NSAIDs and ECMO (9 vs. 4%, p < 0.05) [24]. Thus, while standard
such as aspirin during late gestation may be associated hypothermia at 33.5 C does not worsen PPHN, deeper

with closure of the fetal ductus arteriosus and PPHN. hypothermia appears to be significant risk factor and
Based on a recent epidemiologic study, the NSAID asso- should be avoided.
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. New Therapeutic Insights
Unlike PH in older patients, few genetic risk factors for
PPHN have been identified. Children with Down syn- General management principles for PPHN have not
drome (trisomy 21) commonly develop PH in association changed much in the last decade and include mainte-
with structural heart defects, but the risk for idiopathic nance of normal body temperature, electrolytes (particu-
PPHN is also increased by nearly tenfold. In a Dutch co- larly calcium), glucose and intravascular volume. Polycy-
hort with excellent early ascertainment, PPHN was docu- themia should be corrected with a partial exchange trans-
mented in 5.2% of Down syndrome infants [15] and oth- fusion. Other general principles include optimization of
er studies have shown that Down syndrome infants are lung function and support of cardiac function and oxygen
overrepresented in neonates requiring ECMO support delivery including maintaining sufficient hemoglobin
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[16]. A recent single-center study reported the results of levels to optimize blood oxygen carrying capacity. - 6/18/2016 7:15:25 PM

336 Neonatology 2016;109:334344 Steinhorn

DOI: 10.1159/000444895
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Pulmonary Management Cardiac Support

Neonates with clinically significant PPHN almost al- Systemic blood pressure should be maintained at nor-
ways require mechanical respiratory support, although mal levels for age with volume and cardiotonic therapy
few guidelines exist to standardize ventilator manage- with a primary goal of optimizing both left and right ven-
ment. Some advocate a gentle ventilation approach with tricular dysfunction and enhancing systemic oxygen
avoidance of paralysis and blood gas goals consisting of a transport. PPHN is frequently associated with low sys-
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 increased right ventricular afterload, bowing of the intra-
tested [25], but may be the optimal strategy for infants in ventricular septum and restriction of left side filling, and
the early phases of disease. When significant parenchy- myocardial dysfunction. Infants with PPHN typically
mal lung disease is present, high-frequency ventilation have right-to-left shunting at the atrial and ductal level.
improves lung expansion and amplifies the oxygenation Because this extrapulmonary shunting can produce se-
response to iNO [26]. vere hypoxemia, it can be tempting to elevate systemic
Surfactant deficiency (respiratory distress syndrome) vascular resistance to reverse the ductal shunt and im-
or inactivation (e.g. from MAS or pneumonia) is common- prove pulmonary blood flow and oxygenation. While this
ly associated with PPHN, and surfactant therapy can be approach may temporarily improve oxygenation, the
useful when significant parenchymal disease exists. A small neonatal right ventricle is poorly adapted to handle an
randomized study in 40 neonates with MAS reported that acute elevation in afterload [33] and using pressors to
3 doses of surfactant improved oxygenation and reduced raise systemic blood pressure may induce right ventricu-
the need for ECMO, duration of oxygen therapy and length lar failure if PVR does not also fall. It is also important to
of hospitalization (p < 0.05 for each) [27]. A subsequent remember that an open ductus can also protect the right
large prospective multicenter trial found that surfactant ventricle by providing a pop-off that relieves some of the
therapy reduced the need for ECMO by 30% relative to a right ventricular afterload.
control group [28]. However, neonates enrolled late in the Some infants may develop the worrisome finding of
course of disease [oxygenation index (OI): 3139] experi- left-to-right shunt at the foramen ovale despite predomi-
enced no benefit while those with less severe or early dis- nant right-to-left shunting at the ductus. When this oc-
ease (OI: 1522) had a threefold reduction in the need for curs, left ventricular dysfunction is contributing to the
ECMO (p = 0.013). More recently, a retrospective analysis underlying pathophysiology which increases left atrial
of a large group of infants with moderate PPHN found that and pulmonary venous pressure, elevates pulmonary ar-
use of surfactant was significantly associated with de- terial pressure and causes right-to-left shunting with little
creased risk of ECMO/death [29]. Similar to high-frequen- vasoconstriction. In such cases pulmonary vasodilators
cy ventilation, improving lung expansion by surfactant ad- will not improve oxygenation and may cause or aggravate
ministration may be important in optimizing the effect of pulmonary edema; therefore, they must be accompanied
iNO. However, neither of these strategies is effective for by therapies targeted to increase cardiac performance and
idiopathic PPHN because the lungs are already well ex- decrease left ventricular afterload.
panded and without airspace disease. Dopamine remains the most commonly used first-line
Acidosis is a pulmonary vasoconstrictor and enhances agent: it stimulates dopaminergic, 1-, 2- and 1-receptors,
hypoxic vasoconstriction, and should be avoided. Its con- and reliably increases systemic blood pressure in neonates.
verse, alkalosis induced by hyperventilation or infusion of However, some animal studies have shown that high doses
sodium bicarbonate, produces transient pulmonary vaso- of dopamine will elevate both systemic and pulmonary
dilation and was frequently employed prior to the avail- vascular resistances, particularly if pulmonary vascular re-
ability of specific pulmonary vasodilators such as iNO [1]. modeling is present [34]. Milrinone, which inhibits phos-
However, no long-term benefit has ever been documented phodiesterase (PDE) 3 (cAMP PDE) activity in cardiomy-
and prolonged alkalosis may paradoxically worsen pul- ocytes and pulmonary arterial smooth muscle, is viewed as
monary vascular tone, reactivity and permeability edema an inodilator that may be especially useful in the context
[30]. Even more importantly, alkalosis produces cerebral of left ventricular dysfunction and pulmonary venous hy-
vasoconstriction and reduced cerebral blood flow, and is pertension [35]. Since iNO inhibits PDE3 activity both in
associated with neurodevelopmental impairment, includ- vitro and in vivo, milrinone may also be particularly effec-
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ing sensorineural hearing loss [31, 32]. tive as adjunctive therapy for iNO [36, 37]. Arginine vaso- - 6/18/2016 7:15:25 PM

Advances in Neonatal PH Neonatology 2016;109:334344 337

DOI: 10.1159/000444895
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pressin was recently reported to improve both oxygenation
and systemic hypotension in infants with PPHN and con- Prostacyclin (inhaled)
Treprostanil (IV, SQ)
genital heart disease [38]; more studies are needed to de-
termine its mechanism of action and safety. NO PGI2 ET-1

Pulmonary Vasodilation ETB
Guanylate cyclase Adenylate cyclase
Oxygen 5GMP cGMP cAMP AMP muscle
Vasoconstriction cell
Oxygen is a mainstay of PPHN therapy to maintain
oxygen delivery to the brain and other tissues, and to Vasodilation
facilitate pulmonary vasodilation. Alveolar hypoxia and
hypoxemia are pulmonary vasoconstrictors and contrib- Milrinone
ute to the pathophysiology of PPHN and should be avoid-
ed. On the other hand, the degree of hyperoxic ventilation
Fig. 2. Schematic of the NO, PGI2 and ET-1 signaling pathways,
needed for pulmonary vasodilation has recently come un- and therapies taking advantage of the signaling abnormalities. NO
der scrutiny (fig.2). While oxygen is a pulmonary vaso- stimulates sGC to increase intracellular cGMP, and PGI2 stimu-
dilator, the use of concentrations >50% has not been lates adenylate cyclase to increase intracellular cyclic AMP (cAMP).
shown to provide any additional benefit in pulmonary Both cGMP and cAMP indirectly decrease free cytosolic calcium,
vasodilation. Moreover, hyperoxic ventilation increases resulting in smooth muscle relaxation. ET-1 produced by endothe-
lial cells binds ETA and ETB receptors on smooth muscle cells.
oxidant stress and lung injury and may paradoxically im- Sildenafil inhibits PDE5 in vascular smooth muscle, and milrinone
pair the vasodilator response to iNO. Therefore, the oxy- inhibits PDE3 in cardiomyocytes and vascular smooth muscle.
gen concentration and PaO2 should be titrated to maxi- Prostanoids such as Flolan (PGI2) and treprostinil can be given
mize pulmonary vasodilation. Studies in newborn lambs by inhaled or intravenous routes. The ET-1 receptor antagonist
suggest that the lowest PVR can be maintained with a bosentan blocks ET-1 effects and reduces vasoconstriction.
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. with decreased use of ECMO compared to initiation at an
OI >20. This early phase of disease could be optimal for
Inhaled Nitric Oxide future study of pulmonary vasodilators for PPHN. Pre-
NO production is diminished in PPHN, so the thera- term infants with severe hypoxemic respiratory failure
peutic use of inhaled nitric oxide (iNO) was a logical ad- and PPHN presenting on the first day of life will show
vance. iNO reduces PVR and extrapulmonary right-to- marked improvement in oxygenation after treatment
left shunting and improves intrapulmonary ventilation with iNO, similar to the response typical for the term
perfusion matching. iNO acutely improves oxygenation newborn with idiopathic PPHN [43]. Recent reports have
and decreases the need for ECMO support in newborns indicated that iNO use ranges from 4 to 8% in extremely
with PPHN and an OI >25. However, up to a third of in- preterm infants (fig.3) [44].
fants fail to achieve a sustained improvement in oxygen- iNO has potential risks including methemoglobin-
ation and no studies have demonstrated that iNO reduc- emia and increased bleeding time, but over the last 15
es mortality or length of hospitalization. years it has proven to be an exceptionally safe therapy. As
The optimal window for introduction of therapy with iNO consistently reduces the need for ECMO, it seemed
iNO remains uncertain. The initial randomized trials logical that it would improve rates of neurodevelopmen-
studied term and near-term infants with severe PPHN tal impairment. However, follow-up to the pivotal studies
and an OI of 2540 [41, 42]. A subsequent large trial test- used for FDA approval found similar rates of neurodevel-
ed earlier use of iNO in infants with moderate respiratory opmental, behavioral or medical abnormalities at 2 years
failure (median OI of 20), but did not report reductions of age for infants treated with iNO versus placebo [45, 46].
in ECMO/death relative to controls (16.7 vs. 19.5%, re- This surprising finding suggests that neurodevelopmen-
spectively; p = n.s.). However, a post hoc analysis sug- tal impairment could be the result of antenatal or other
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gested that initiating iNO at an OI <20 was associated factors prior to iNO initiation. - 6/18/2016 7:15:25 PM

338 Neonatology 2016;109:334344 Steinhorn

DOI: 10.1159/000444895
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Color version available online

Percent receiving iNO

20 25 30 35 40 45
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 sildenafil as an enteral preparation also makes it feasible

PDE5 catalyzes the breakdown of cGMP and is a key for long-term therapy for infants with chronic PH associ-
regulator of cGMP levels. Similar to endothelial NO syn- ated with CDH [54], but chronic treatment needs more
thase and soluble guanylate cyclase (sGC), expression of study. Long-term follow-up will be important to deter-
PDE5 in the lungs peaks in the immediate newborn pe- mine the efficacy and safety of this approach [55] particu-
riod in sheep and rats, indicating its importance in regu- larly given the findings of the STARTS-2 trial, which
lating pulmonary vascular tone at the time of transition. studied long-term sildenafil in older children (>1 year of
Increased activity of PDE5 is a consistent finding in ex- age) with PH that was idiopathic or due to heart disease
perimental models of PPHN [47, 48]. More recently, in [56]. A multicenter, randomized clinical trial to test the
vitro and in vivo studies have shown that even brief peri- efficacy of sildenafil in iNO-resistant PPHN is nearing
ods of hyperoxia independently increase the activity of completion (NCT01720524). Other PDE inhibitors in-
PDE5 by a mechanism that appears to involve reactive clude tadalafil and vardenafil, but their use in PPHN has
oxygen species (ROS) [4850]. This finding could par- not yet been reported.
tially explain why some infants do not respond favorably
to iNO.
Sildenafil is the best studied of the available phospho- Other Pulmonary Vasodilators
diesterase inhibitors and can be administered by the en-
teral and intravenous routes. A small randomized trial Prostanoids
found that enteral sildenafil improved oxygenation and A complementary vasodilatory pathway in the perina-
survival in term and late preterm neonates with PPHN tal lung is mediated by prostacyclin (PGI2), a metabolite
[51]. In a subsequent dose-finding study, intravenous of arachidonic acid that is endogenously produced by the
sildenafil improved oxygenation in neonates with and vascular endothelium. Similar to NO, PGI2 production
without concurrent iNO treatment [52], suggesting that increases in late gestation and early postnatal life, indicat-
sildenafil may be a useful adjunct in patients with partial ing its importance in the pulmonary vascular transition.
or poorly sustained responses to iNO [53]. Theoretically, Neonatal PH is associated with decreased PGI2 levels ac-
sildenafil may be particularly effective in neonates with companied by increased synthesis of the vasoconstrictor
PPHN following prolonged hyperoxic ventilation since thromboxane A2 [57, 58].
PDE5 expression and activity are increased following PGI2 (epoprostanol) was approved by the FDA in 1995
ventilation with high concentrations of oxygen and expo- for treatment of adult pulmonary arterial hypertension.
sure to ROS. Sildenafil is generally well tolerated, al- While intravenous PGI2 remains a mainstay of therapy
though hypotension can occur particularly if a loading for treatment of PH in adults, rapid dosage escalation is
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dose is given rapidly (<60 min) [52]. The availability of often necessary for acute disease and can produce sys- - 6/18/2016 7:15:25 PM

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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
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 of small pulmonary arteries in utero, decreases right ven-
care unit setting is also limited by the need for a dedicated tricular hypertrophy, and increases the fall in PVR at de-
central venous catheter, the potential to worsen ventila- livery in newborn lambs with PPHN [66]. Thus, it is like-
tion-perfusion matching and other systemic side effects ly that ET-1 acting through the ETA receptor contributes
including pain. to the pathogenesis and pathophysiology of PPHN.
Aerosolized PGI2 has been widely adopted in adult Bosentan, a nonspecific ET-1 receptor blocker, is an es-
critical care units for treatment of PH [59]. While fewer tablished treatment for PH in adults. Two recent trials
reports describe its use in infants, case series indicate that have shown that bosentan is well tolerated in neonates
continuous inhaled PGI2 (50100 ng/kg/min) is well tol- with PPHN. One single-center trial reported that bosen-
erated and improves oxygenation in infants with severe tan led to substantial improvements in oxygenation in an
PPHN and inadequate response to iNO [60, 61]. Risks iNO-nave population of PPHN infants [67], but a subse-
include airway irritation from the alkaline solution need- quent multicenter trial (FUTURE-4) found that bosentan
ed to maintain drug stability, rebound PH if the drug is as adjunctive therapy for iNO did not improve PPHN
abruptly discontinued and inconsistent drug delivery due outcomes, time on iNO or time to extubation, due pos-
to drug loss into the circuit. New, more stable prepara- sibly in part to inconsistent intestinal absorption [68].
tions are emerging that are specifically designed for inter-
mittent nebulization, such as iloprost or treprostinil.
Treprostinil is particularly promising because it is also Outcomes of PPHN
suitable for systemic administration, including by the
subcutaneous route [62]. A randomized study of intrave- Infants with PPHN are among the most critically ill
nous remodulin for PPHN and CDH recently began en- patients cared for in the neonatal intensive care unit.
rolling patients (NCT02261883). They often have a perinatal history that includes low Ap-
gar scores or fetal compromise that place them at high
Endothelin Receptor Antagonists risk for abnormal outcomes. The treatment of PPHN in-
Endothelin-1 (ET-1) is a potent vasoconstrictor syn- volves the use of therapies, including high-frequency ven-
thesized by vascular endothelial cells that acts through tilation, ECMO, hyperoxia and iNO, which may also ad-
two receptors; ETA and ETB. The ETA receptor plays a versely affect outcome. Long-term outcomes for the larg-
critical role in vasoconstriction, and selective blockade of est iNO trials are summarized in table1; these trials also
the ETA receptor causes fetal pulmonary vasodilation provide the most comprehensive, standardized assess-
[63]. ET-1 gene expression and levels are increased in the ment for PPHN infants treated with and without iNO.
lungs and pulmonary arterial endothelial cells in the fetal Overall, these results highlight that neurodevelopmental
lamb model of PPHN [64, 65], and chronic intrauterine impairment is high in this population (1430%) and not
ETA receptor blockade following ductal ligation decreas- improved by iNO [45, 46, 69, 70]. In each of these trials a
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es pulmonary arterial pressure and distal muscularization trend towards higher motor impairment was observed in - 6/18/2016 7:15:25 PM

340 Neonatology 2016;109:334344 Steinhorn

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

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