Neonatologia

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article as doi: 10.1002/ppul.25073.
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Article Erica Mandell ORCID iD: 0000-0002-7089-7410
Persistent Pulmonary Hypertension of the Newborn
Erica Mandell, DO1,2
John P.Kinsella, MD1,2
Steven H. Abman, MD1,3
Affiliations: The Pediatric Heart Lung Center1
, Sections of Neonatology2
and Pulmonary
Medicine3
, Department of Pediatrics, Children’s Hospital Colorado and University of
Colorado Anschutz Medical Center, Aurora, CO.
Correspondence:Erica Mandell, DO, Neonatology, University of Colorado School of
Medicine and Children's Hospital Colorado, Mail Stop B395, 13123 East 16th Avenue,
Aurora CO 80045 USA Office phone: 720-777-5821; Email:
erica.mandell@childrenscolorado.org
Running title: Persistent Pulmonary Hypertension of the Newborn
Conflict of Interest: None
ABTRACT:
Persistent Pulmonary Hypertension of the Newborn (PPHN) is a significant clinical
problem characterized by refractory and severe hypoxemia secondary to elevated
pulmonary vascular resistance resulting in right-to-left extrapulmonary shunting of

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Article deoxygenated blood. PPHN is associated with diverse cardiopulmonary disorders and
high early mortality rate for infants with severe PPHN. Surviving infants with PPHN have
increased risk of long-term morbidities. PPHN physiology can be categorized by
(1)maladaptation: pulmonary vessels have normal structure and number but have
abnormal vasoreactivity; (2) excessive muscularization: increased smooth muscle cell
thickness and increased distal extension of muscle to vessels that are usually not
muscularized; and (3) underdevelopment: lung hypoplasia associated with decreased
pulmonary artery number. Treatment involves adequate lung recruitment, optimization of
cardiac output and left ventricular function and pulmonary vasodilators such as inhaled
nitric oxide. Infants who fail to respond to conventional therapy should be evaluated for
lethal lung disorders including ACD, TBX4, TTF-1, ABCA3 and surfactant protein
diseases.
Introduction
Fetal oxygenation is dependent upon placental function and umbilical circulation as the
pulmonary vascular resistance (PVR) is high leading to low pulmonary blood flow (Qp)
(38). At birth, the newborn lung must rapidly assume the function the gas exchange to
support tissue oxygenation. In addition to clearance of fetal lung liquid with the
establishment of a gas–liquid interface at the onset of ventilation, PVR must quickly
decrease to allow forthe 8–10 fold increase in Qpin order for sufficient gas exchange
and newborn survival(47). Infants who fail to achieve or sustain the necessary and
normal decrease in PVR right after birth will develop severe hypoxemia, referred to as
persistent pulmonary hypertension of the newborn (PPHN).
PPHN is a syndrome characterized by sustained elevation of PVR with severe

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Article hypoxemia due to extrapulmonary shunting of deoxygenated blood right-to-left across
the patent ductus arteriosus (PDA) and patent foramen ovale (PFO). PPHN can be seen
with many cardiopulmonary disorders with an incidence ranging from 0.4-6.8 per 1000
live births and 5.4 per 1000 live births in late preterm infants (67, 70). Mortality of all
newborns with PPHN have been reported at 7.6% for and 10.7% for infants with severe
PPHN(67). Surviving infants with PPHN have increased risk of long-term morbidities,
including ~25%neurodevelopmental impairment at 2 years(40). This chapter will review
normal fetal pulmonary vascular development and physiology, the pathophysiology of
PPHN, and current clinical strategies including medications that apply a physiologic
approach to the treatment of newborns with severe PPHN.
Fetal Lung Vascular Tone and Regulation
PVR remains high throughout fetal life, particularly in comparison with the low
resistance placental circulation which maintains low systemic vascular resistance. The
majority of the right ventricular output crosses the ductus arteriosus (DA) to the aorta.
Rasanenet al. used doppler ultrasound to demonstrate that human fetal lung receives
about 13% of cardiac output at 20 weeks gestation, and 20% of combined cardiac output
at 30 weeks gestation(57) as compared to animal studies which estimate about 10% of
pulmonary blood flow(59). More recent work in the late gestation fetus using phase-
contrast MRI confirmed previous findingsthat the fetal lung receives 15% of cardiac
output at 37 weeks gestation (56). Throughout gestation both pulmonary artery pressure
(PAP) and pulmonary blood flow progressively increase with the developing growth of
the lung vasculature(28). Despite the progressive increase in lung vascular growth, high

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Article PVR is maintained and even increases during gestation when corrected for gestation age.
The normal fetal pulmonary circulation has been shown to undergo a functional
maturational change in vasoregulation(16, 28), leading to increased vascular tone and
sustained elevations of PVT in late gestation.Initially, the fetal pulmonary circulation is
poorly responsive to diverse stimuli, but reactivity to vasoconstrictor and vasodilator
agonists increases during late gestation(23).
The elevated PVR in fetal life is maintained by many factors, such as mechanical
compression of pulmonary blood vessels from fluid filled alveoli, hypoxic pulmonary
vasoconstriction, increased production of circulating vasoconstrictors (endothelin-1,
thromboxane and leukotrienes), low levels of vasodilator products (nitric oxide [NO]
and prostacyclin [PgI2]), and abnormal smooth muscle cell reactivity leading to
enhanced myogenic tone (47).In the early gestation fetal sheep it has been demonstrated
that thepulmonary vasculature can respond to vasoactive stimuli such as NO(36).
However, pulmonary vascular reactivity to oxygen and acetylcholine has been shown to
increase with maturation during late gestation in the ovine fetus (19, 68). The
vasodilator response to various stimuli, including increased oxygen tension or the
effects of mechanical compression of the ductus arteriosusis often transient, reflecting
the presence of strong vasoconstrictor mechanisms that maintain low pulmonary blood
flow through out gestation(2, 3, 6).It has been suggested that an exaggerated
vasoconstricting myogenic response is the underlying pathophysiology in experimental
PPHN, in part due to the loss of endogenous vasodilators, such asdecreased NO
production, and functional changes in hypertensive vascular smooth muscle(68).

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Article Mechanisms of Pulmonary Vasodilation at Birth
Normally, at birth several simultaneous events occur for a smooth transition from
intrauterine to extrauterine circulation. This transition must include a dramatic fall in
PAP with a concurrent increase in pulmonary blood flow with the clamping of the low
resistance circuit of the placenta. Pulmonary vasodilation is in part stimulated by
physical stimuli such as ventilation of the lungs, an increase in oxygen tension and
sheer stress. This physical stimulation mediates pulmonary dilation in part through
increased production of vasodilators such as PgI2and NOfrom the endothelium(4).
Endothelial NO has been shown to mediate pulmonary vasodilation via the soluble
guanylate cyclase and cyclic guanosine monophosphate (cGMP) pathways.
Additionally, the arachidonic acid-prostacyclin pathway contributes to pulmonary
vasodilation via activation of adenylate cyclase with a subsequent increase in cyclic
adenosine monophosphate (cAMP) concentration within the vascular smooth muscle
cells.
Persistent Pulmonary Hypertension at Birth
PPHN of the newborn occurs from the failure of normal transition of thefetal
circulation at birth leading to persistent elevation of PVR and low pulmonary blood
flow. When the pulmonary blood flow remains low secondary to sustained elevations in
PVR, right to left shunting of deoxygenated blood occurs at the foramen ovale and DA
leading to refractory hypoxemia. Term newborns with hypoxemic respiratory failure is
often presumed to be secondary to PPHN physiology, however,many hypoxemic
newborns lack echocardiographic findings of extrapulmonary shunting across the PDA

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Article or PFO. Thus, PPHN describes hypoxemic newborns with evidence of extrapulmonary
shunting.
The clinical presentation of infants with PPHN includes labile hypoxemia and
often includes the findings of a gradient in oxygen saturations between pre-ductal (right
upper extremity) andpost-ductal values greater than 10% (45). The presence of a pre
and post ductal oxygen saturation gradient over 10% suggests the presence
ofextrapulmonary right to left shunting at the DA. Infantswith PPHN canhave wide
swings in arterial oxygen saturation levels which is due to rapid changes in pulmonary
blood flow and right-to-left shunting associated with acute changes in PVR in response
to minimal stimulation. Physical exam findings are often subtle but may include a loud
second heart sound and a systolic murmur of tricuspid regurgitation. A chest radiograph
is often helpful to differentiate primary parenchymal lung disease (meconium aspiration
syndrome [MAS]) or respiratory distress syndrome [RDS]) from other non-pulmonary
etiologies of PPHN. Typical radiographic findings in idiopathic PPHN include
pulmonary vascular oligemia, normal or slight hyperinflation and a lack parenchymal
infiltrates. In primary PPHN, the degree of hypoxemia is disproportionate to the
severity of radiographic findings of lung disease.
The etiology of PPHN is broad, but can generally be classified into 1 of 3
categories: (1) maladaptation: pulmonary vessels have normal structure and number but
have abnormal vasoreactivity (respiratory distress syndrome (RDS), meconium aspiration
syndrome (MAS), sepsis, orpneumonia); (2) excessive muscularization: increased smooth
muscle cell thickness and abnormal distal extension of muscle into vessels that are

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Article usually not muscularized (chronic fetal hypoxia, idiopathic PPHN); and (3)
underdevelopment: lung tissue hypoplasia associated with decreased pulmonary artery
number (congenital diaphragmatic hernia (CDH), oligohydramnios) (Figure 1). This
designation is imprecise, however, asmanypatients often have elevated PVR that involves
overlapping categories.For example, infants with CDH related PPHN may be due to not
only underdevelopment of the pulmonary vasculature, but also abnormal maladaptation
of the vasculature with abnormal vasoreactivity. Similarly, in infants with PPHN
secondary to MAS the pulmonary vasculature can exhibit excessive muscularization of
vessels in addition to abnormal vasoreactivity. There are many diseases associated with
PPHN in the newborn period (Table 1).
The echocardiogram is an essential diagnostic tool for identifying and managing
newborns with PPHN. Not all term newborns with hypoxemia have PPHN physiology.
Echocardiographic evaluation will rule out anatomic heart disease, including “PPHN
mimics” such as total anomalous pulmonary venous return, severe coarctation of the
aorta and hypoplastic left heart syndrome(associated with obligate right-to-left shunting
across the ductus arteriosus). Echocardiographic studies must determine the predominant
direction of shunting at the PFO as well as the PDA.Although high PAP is commonly
found in neonatal lung disease, the diagnosis of PPHN should not be made without
evidence of bidirectional or predominantly right-to-left shunting across the PFO or PDA.
Echocardiographic signs of increased right ventricular systolic time intervals and septal
flattening are less suggestive of pulmonary hypertension. The echocardiogram is also
useful for evaluation of left ventricular function. While right-to-left shunting at the PDA
and PFO is typical for PPHN, predominant right-to-left shunting at the PDA with left-to-

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Article right shunting at the PFO suggests left ventricular dysfunction which may be related tothe
underlying pathophysiology. Treatment of pulmonary hypertension and severe left
ventricular dysfunction with a pulmonary vasodilation alone may be ineffective in
improving oxygenation, and may be harmful. In this clinical situation, it is important to
enhance cardiac performance and decrease left ventricular afterload in addition
totherapies that decrease PVR. When LV performance is impaired, the use of cardiotonic
therapies that increase systemic vascular resistance may further worsen LV function
leading to increased PAP. Echocardiography provides invaluable information about the
underlying pathophysiology and can guide medical management(26).
Traditional echocardiographic evaluations of the right ventricle (RV) in infants
with PPHN focus on the tricuspid regurgitation jet (TRJV) and PDA shunt direction.
However, cardiac function can be significantly decreased in infants with PPHN
secondary to persistent RV afterload or prolonged hypoxemia(37). Thus, while TRJV can
be elevated in infants with PPHN its lack of presence does not consistently correlate with
clinical outcomes and many times is not reliably measurable in some patients(20, 49).
Malowitz and colleagues have also demonstrated that echocardiography measurements of
tricuspid annular plane systolic excursion (TAPSE) and right ventricle global longitudinal
peak strain (GLPS) in addition to a predominate right-to-left shunt across the PDA have
been demonstrated to be more predictive of progression to death or ECMO in infants with
PPHN(49).
Treatment of PPHN
Management of newborns with PPHN should includetreatment of hypothermia,

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Article hypoglycemia, anemia and/or hypovolemia,sepsis evaluation,correction of metabolic
acidosis,with frequent monitoring of arterial blood pressure, pulse oximetry (pre- and
post-ductal), and transcutaneous PCO2. Additionally, optimization of systemic
hemodynamics with volume and cardiotonic therapy to improve cardiac output and
systemic O2 transport is essential.Newborns who fail to respond to medical
management, as determined by a failure to maintain improvements in oxygenation with
good hemodynamic function, often require treatment with extracorporeal membrane
oxygenation (ECMO)(1). Although ECMO can be a life-saving therapy, it can have
severe complications, such as intracranial hemorrhage. Arterio-venous ECMO
commonlyinvolves ligation of the common carotid artery, and thus the potential for
acute and long-term CNS injuries is a major ongoing concern.
Oxygen therapy and mechanical ventilation
The goal of mechanical ventilation is to improve oxygenation by achieving “optimal”
lung volumes that will minimize the risk for ongoing lung injury secondary to
volutrauma, barotrauma, or atelectotrauma. Inappropriate mechanical ventilation
settings can lead to acute lung injury (ventilator-induced lung injury; VILI). VILI is
characterized by pulmonary edema leading to decreased lung compliance, increased
lung inflammation due to upregulated cytokine production and lung neutrophil
recruitment. Significant VILI can bea critical determinant of the clinical course and
effect outcomes of newborns with hypoxemic respiratory failure. In addition, postnatal
lung injury can worsen the degree of pulmonary hypertension(8, 35, 53). In contrast,
failure to achieve and maintain adequate lung volumes (functional residual capacity)
has been shown toworsen hypoxemia and contribute to persistently high PVR in

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Article newborns with PPHN. In some newborns with parenchymal lung disease and PPHN
physiology will actually improve their oxygenation and decrease right-to-left
extrapulmonary shunting with aggressive lung recruitment using high frequency
oscillatory ventilation (35) or with an “open lung approach” using higher positive end-
expiratory pressure (PEEP) with low tidal volumes, a ventilator strategy more
commonly utilized in older patients with ARDS (8).
It has been demonstrated that acute hyperventilation can improve PaO2 in neonates
with PPHN, however, there are many potential side effects with the prolonged use of
hypocarbic alkalosis from hyperventilation. Hyperventilation can increase the risk of
VILI and its ability to maintain a sustained decrease in PVR is unproven as
experimental studies suggest that the response to alkalosis is transient. Additionally,
these studies show that alkalosis may paradoxically worsen pulmonary vascular tone,
reactivity and permeability edema (8, 44). Prolonged hyperventilation has also been
shown to decrease cerebral blood flow and thus oxygen delivery to the brain,
potentiating unfavorable neurodevelopmental outcomed.
Nitric oxide
Inhaled nitric oxide (iNO) remains the only United States Food and Drug Administration
(FDA)approved pulmonary vasodilator therapy for late preterm and term infants with
PPHN. Endogenous NO is produced by endothelial cells and causes pulmonary
vasodilation through the generation of cGMP. Studies have shown that inhaled NO
diffuses from the alveolus into the smooth muscle cells and leads to selective pulmonary
vasodilation.It is inactivated by hemoglobin in the circulation and hence has minimal
systemic vasodilator effect(35, 39). Inhaled NO vasodilates pulmonary blood vessels that

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Article are adjacent to well-ventilated alveoli causing decreased intrapulmonary right-to-left
shunting and improved V/Q matching.
The response to iNO is both therapeutic and diagnostic (Figure 2). Failure to respond to
iNO is commonly associated with inadequate lung recruitment. Thus, lung recruitment
optimization with the use of PEEP to achieve and maintain functional residual capacity
(FRC) (approximately 8–9 posterior rib expansion on anteroposterior chest X-ray) often
ensures adequate lung recruitment and improves iNO responsiveness.Under- orover-
inflation of the lung can increase PVR secondary to the mechanical compressional effects
on the extra-alveolar and intra-alveolar pulmonary blood vessels. Atelectasis, under-
inflation, increases intrapulmonary right-to-left shunting from inadequate ventilation and
oxygenation leading to worsening hypoxia and hypercarbia. Lung over-inflation can
impede venous return and cause systemic hypotension.
Sildenafil
Although not approved by the FDA for treatment of PPHN in newborns, strong clinical
data and growing experience suggest that sildenafil therapy may provide additional
benefit for the treatment of infants with severe PPHN who fail to fully respond to iNO or
if iNO is not available. A pilot randomized controlled trial of oral sildenafil (2 mg/kg
every 6 hours) demonstrated improvement in oxygenation in newborns with PPHN when
compared with placebo controls(12). Studies have shown intravenous sildenafil is
effective in improving oxygenation in patients with PPHN independent of their exposure
to iNO(65) and may diminish the rebound pulmonary hypertension that can be seen
during weaning of iNO.

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Article Milrinone
Milrinone is an inotropic vasodilator that acts by inhibiting PDE3 and is oftenused in
pediatric cardiac intensive care units to improve inotropy, reduce left ventricular afterload
and augment pulmonary vasodilation, particularly in infants with post-operative low
cardiac output syndrome. Milrinone has been shown to relax pulmonary arteries in a fetal
lamb model of PPHN(46), but is not as potent as agents that directly augment cGMP
signaling. Milrinone can improve oxygenation in selective infants with severe PPHN,
including some infants with partial responsiveness to iNO(13, 50). Milrinone can
improve both right and left ventricular function, (33). Perhaps its greatest utility is in the
setting of PPHN with LV dysfunction, in which lowering systemic vascular resistance
with milrinone may improve LV performance and by lowering pulmonary venous
pressure, can reduce right to left shunting. However, milrinone can reduce systemic blood
pressure and cause systemic hypotension, (17). which may further impair myocardial
perfusion and worsen cardiac function. A small case series suggested identified the
potential risk for systemic hypotension and perhaps intraventricular hemorrhage (13),
which may be worse in the setting of PPHN in preterm infants.(52).
Prostacyclin
Prostacyclin (PGI2) is a potent drug that induces vasodilation through activation of
adenylate cyclase and increasingcAMP in pulmonary arterial smooth muscles. Unlike
iNO, intravenously delivered PGI2can potentiallyworsen ventilation-perfusion matching
in the setting of lung disease and can cause systemic hypotension.Past reports have
shown that PGI2, administered through inhalation or intravenously, may improve
oxygenation andpulmonary hemodynamics in infants who are poorly or partially

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Article responsive to inhaled NO(34). While inhalationalPGI2 administration is commonly used
in adult ICUs, clinical experience has shown that in some settings, PGI2 mayinduce
systemic hypotension in children due to marked systemic vasodilation.
Bosentan
Bosentan is an oral agent that acts through inhibition ofET-mediated vasoconstriction
through endothelin receptorantagonism. It has been actively studied and iscurrently
approved for use in adults with chronic pulmonary hypertensionbut has also shown
promise in neonatal PPHN. Pre-clinical studies using a fetallamb model of PPHN,
demonstrated that chronic in utero ET receptor blockadewas shown to decrease PAP,
right ventricular hypertrophy,and distal muscularization of small pulmonary arteries(30-
32). Clinically, a pilotstudy suggested that bosentan improved oxygenation inneonates
with PPHN(7),but preliminary reports of a recent multicenter trial foundno benefit when
bosentan was administered in combinationwith iNO in infants with PPHN (64).
Extracorporeal membrane oxygenation
Extracorporeal membrane oxygenation (ECMO) providestime for underlying heart and
lung pathology to resolve. Itsuse has dropped dramatically after adoption of improved
ventilationstrategies such as HFOV and pulmonary vasodilationwith iNO, but ECMO
remains an effective and potentially lifesavingrescue therapy for infants with severe
PPHN. With changes in ventilator strategies and selective pulmonary vasodilation with
iNO, ECMO usehas decreased in MAS, but little change in ECMO utilization has
occurred for CDH.
Other Therapies

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Article Other therapies that have be trialed for treatment of PPHN include intravenous (IV)
magnesium sulfate (MgSO4). A randomized controlled study comparing clinical efficacy
of IV magnesium sulfate vs. oral sildenafil in infants with PPHN did not find MgSO4 to
be more effective than oral sildenafil in lowering oxygen index (OI) and pulmonary
artery pressure(69). However, MgSO4 was shown to have a decrease in pulmonary artery
pressure but have a higher rate of systemic hypotensive events.
PPHN in Developmental Lung Disease
Patients with severe hypoxemia who are not responding to conventional therapies should
be evaluated for developmental lung diseases associated with refractory PPHN.
Evaluation for genetic etiologies of refractory PPHN should include: inherited surfactant
dysfunction disorders, such as SP-B/C or ATP-binding cassette A3 gene (ABCA3)
deficiency(43, 62); genetic disruption of distal lung development, such as TTF-1 and Nkx
2.1;FOXF1 mutations leading to alveolar capillary dysplasia (ACD)(63),T-Box
transcription factor 4 gene (TBX4)(22); genetic variants in corticotropinreleasing
hormone (CRH) receptor 1 and CRH-binding protein(15),and inborn errors of
metabolism, such as methylmalonic acidemia.
Preterm Infants and PPHN
Data from the Neonatal Research Network Japan identified the annual incidence rate of
preterm infants with PPHN to be increasing. In 2003 they report 54 cases which
increased to 147 cases in 2012, the annual increase seen mostly in infants born at 22–24
weeks gestation (51). The etiology of PPHN in preterm infants is usually secondary to
hypoxemic respiratory failure related to significant lung pathology soon after birth such

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Article as RDS, PPROM or oligohydramnios causing pulmonary hypoplasia. Respiratory support
(both invasive vs. non-invasive) and surfactant therapy are cornerstones in the
management of RDS. The maintenance of optimal lung volume is crucial regardless of
the underlying lung pathology.
The off-label use of iNO in premature infants has increased dramaticallyin the past two
decades, with the greatest increased use among extreme preterm infants(23 to 26 weeks’
gestation)(41). Randomized controlled trials have demonstratedthat the efficacy of
routine administration of iNO in preterm infants with GA ⩽ 34 weeks to prevent BPD
has varying results, subsequentmeta-analyses have failed to demonstrate decreased BPD
rates(11). However, a post hoc analysis of a larger study, which randomized over 700
mechanically ventilated infants to placebo or iNO, demonstrated a reduction in the
combined outcome of BPD/death in infants who received iNO plus vitamin A for the
750- to 999-g group as compared with iNO alone(21). Additionally, there was an overall
improvement in neurocognitive outcomes at the 1-year assessment in infants (500- to
749-g birth weight group) in the iNO plus vitamin A group compared with those in the
iNO alone group(21).Observational studies have shown a favorable response to iNO
therapy in preterm infants born after PPROM and oligohydramnios (9, 61).
While the routine use of early iNO to prevent BPD is not supported by data from
randomized clinical trials and is not anFDA-approved use of iNO, the successful use of
iNO administration to treat early HRF with strong evidence forPPHN in preterm infants
has been demonstrated in multiple case series(9, 18, 24, 54, 60). Based on these reports
and expert opinion, guidelines for the treatment of pediatric PHpublished by the

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Article American Heart Association and American Thoracic Society in 2015, recommend the use
of iNO in preterm infants with severe hypoxemia primarily due to PPHN physiology,
particularly if associated with PPROM and oligohydramnios(5).
Risk Factors for PPHN
Data from a recent large California birth cohort database identified late preterm infants
(34–36 weeks) having the highest risk of PPHN (5.4 per 1000)(67) with infants of 39 to
40 weeks’ gestation demonstrating the lowest risk of PPHN.Specificantenatal risk factors
for developing PPHN include prolonged premature rupture of membranes (PPROM),
oligohydramnios and pulmonary hypoplasia, in utero closure of the PDA, infants with
trisomy 21, infants of diabetic mothers, IUGR, SGA and LGA infants, chorioamnionitis
and male sex.(14, 27, 42, 58, 67)Specific maternal factors that contribute to an increased
risk of PPHN include race, BMI, diabetes, preeclampsia, maternal smoking, maternal
selective serotonin reuptake inhibitors (SSRI) and non-steroidal anti-inflammatory drug
(NSAID) use during pregnancy.(10, 27, 29)Oligohydramnios-pulmonary hypoplasia
resulting from lung pathologies such as congenital diaphragmatic hernia and renal
anomalies are major risk factors for PPHN(25, 55).
Outcomes
Outcomes of newborns with PPHN are highly dependent on the etiology underlying
PPHN and the resultant pathophysiological changes in pulmonary vasculature. Survivors
can have higher morbidity, including neurodevelopmental and audiological impairments
and rehospitalization, especially in infants with PPPHN associated primary
developmental lung diseases, such as congenital diaphragmatic hernia or genetic

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Article disorders, including alveolar capillary dysplasia, TBX4 mutations, Down syndrome and
others(48, 66). Although PH typically improves and resolves, some patients show
evidence of persistent or recurrent PH, when associated with developmental lung
diseases.
Summary
Newborn infants with PPHN remain at high risk for significant morbidity and mortality
despite major advances in the treatment of PPHN over the past three decades.
Manifestations of PPHN often involve dysfunctional pulmonary vasoregulation with
suprasystemic pulmonary hypertension causing extrapulmonary shunting, pulmonary
parenchymal disease causing intrapulmonary shunting, and systemic hemodynamic
deterioration. Effective management of PPHN depends upon the use of appropriate
strategies to manage the cardiopulmonary interactions. Inhaled nitric oxide therapy serves
as both a therapeutic and diagnostic tool, with a failure to respond to treatment prompting
investigation into other causes of critical hypoxemia.
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Article 13. Bassler D, Choong K, McNamara P, and Kirpalani H. Neonatal persistent
pulmonary hypertension treated with milrinone: four case reports. Biology of the
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Table
ETIOLOGY OF PPHN BY SYSTEM
Pulmonary Genetic/Rare Lethal Lung
Developmental Disorders
• Meconium Aspiration
Syndrome
• Respiratory Distress Syndrome
• Pulmonary Hypoplasia
(Oligohydramnios)
• Congenital Diaphragmatic
Hernia
• Pneumonia/Sepsis
• Idiopathic
• Pulmonary interstitial
glycogenosis
• Congenital Surfactant deficiencies
(SP-B/C, ABCA3)
• TTF-1/Nkx 2.1
• FOXF1 mutation (ACD)
• Mutation of CRH receptor-1
• TBX-4 mutation
• Inborn error of metabolism
• Trisomy 21

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Accepted
Article • Congenital pulmonary
lymphangiectasia
Cardiovascular Other
• Myocardial Dysfunction
• Structural Cardiac Disease
• Mitral Stenosis
• Pompe’s Disease
• Aortic Atresia
• Coarctation of the Aorta
• Interrupted Aortic Arch
• Transposition of Great
Vessels
• Ebstein’s anomaly
• Hepatic Arteriovenous
Malformations (AVM)
• Cerebral AVMs
• Total Anomalous Pulmonary
Venous Return
• Pulmonary Vein Stenosis
• Pulmonary Atresia
• Premature closure of the DA
• Neuromuscular disease
• Polycythemia
• Maternal NSAID or SSRI use
• Maternal smoking
Figures

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Accepted
Article