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Pulmonary Vasodilators in the Treatment of Persistent Pulmonary Hypertension of the Newborn (PPHN)

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Development of inhaled nitric oxide (iNO) therapy for persistent pulmonary hypertension of the newborn (PPHN) is one of the most important therapeutic advances in neonatology. Along with antenatal steroids and surfactant therapy, iNO had a dramatic impact on the outcomes for newborn infants in the NICU. PPHN occurs when the pulmonary vascular resistance fails to decrease at birth. Pulmonary vasodilators, such as, iNO are the mainstay of treatment for PPHN. PPHN can occur in the absence of known parenchymal lung disease (idiopathic or primary PPHN), but more commonly is associated with parenchymal lung disease. Lung recruitment, maintaining normal oxygenation and acid base balance and optimum cardiac function are essential components of relieving pulmonary vasoconstriction in the affected infants. When these measures are insufficient, pulmonary vasodilators can reverse the right to left shunting of blood and rapidly improve oxygenation in PPHN. Cyanotic congenital heart disease should be excluded as the cause of hypoxemia prior to using pulmonary vasodilator therapy. When infants with PPHN fail to respond to iNO therapy, other agents that target cGMP or cAMP in the vascular smooth muscle cells should be considered. Endothelin receptor antagonists are another option, although the evidence for their use in infants is limited. Phosphodiesterase-V (PDE) inhibitors that increase cGMP levels can be orally administered and are an attractive option in the resource limited areas for treatment of PPHN.
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Pulmonary Vasodilators in the Treatment
of Persistent Pulmonary Hypertension
of the Newborn
Ru-Jeng Teng, MD, G. Ganesh Konduri, MD
Introduction
Persistent pulmonary hypertension of the newborn
(PPHN) is a syndrome caused by failure of the pulmonary
vascular resistance (PVR) to decrease at birth. Elevated
PVR can be secondary to pulmonary vasoconstriction,
structural thickening of pulmonary arterial wall, or dys-
morphic angiogenesis in the lung. Prompt recognition
and management of underlying lung disease is an inte-
gral part of the overall approach to PPHN [1]. The over-
all prevalence of PPHN remains constant at 2 per 1000
live births [2,3]. However, the lung diseases contributing
to PPHN have changed over the last 20 years with the
decreasing incidence of meconium aspiration syndrome
[4]. Congenital diaphragmatic hernia is now the leading
cause of severe PPHN among infants needing ECMO can-
nulation for neonatal respiratory failure (Fig. 21.1). This
is followed by meconium aspiration syndrome, primary
PPHN, and surfactant deficiency due to pneumonia or
respiratory distress syndrome. Genetic causes of respi-
ratory failure are increasingly being recognized among
infants with severe PPHN. These include surfactant pro-
tein B and ABCA3 deficiency and alveolar capillary dys-
plasia. Additionally, PPHN can complicate the course
of infants being treated with hypothermia for hypoxic
ischemic encephalopathy [5]. The appropriate treatment
depends on the underlying lung disease contributing to
PPHN. Echocardiography is an essential tool to rule out
congenital heart disease as a cause of cyanosis and to doc-
ument pulmonary hypertension.
CHAPTER CONTENTS HD
Introduction 1
Regulation of vascular tone
in pulmonary circulation 2
General management of PPHN 4
Use of surfactant therapy for PPHN 5
High frequency ventilation 5
Inhaled nitric oxide therapy 5
Phosphodiesterase-5 inhibitors 10
Prostaglandins in PPHN 10
Phosphodiesterase-3 inhibitors 14
Endothelin receptor antagonist 14
Other vasodilators tested in PPHN 14
Conclusions 15
References 15
CHAPTER POINTS
• PPHN remains a challenging clinical problem,
associated with significant morbidity and mortality
for the affected infants
• The introduction of inhaled nitric oxide and other
pulmonary vasodilators have greatly improved the
outcomes in PPHN
• This chapter summarizes our current
knowledge of pulmonary vasodilator therapy,
the challenges that remain and future directions
for research
These proofs may contain colour figures. Those figures may print black and white in the final printed book if a colour print product has not been
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Regulation of vascular tone
in pulmonary circulation
Vascular tone is determined by the continuous balance
between vasoconstrictor and vasodilator influences that
operate on these vessels. The pulmonary vessels are capable
of autonomous regulation of tone, although various neu-
ral, endocrine, and paracrine factors influence the regula-
tion of tone. Fetal pulmonary circulation is in relatively low
oxygen tension (20–39 torr), which facilitates pulmonary
vasoconstriction. This tilt in balance toward vasoconstric-
tion is reversed during postnatal transition, favoring rapid
onset of pulmonary vasodilation. During fetal life, increased
levels of endothelin-1 (ET-1) and thromboxane A2 (TxA2)
contribute to increased tone. Endothelin, a potent peptide
released by vascular endothelial cells [6], exists in at least
three isoforms: ET-1, ET-2, and ET-3, which interact with at
least four known endothelin receptors: ETA, ETB1, ETB2 and
ETC [7]. ET-1 is the most extensively studied vasoconstric-
tor in PPHN; elevated levels have been demonstrated in
PPHN infants [8]. The ETA receptor is primarily located on
vascular smooth muscle cells and mediates vasoconstric-
tion. ET-1 also induces vasoconstrictor effects by the gen-
eration of endothelium-derived TxA2 [9]. The ETB receptor
is primarily located on endothelial cells and its activation
leads to release of NO and prostacyclin when activated, to
cause vasodilatation [6]. However, ETB receptor on vas-
cular smooth muscle cells mediates vasoconstriction and
stimulates cell proliferation. In healthy vasculature, ET
can mediate vasorelaxation due to its site-specific effect on
endothelial ETB receptor, but causes vasoconstriction in
diseased vasculature due to different expression patterns
of the ET receptors [7]. Increased expression of ETA and
ETB receptors on the vascular smooth muscle cells may be
a contributing factor for PPHN. TxA2, the vasoconstrictor
eicosanoid, is a product of PGH2 metabolism by throm-
boxane synthase. Since prostacyclin synthase and throm-
boxane synthase compete for PGH2, decreased expression
or activity of one can lead to higher levels of vasodilator
PGI2 or constrictor, TxA2. Studies in fetal lamb model of
PPHN demonstrated that reciprocal decrease in PGI2 syn-
thase expression and activity is associated with increased
expression and activity of thromboxane synthase and
higher levels of TxB2, the stable metabolite of TxA2 [10].
These studies demonstrate that the vascular tone balance is
shifted toward vasoconstriction in PPHN.
Vasodilation in the perinatal pulmonary circulation is
largely mediated by cGMP- and cAMP-dependent signaling
mechanisms (Fig. 21.2). These two complementary systems
are activated by the release of endothelium derived nitric
oxide for cGMP and prostacyclin for cAMP. Nitric oxide
is the catalytic by-product of the oxidation of
l
-arginine
on the terminal amino group by the enzyme, nitric oxide
synthase, which generates
l
-citrulline. The levels of lung
endothelial NOS protein increase in late gestation to ensure
that pulmonary circulation is primed for the release of NO
immediately after onset of respiration [11]. Both lung dis-
tension and increase in oxygen tension at birth activate
eNOS either directly or indirectly by release of paracrine
factors, such as vascular endothelial growth factor (VEGF)
450
300
360
90
170
246
ELSO registry for neonatal respiratory diseases for 2010 and 2011; n = 1616
RDS
Sepsis
Fig. 21.1 Incidence of Lung Diseases Associated With Hypoxic Respiratory Failure in Term and Late Preterm Infants
Who Required ECMO Cannulation During the Years 2010 and 2011. Data are from the ELSO Registry for neonatal respiratory
indications for ECMO, shown for this 2-year period. Congenital diaphragmatic hernia (CDH) was the most common indication,
followed by primary PPHN (PPHN), meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), and pneumonia/
sepsis. Other includes hypoxic ischemic injury, genetic causes, and other causes of lung hypoplasia.
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Pulmonary Vasodilators
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ISBN: 978-81-312-4998-7; PII: B978-81-312-4998-7.00024-3; Author: VIDYASAGARENGLISH; Document ID: 00024; Chapter ID: c0120
To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s),
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property of the publisher and is confidential until formal publication.
and ATP. NO diffuses to adjacent vascular smooth muscle
cell to activate soluble guanylate cyclase, which initiates
synthesis of cGMP from GTP (Fig. 21.2). Cyclic GMP acti-
vates protein kinase G to decrease the contractility of vas-
cular smooth muscle cell, which leads to vasodilation. The
levels of cGMP in the cell are tightly regulated by the activity
of type V phosphodiesterase in the vascular smooth muscle
which breaks down cGMP to limit the duration of vasodi-
lation (Fig. 21.2). Studies in neonates with PPHN and the
fetal lamb model of PPHN demonstrated downregulation
of NO-cGMP signaling at multiple levels due to increased
oxidative stress. The expression of eNOS and plasma levels
of NO metabolites are decreased in neonates with PPHN
[12,13]. Studies in the fetal lamb model of PPHN demon-
strated that both the expression of endothelial NOS and
its function are decreased with depletion of NOS cofactor,
tetrahydrobiopterin (BH4) and the interaction of eNOS
with its chaperone, Hsp90 [14,15]. Additionally, oxidation
of heme component of soluble guanylate cyclase leads to
decreased sensitivity to NO in PPHN [16]. Increased activ-
ity of PDE-5 also leads to accelerated degradation of cGMP
in the VSM and promotes vasoconstriction [17].
Prostacyclin initiates vasodilation through the activa-
tion of adenylate cyclase, which converts ATP to cAMP,
and activation of protein kinase A (Fig. 21.2). The effects
of PKA activation are similar to PKG activation and leads
to decreased VSM contractility and vasodilation. The levels
of cAMP are also tightly regulated by rapid breakdown of
cAMP by type III phosphodiesterase (Fig. 21.2). Previous
studies in the endothelial cells from fetal lamb model of
PPHN demonstrated decreases in the expression of cyclo-
oxygenase and PGI2 synthase and the levels of PGI2 [10],
suggesting a coordinated downregulation of both cGMP-
and cAMP-dependent signaling in PPHN.
The development of pulmonary vasodilators for PPHN
parallels our understanding of vascular biology of perinatal
circulation as summarized earlier. The available agents tar-
geting the cGMP signaling include inhaled NO, sGC acti-
vators, cinaciguat [16] and riociguat and PDE-5 inhibitors,
sildenafil and tadalafil. Both inhaled nitric oxide (iNO) and
sildenafil have been investigated in neonates with PPHN
through randomized controlled trials (RCTs) and are cur-
rently being used. The sGC activators have been tested in
adults with pulmonary hypertension, but no case reports or
ET-1
ETA
ETA
ET-1
Satyan
ETB1
ETB1
ETB2
PGH
Thromboxane
synthase
Prostacyclin
synthase
TXAPGI
L-arginine L-citrulline
eNOS
Shear stress Lung distension Oxygen ATP VEGF
NO
ET-1
ETA
sGC
NO
cGMP
PGI
IP receptor
AC
cAMP
PKA PKG
Ca++
PDE V
BH
HSP90
PDE III
Endothelial
cell
Smooth
muscle
cell
TP
Vasoconstrictor pathways
Vasodilator pathways
Fig. 21.2 Mechanism of Endothelium-Dependent Pulmonary Vasodilation and Vasoconstriction During Birth-Related
Transition. Birth-related stimuli, including oxygen and lung distension, activate endothelial nitric oxide synthase (eNOS) and
cyclooxygenase directly or indirectly through release of paracrine factors, VEGF and ATP. Release of NO and prostacyclin (PGI2)
leads to activation of guanylate cyclase and adenylate cyclase, respectively in vascular smooth muscle cell. These enzymes in turn
generate cGMP and cAMP, respectively. The cyclic nucleotides then activate their corresponding protein kinases, which lead to
decreased Ca++ and smooth muscle cell relaxation. The phosphodiesterases-V and III breakdown cGMP and cAMP, respectively, to
limit the duration of vasodilation. Two important vasoconstrictor pathways are conversion of PGH2 to thromboxane A2 (TxA2) by
thromboxane synthase and synthesis and release of endothelin-1 (ET-1). Both TxA2 and ET-1 are potent vasoconstrictors released in
response to hypoxia, elevated pressure, or inflammation. Copyright: Satyan Lakshminrusimha.
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To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s),
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clinical trials have been published about their use in neo-
nates. Among cAMP-targeted therapies, intravenous, inhaled,
and subcutaneous PGI2 or its analogs have been studied in
pulmonary hypertension as discussed in detail later. Addi-
tionally, limited data suggest that milrinone, a phosphodies-
terase-3 (PDE-3) inhibitor, improves oxygenation in PPHN
and is currently being used in neonates who fail to respond
to iNO therapy. ETA inhibitor, bosentan has been tested in
case reports and a pilot randomized trial in neonates with
PPHN; current experience with this agent is very limited and
is not recommended as a primary vasodilator in PPHN.
General management of PPHN
Optimum response to pulmonary vasodilator therapy
requires adequate expansion of the lung, proper acid–base
balance, sufficient preload for the left heart, and optimum
cardiac performance (Fig. 21.3). Appropriate use of the
adjunct therapies is as important as the selection of right
vasodilator for the infant (Fig. 21.3). These therapies should
be targeted to the underlying lung disease associated with
PPHN. For parenchymal lung disease secondary to RDS,
pneumonia or perinatal aspiration syndrome, early surfac-
tant therapy can rapidly improve oxygenation and decrease
the level of ventilator support needed for lung recruitment.
Additionally, use of higher PEEP on conventional mechani-
cal ventilation (CMV) or high frequency oscillation (HFO)
in the presence of parenchymal lung disease may enhance
the response to iNO therapy. These two approaches are
discussed further in following sections. The traditional
practice of targeting a high PO2 (>100 torr) and low PCO2
(<40 torr) to achieve pulmonary vasodilation has not been
shown to improve outcomes and is potentially harmful to
the developing lung and cerebral perfusion. While achiev-
ing a normal PaO2 of 60–90 torr is important for restor-
ing postnatal adaptation, there is no evidence that a PaO2
Right
ventricle
Left
ventricle
Pulmonary
artery Pulmonary
vein
Aorta
PDA
Parenchymal
lung disease
Satyan
Optimal
right
ventricular
performance
Left
ventricular
preload
Optimal
left
ventricular
performance
Lung
recruitment
Early
surfactant
therapy
Mean
airway
pressure
Pulmonary
vasodilator
therapy
Satyan
PaO : 60–90 torr
pH : 7.30–7.40
PaCO : 40–50 torr
Right
atrium Left
atrium
Fig. 21.3 A Schematic for the Initial Approach to Management of Hypoxic Respiratory Failure. An integrated approach,
including lung recruitment, pulmonary vasodilation, and optimizing cardiac function with attention to preload, inotropic state, and
afterload is needed for relieving hypoxemia. Copyright: Satyan Lakshminrusimha.
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property of the publisher and is confidential until formal publication.
>100 causes a greater reduction in PVR [18]. Similarly, it
is important to maintain normal acid–base balance (pH
7.30–7.40 and PCO2 40–50 torr) to optimize the responses
to pulmonary vasodilator therapy; however, hypocarbia
and alkalosis should be avoided [19].
Use of surfactant therapy for PPHN
A number of previous studies have demonstrated that sur-
factant improves oxygenation and decreases the need for
ECMO in term and late preterm infants with hypoxic respi-
ratory failure and PPHN [20]. Findlay and coworkers dem-
onstrated in a pilot RCT in 40 term infants with meconium
aspiration syndrome that surfactant improves oxygenation
and decreases the need for ECMO [21]. Neonates treated
with surfactant in this study also had decreased length of
stay on the ventilator, oxygen therapy, and hospital stay.
A subsequent multicenter trial by Lotze et al. randomly
assigned 328 term infants (gestational age >36 weeks)
with respiratory failure to either surfactant therapy or pla-
cebo [22]. The infants treated with surfactant had decreased
need for ECMO. The best responses were observed for
infants with meconium aspiration syndrome or sepsis/
pneumonia and no response was seen for infants with a
diagnosis of primary PPHN. Best responses were also seen
when surfactant was given early in respiratory failure, at an
oxygenation index (OI) of 15–23. Surfactant was less effec-
tive when given at an OI of 23–30 and ineffective when
given at an OI >30, suggesting the need for early treatment
with surfactant for these infants. These two studies were
done before the wide availability of iNO therapy, which
was not used in the study patients. The RCT of early iNO
study done by Konduri et al. reported that infants treated
with surfactant at an OI of 15–25 had a twofold reduc-
tion in the risk of mortality/need for ECMO, compared to
infants that did not receive surfactant [23]. No improve-
ment in outcome was observed with surfactant therapy for
primary PPHN in this study also. However, infants with
any parenchymal lung disease showed a highly significant
(P < 0.001), threefold reduction in the risk of mortality/
need for ECMO. Additionally, surfactant-treated infants
were also significantly more likely to be discharged home
at 30 and 60 days, compared to untreated infants. Surfac-
tant-treated babies in this study also had a decreased length
of stay on the ventilator. These data suggest that surfactant
therapy given early in respiratory failure for parenchymal
lung disease improves the outcomes for the affected infants.
Based on the strength of these data, we recommend that
any late preterm or term neonate requiring intubation and
mechanical ventilation for respiratory failure secondary to
parenchymal lung disease should be given surfactant, early
in the course of illness. A consistent need for FiO2 >40%
on positive pressure support should trigger an evaluation
of underlying lung disease and lung expansion to assess the
need for surfactant therapy.
High frequency ventilation
Although high frequency ventilation (HFV) has been exten-
sively studied in the management of RDS in preterm infants,
few studies were done in term and late preterm infants with
respiratory failure and PPHN. Clark et al. conducted a res-
cue study of HFV versus CMV in a group of 79 neonates
with respiratory failure who met ECMO criteria [24]. They
randomized 40 infants to CMV and 39 to HFV. The treat-
ment failure criteria were met more often by the infants ran-
domized to CMV, although the difference between the two
groups was not significant. The study included a crossover
design for infants who met treatment failure criteria; 16/24
infants who failed CMV and crossed over to HFV improved
their oxygenation, compared to 4/17 who failed HFV and
crossed over to CMV; the difference between the two groups
was significant. An RCT of prophylactic use of HFO early
in respiratory failure did not show a difference in mortal-
ity risk or incidence of air leak, compared to CMV group
[25]. Kinsella et al. randomly assigned neonates with respi-
ratory failure and PPHN to conventional ventilation with
iNO or HFV alone [26]. Infants who failed to respond to
either therapy crossed over to HFV + iNO. They reported
greater oxygenation response to iNO with HFV for infants
with meconium aspiration syndrome or RDS. Infants with
primary PPHN responded to iNO equally whether it was
given with CMV or HFV. These data suggest that a lung
recruitment strategy with the application of HFV, with its
higher mean airway pressure, led to better responses to
iNO, when PPHN is secondary to parenchymal lung dis-
ease. These studies with surfactant and HFV demonstrate
broadly the importance of lung recruitment for optimizing
the outcomes for infants with PPHN. Based on these data,
HFO should be considered for infants with parenchymal
lung disease who fail to improve their oxygenation despite a
trial of surfactant replacement and iNO or other pulmonary
vasodilator therapy. HFO merits consideration when the OI
is >15 despite these measures, since it provides a safe way
to use higher distending pressure, to distribute the vasodila-
tor more uniformly and reduce V/Q mismatch in the lung.
Inhaled nitric oxide therapy
The introduction of iNO therapy had a dramatic impact
on the outcome of babies with PPHN [27]. Hageman et al.
reported 30% mortality risk for infants with PPHN in a
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property of the publisher and is confidential until formal publication.
study published in 1984 [28]. The mortality risk decreased
to <10% in the most recent RCT of iNO therapy, when this
therapy was given early in respiratory failure [29]. Develop-
ment of this approach for PPHN is a remarkable example of
the bench-to-bedside translational biology research done
by several investigators. Shortly after the discovery of NO
as the endothelium-derived relaxing factor was reported in
1987, inhalation of NO as a therapy for pulmonary hyper-
tension was tested in animal models. Inhaled NO was
shown to cause selective pulmonary vasodilation at doses
<100 parts per million (ppm) in a sheep model of pulmo-
nary hypertension [30]. Inhaled NO gas reaches alveolar
space quickly and diffuses to the vascular smooth muscle
of the adjacent pulmonary artery from the abluminal side
(Fig. 21.4). In the smooth muscle cell, NO causes relax-
ation by increasing the intracellular cGMP levels. As NO
continues to diffuse into the lumen of pulmonary artery, it
is rapidly bound and inactivated by Hb, limiting its effect
to the pulmonary circulation. Inhaled NO is also prefer-
entially distributed to the ventilated segments of the lung,
resulting in increased perfusion of the ventilated segments,
thereby optimizing the VQ match (Fig. 21.4). The effect of
iNO on pulmonary circulation is also not limited by the
presence of extra-pulmonary right–left shunts, which often
lead to hypotension with intravenous vasodilators. These
properties make iNO the ideal pulmonary vasodilator in
neonatal respiratory failure. Recent studies demonstrated
that NO levels in the nasal cavity of premature infants can
reach 50–100 parts per billion [31,32]. Significant exhaled
NO concentrations are measured in these infants, suggest-
ing that inhalation of NO occurs physiologically during
tidal respiration [32] in neonates. Pilot studies in neonates
with PPHN reported a rapid and sustained improvement
in oxygenation with iNO [33,34]. The improvement in
oxygenation is usually evident within a few minutes of
starting iNO, which facilitates the rapid stabilization of a
severely hypoxic and compromised neonate. Several large
randomized clinical trials demonstrated that iNO therapy
decreases the need for ECMO/risk of mortality in full term
and late preterm (34 weeks gestation) infants with severe
Satyan
Healthy alveolus
Inhaled nitric oxide
Nitric oxide gas
Diseased alveolus
Lack of NO and
vasoconstriction
(microselective effect)
Selective
pulmonary
vasodilation
adjacent to
ventilated
alveoli
Inactivation of
NO by hemoglobin
Fig. 21.4 Mechanism of Pulmonary Vasodilation in Response to Inhaled Nitric Oxide (NO) Therapy. NO gas enters
alveolar space and diffuses freely across the alveolar epithelium to come in contact with the adjacent pulmonary arteries. Here, NO
initiates vasodilation by increasing cGMP levels in the smooth muscle cells. As NO continues to diffuse into the blood, it binds and
gets inactivated by Hb, restricting the vasodilator effect to pulmonary circulation. Additionally, NO enters only ventilated segments
of the lung and dilates blood vessels only in the ventilated segments, improving VQ match. These properties make it the ideal
pulmonary vasodilator. Copyright: Satyan Lakshminrusimha.
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Pulmonary Vasodilators
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ISBN: 978-81-312-4998-7; PII: B978-81-312-4998-7.00024-3; Author: VIDYASAGARENGLISH; Document ID: 00024; Chapter ID: c0120
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property of the publisher and is confidential until formal publication.
hypoxic respiratory failure and pulmonary hypertension
[32,35–38]. Inhaled NO improves oxygenation in 70%
of the infants with PPHN, with the best responses observed
in idiopathic PPHN [36,37]. Based on the results of these
trials, iNO therapy has been approved for clinical use in
term/late preterm newborn infants (34 weeks gestation)
with hypoxic respiratory failure since 2000 by FDA [1].
Randomized clinical trials suggested that the ideal starting
dose for iNO is 20 ppm with the effective doses between
5 and 20 ppm [29]. Doses >20 ppm did not increase the
efficacy and were associated with more adverse effects in
these infants [37,39].
The timing of initiation of iNO therapy is an important
consideration in the management of PPHN. The RCT of
early iNO for hypoxic respiratory failure has randomized
neonates with moderate respiratory failure (OI 15–25) to
iNO therapy at this OI or to a placebo group that received
standard iNO therapy at OI >25. The group randomized to
early iNO had decreased progression of respiratory failure
to OI >30 or OI >40. On a subgroup analysis of the study
results [23], neonates who received iNO at an OI of 15–20
had a 2.5-fold reduction in the need for ECMO/mortality
risk, which was significant, compared to treatment at OI of
20–25 (P = 0.015). Early iNO also decreased the composite
outcome of progression to OI >30 and/or need for ECMO/
mortality risk [23]. Treatment of neonates with iNO at an
OI of 15–20 also decreased the time to discharge from the
hospital, with an overall decrease in the cost of hospital
care for infants treated at OI of 15–20 compared to those
treated at an OI of 20–25 [40]. Additionally, a review of the
previous clinical trials of iNO therapy shows that decrease
in ECMO/mortality risk parallels the OI at the time of initi-
ation of iNO therapy (Fig. 21.5). The ECMO rates observed
for iNO-treated infants in these trials correlate well with the
OI at the time of initiation of iNO and range from 40% to
11% (Fig. 21.5). The optimum time for initiation of iNO
is before the infant develops severe respiratory failure sec-
ondary to progression of lung disease and/or lung injury.
Taking these data together, we recommend the initiation
of iNO therapy when respiratory failure progresses and OI
reaches 15–20 on at least two blood gases. The randomized
controlled studies of iNO also demonstrated both short-
and long-term safety of this therapy in infants with PPHN.
Inhaled NO therapy can be associated with three potential
adverse events: methemoglobinemia generated by oxida-
tion of Hb by NO, exposure to NO2 generated by reaction of
NO and O2, and inhibition of platelet aggregation by NO.
Previous iNO trials reported low methemoglobin levels
and no significant exposure to NO2 when doses 20 ppm
are used. Davidson et al. reported that at doses of 80 ppm,
the average methemoglobin levels peak at >5% with up
to one-third of babies having levels >7% [39]. Significant
levels of NO2 were also measured at the 80 ppm dose.
Generally, methemoglobin levels <5% are well-tolerated
by neonates and levels 5% should trigger a weaning of
iNO dose and frequent checks of repeat metHb levels until
these levels return to safer range. Abrupt discontinuation
of iNO dose should be avoided. Levels 10% lead to tissue
0
10
20
30
40
50
60
10 15 20 25 30 35 40 45 50 55
Incidence of ECMO and death (%)
Oxygenation index (at initiation of iNO)
43
43
37
30
24
25
22
17
NINOs (1997)
Roberts (1997)
Clark (2000)
Wessel (1997)
Davidson (1998)
Konduri (iNO std 2004)
Konduri (Early 20–25 2013)
Konduri (Early 15 to <20
2013)
Fig. 21.5 Relationship of Severity of Respiratory Failure, Indicated by Oxygenation Index (OI) at the Time of Initiation
of iNO Therapy and the Requirement for ECMO and/or Mortality Risk. The outcome of ECMO/mortality incidence is shown
for the iNO arm of the published randomized trials of iNO therapy in term and late preterm infants with respiratory failure. The
rate of ECMO/mortality risk for the treated infants correlates directly with the OI at the time of initiation of iNO therapy.
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**********To Come**********
| IV |
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hypoxia from inability to adequately saturate the Hb and
lead to lowering of pulse oximeter-measured O2 saturation
despite having a normal or near normal PaO2. This dispar-
ity between PaO2 and pulse oximetry measured-O2 satura-
tion should lead to suspicion of altered Hb affinity for O2
and metHb is a leading cause of decreased O2 affinity of Hb.
In view of the risk of metHb in the babies on iNO therapy,
the level of metHb should be checked 12–24 h after start-
ing this therapy and periodically while the infant remains
on this therapy. In our practice, if the first two checks show
low metHb values, we will monitor them once a week for
the duration of iNO therapy. NO2 levels should be 1 ppm
while receiving iNO therapy. Although a spike in NO2 lev-
els in the circuit can be transiently observed, these levels
should quickly return to 1 ppm. Persistence of higher lev-
els should lead to rapid weaning of iNO and checking of
the equipment and tanks of NO gas for potential leak with
mixing of ambient air with NO. Although altered platelet
function is a potential complication, Christou et al. found
no difference in platelet activation by ADP in babies receiv-
ing 40 ppm of iNO and placebo group [35]. Inhaled NO
therapy is contraindicated in neonates with congenital
heart disease with ductal-dependent systemic blood flow
and in total anomalous pulmonary venous return. In con-
genital heart defects where the systemic blood flow is only
maintained by right ventricular blood flow coming across
the PDA (hypoplastic left heart syndrome, interrupted aor-
tic arch, and severe coarctation), pulmonary vasodilation
can rapidly decompensate the infant. In total anomalous
pulmonary venous return with obstruction of pulmonary
veins, pulmonary vasodilation can worsen the pulmonary
edema and rapidly worsen the respiratory failure. It is
important to use echocardiography to rule out these defects
in a setting where iNO therapy is being used for hypoxic
respiratory failure.
Once an infant’s oxygenation is stabilized, FiO2 and ven-
tilator settings can be weaned before weaning the iNO dose.
Weaning of iNO can commence once FiO2 is decreased to
60% or less. A concern about weaning of the iNO dose after
obtaining oxygenation response is a decrease in PaO2. The
NINOS study used the approach of weaning the dose in
20–10–5–4–3–2–1–0 ppm algorithm. A secondary analy-
sis of arterial blood gas data from the NINOS study by
Sokol et al. reported that weaning from 20 to 10 ppm and
to 5 ppm led to only modest decreases in PaO2 [41]. They
also reported that weaning below 5 ppm in 1 ppm decre-
ments led to small decreases in PaO2, while weaning from
5 to 0 ppm was associated with significant drop in PaO2.
Based on this analysis, iNO should be weaned by 1 ppm
decrements at doses below 5 ppm until the dose is finally
weaned from 1 to 0.5 ppm and then off [41]. Increasing the
FiO2 by 20% at the time of discontinuation can also moder-
ate the decrease in PaO2. Generally, the endogenous eNOS
activity is restored after 30 min to 1 h.
Exposure to iNO even for a brief period can sensitize the
pulmonary circulation to rebound vasoconstriction dur-
ing discontinuation of iNO therapy, even in the absence
of oxygenation response. A significant drop in PaO2 dur-
ing withdrawal of iNO can be avoided by weaning the dose
gradually in steps from 20 ppm to the lowest dose possible
(0.5–1 ppm) for a period of time before its discontinuation
[41]. Even in babies that show no response to iNO, sudden
discontinuation can precipitate pulmonary vasoconstric-
tion and rapid deterioration [1]. When iNO therapy is used
in non-ECMO centers, it should be continued during trans-
port of the infant to ECMO center [1]. Non-ECMO centers
should establish treatment failure criteria for iNO in col-
laboration with the nearest ECMO center so that transfer
of an ill infant is not delayed while waiting for a response
to iNO [1].
Based on the efficacy and safety of iNO from controlled
clinical trials, we recommend using this therapy early,
before prolonged exposure to high FiO2 or maximal ven-
tilator support (Fig. 21.6). Exposure to 100% O2 even for a
brief period can induce vascular dysfunction, increase oxi-
dative stress, and impair subsequent response to iNO [18].
Inhaled NO facilitates rapid weaning of FiO2 and decreases
oxidative stress from O2 in an animal model of PPHN [42].
The recommended starting dose for iNO is 20 ppm. The
dose can be weaned once the infant’s oxygenation is stabi-
lized. Monitoring the metHb levels and NO2 levels to avoid
side effects is important during iNO therapy. Discontinua-
tion of iNO therapy should be done carefully while moni-
toring the oxygenation of the infant.
Use of iNO therapy in premature
infants for hypoxic respiratory
failure and prevention of BPD
Since iNO improves oxygenation in neonates with paren-
chymal lung disease and VQ mismatch, a number of stud-
ies have been done to investigate its use in premature
infants in RDS. These studies have shown that up to 60%
of extremely preterm infants with RDS show improved
oxygenation with iNO therapy [43]. However, iNO therapy
did not improve either survival rate or survival free of BPD
[43]. Several multicenter RCTs investigated the use of iNO
administered in early prophylaxis approach [44,45] or for
prevention of BPD in infants at higher risk for this compli-
cation [46,47]. Ballard et al. conducted a multicenter RCT
in premature infants still requiring mechanical ventilation
at 1–3 weeks of postnatal age, which indicates an increased
risk of BPD [48]. They observed a 7% improvement in sur-
vival free of BPD for infants who received iNO compared to
placebo. On subgroup analysis, most of the improvement
occurred in infants who were given iNO therapy starting at
1–2 weeks of postnatal age [46]. A subsequent multicenter
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Pulmonary Vasodilators
| 21 |
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property of the publisher and is confidential until formal publication.
study has attempted to verify the potential benefit of iNO
therapy suggested in this subgroup analysis, with a larger
sample size [49]. The trial has randomized premature
infants requiring mechanical ventilation at 1–2 weeks of
postnatal age to iNO or placebo. This recent study did not
observe a difference in rates of survival, free of BPD in the
two study groups [49]. Based on these large RCTs, iNO
therapy cannot be recommended for prevention of BPD in
premature infants with respiratory distress. However, some
premature infants present with severe hypoxemia second-
ary to PPHN physiology, despite adequate lung recruitment
with surfactant therapy [50–53]. These infants typically
have pulmonary hypoplasia secondary to premature pro-
longed rupture of membranes, oligohydramnios, and/or
intrauterine growth restriction [50–53]. Limited observa-
tional studies suggest that the use of iNO therapy in these
high-risk infants can be of benefit in relieving hypoxemia
and in lowering mortality risk [50].
Use of vasodilators in BPD
pulmonary hypertension
Pulmonary hypertension has also been recognized as a late
complication of bronchopulmonary dysplasia. The risk of
this complication is higher in infants with IUGR, prenatal
infection, postnatal sepsis or necrotizing enterocolitis, and
prolonged patency of ductus arteriosus [54]. The preva-
lence of pulmonary hypertension in BPD has been esti-
mated to be from 14% to 18% [55–57] in prospective or
retrospective screening studies where PH was identified by
echocardiography done at 32–36 weeks of postmenstrual
age. PH increases the risk of morbidity and mortality in
BPD infants. The current vasodilator management of PH
in BPD is largely based on experience extrapolated from
term PPHN infants. There are currently no RCTs that tested
the efficacy of vasodilator therapy in BPD-PH. The agents
currently used target NO-cGMP system or PGI2-cAMP sys-
tem and ET-receptor antagonists [54]. Since BPD-PH is a
chronic condition in contrast to PPHN in term infants,
therapies that can be used in ambulatory setting are gener-
ally preferred for management of these infants. The com-
monly used agents include enteric sildenafil and bosentan
and subcutaneous treprostinil, a PGI2 analog [54]. Among
these available agents, the largest clinical experience is with
the use of sildenafil. There are no RCTs that tested the effi-
cacy of sildenafil in improving outcomes for BPD infants
with PH. There are four observational cohort studies that
described the outcomes for BPD-PH after sildenafil therapy
[58–61]. These studies had small cohorts ranging from 21 to
25 patients per series. Sildenafil was started at 3–6 months
postnatal age in these reports and the duration of therapy
ranged from 2 to 8 months. Some of the infants were on
other vasodilator medications, including iNO, bosentan,
or milrinone, which makes it hard to assess the response
to sildenafil. Response was evaluated by echocardiography
parameters for pulmonary hypertension, including TR jet
velocity when present, septal flattening, and RV hypertro-
phy. The studies were consistent in reporting improved
PPHN Mild Moderate Severe Panic!
0 15 25 40
OI
100 x MAP x FiO2
Postductal PaO2
OI =
MAP
Ductal
shunt
PaO2
Ventilator
O2
Surfactant for
lung disease
iNOOther agents, HFO
if no response
ECMO
Fig. 21.6 Suggested Timing of Interventions for the Management of Respiratory Failure in Relation to the OI. Early
administration of surfactant, before the infant reaches moderate degree of respiratory failure facilitates optimum lung recruitment.
Early inhaled NO therapy in moderate degree of respiratory failure (OI 15–25) will alleviate pulmonary hypertension early and
shorten the exposure to hyperoxia and barotrauma. If the respiratory failure progresses despite the use of these therapies,
additional lung recruitment measures, such as high frequency ventilation and alternate vasodilators should be considered.
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| IV |
ISBN: 978-81-312-4998-7; PII: B978-81-312-4998-7.00024-3; Author: VIDYASAGARENGLISH; Document ID: 00024; Chapter ID: c0120
To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s),
editor(s), reviewer(s), Elsevier and typesetter Thomson Digital. It is not allowed to publish this proof online or in print. This proof copy is the copyright
property of the publisher and is confidential until formal publication.
hemodynamic parameters in two-thirds of infants after
initiation of sildenafil therapy. However, whether the
improvement occurred from the natural evolution of PH
or as a result of sildenafil therapy remains undetermined
until a prospective RCT is done. The evidence for the use
of bosentan and treprostinil is even more limited with a
few case reports and small case series describing the dose
and route of administration of these agents. PH remains
a long-term complication of BPD and is accelerated by
hypoxia and hypercarbia spells that these infants undergo.
PH appears to be a marker for and contributor to worse
outcomes in BPD and its overall management requires
identification of other BPD complications related to airway
disease, GE reflux, and parenchymal lung disease. Address-
ing these comorbidities can often improve the trajectory of
PH in BPD and should be attempted first before vasodilator
therapy is considered. Additionally, presence of significant
contributors to PH, such as systemic to pulmonary col-
laterals and pulmonary vein stenosis should be carefully
evaluated. Since vasodilator agents can have significant side
effects, initiation of these therapies should be done only
in a setting where multidisciplinary care and follow-up for
infants with BPD and PH are available. Recently, guidelines
for the identification and care of infants with PH secondary
to BPD have been published by investigators from pediatric
pulmonary hypertension network [62].
Phosphodiesterase-5 inhibitors
The PDE-5 inhibitors, sildenafil and tadalafil, have been
investigated widely in adult pulmonary hypertension.
Sildenafil has been investigated to a more limited extent
in neonatal respiratory failure [63,64] and PPHN [65].
Enteric sildenafil was successfully used in an infant with
PPHN with improved oxygenation by the Chief Editor
(RP) in 2002 (BMJ 2002;325:181). Subsequent random-
ized trials have demonstrated its efficacy in improving oxy-
genation and decreasing mortality. A pilot RCT of enteric
sildenafil done in Colombia in a setting where ECMO
was not available showed that it improves oxygenation in
neonates with severe PPHN compared to placebo-treated
infants [65]. The trial was halted early after five out of six
infants in the placebo group died compared to one out of
seven infants in the sildenafil group [65]. Improvement
in oxygenation occurred in the sildenafil-treated infants
6–12 h after the first dose. An RCT of sildenafil given by
enteric route was also done in 51 neonates with PPHN
with 20 infants assigned to placebo group and 31 to oral
sildenafil in a dose of 3 mg/kg/dose in Mexico [66]. This
study reported that sildenafil decreased the mortality risk
significantly from 40% in the placebo group to 6% in the
sildenafil-treated neonates. Improvement in oxygenation
was observed 7 h after the first oral dose of sildenafil. Sys-
temic hypotension was not observed in these studies with
oral/enteric sildenafil. These RCTs show that sildenafil,
used as the primary therapy for PPHN, is effective and
safe in a resource constrained setting where iNO therapy
is not available. A clinical trial of open label IV sildenafil
therapy was done in 36 neonates with PPHN; 29 of the
infants were already receiving iNO therapy [67]. Sildenafil
administration was associated with a significant decrease in
OI, starting 4 h after beginning the infusion. In seven neo-
nates who received sildenafil infusion without iNO, oxy-
genation improved with a decrease in OI from a mean of
24.6–14.7. Overall, one neonate needed ECMO therapy in
this trial. The results of this study suggest that IV sildenafil
can be an alternative or useful adjunct to iNO, when oral/
enteric therapy cannot be given due to the critical nature of
the infant’s illness or side effects from oral sildenafil. Since
hypotension occurred more frequently with IV sildenafil,
we recommend oral/enteric therapy first and attempt IV
infusion when administration by enteric route is not prac-
tical. Initial bolus dose of IV sildenafil also should be given
over 3 h to decrease the risk of hypotension, as shown in
Table 21.1. Tadalafil is a long acting PDE-5 inhibitor that
can be given once a day. An RCT was reported recently
comparing oral sildenafil 1 mg/kg 3 times/day and oral
tadalafil 1 mg/kg once a day; both agents showed similar
efficacy [47]. The dose was chosen based on a recent study
[68]. Once-a-day administration offers better compliance
and ease of administration in practice, when these agents
are used in an ambulatory setting for chronic pulmonary
hypertension. The wide availability and low cost of PDE-5
inhibitors make them ideal alternatives to iNO therapy and
their synergistic effects on NO-cGMP pathway make them
useful adjuncts for infants not responding to iNO therapy
(Fig. 21.6). A suggested algorithm for the application of the
available therapies in neonates with hypoxic respiratory
failure and PPHN is shown in Fig. 21.6.
Prostaglandins in PPHN
Prostacyclin (PGI2) and its analogs relax pulmonary artery
by increasing intracellular cAMP in the smooth muscle
cells [82]. These agents were used as the primary treatment
modality in adults with pulmonary arterial hypertension
for over 3 decades. Most of the experience with prostaglan-
dins in adult patients comes from IV administration of
epoprostenol through a central venous catheter by continu-
ous infusion. However, their use in neonates with PPHN
was more limited since parenteral administration of these
agents can lead to systemic hypotension in the presence of
right to left shunts across PFO or PDA. Additionally, in the
presence of parenchymal lung disease, a global increase in
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Pulmonary Vasodilators
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ISBN: 978-81-312-4998-7; PII: B978-81-312-4998-7.00024-3; Author: VIDYASAGARENGLISH; Document ID: 00024; Chapter ID: c0120
To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s),
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property of the publisher and is confidential until formal publication.
Table 21.1 Vasodilators in PPHN management
Drugs Administration route/dose Mechanism of action Use in PPHN
General treatment
Oxygen To achieve PaO2 60–80 mmHg
or SpO2 90%–97%
Generates ATP in circulation,
enhances NO formation from
endothelium
The first line of treatment
Tolazoline
[69,70]
IV: 0.5–2 mg/kg hr after 1 mg/kg
loading over 10 minutes;
Neb: 1–2.5 mg/kg
Nonspecific endothelium-
independent vasodilation and
α-adrenergic inhibitor
Currently not recommended
due to high risk of systemic
hypotension
Adenosine
[71]
IV: 25–50 µg/kg/min Stimulates A2 adenosine receptor
to induce NO release from
endothelium
• Extremelyshorthalf-life
• Needstobegivencontinuously
through a venous line
Calcium channel blockers
MgSO4[72] IV: 200 mg/kg bolus then
20–150 mg/kg/h
Nonspecific smooth muscle
relaxant
• Slowonsetofresponse
• Musclerelaxation[73] and
sedative effect
Diltiazem [74] IV: 1–2 mg/kg q 12–6 h Block calcium channel Not recommended in neonates
due to adverse cardiac effects
Nitric oxide and nitric oxide donor
Nitric oxide Inhalation: 5–20 ppm Produced in the vascular
endothelium; causes vasodilation
through increase in intracellular
cGMP in the smooth muscle cells
• Thestandardtreatmentfor
PPHN
• Selectivepulmonaryvasodilator
• Needstomonitor
methemoglobin and NO2
during use [75]
Nitroglycerine
[76]
IV: 2–10 µg/kg/min NO donor Not recommended; high risk of
hypotension
Nitroprusside
[77]
IV: 0.2–6.0 µg/kg/min NO donor Monitoring thiocyanate level is
recommended
Prostaglandins
PGI2[78] IV: 2–5 ng/kg/min; increments of
2–5 ng/kg/min q 15 min; aerosol
inhalation of 50 ng/kg/min
continuous [57,69,79,86]:
iloprost 0.5–2 µg/kg/dose q 2–4 h
as inhalation
Produced from arachidonic
acid; causes vasodilatation by
increasing intracellular cAMP in
lung smooth muscle
• Vasodilatationthrough
alternative and complementary
pathway
• MayenhanceNOaction
• Anonspecicpulmonary
vasodilator
• Mayhavesystemiceffects
PGE1[80] IV: 0.01–0.1 µg/kg/min Similar to PGI2Similar to PGI2
PGE2Aerosol inhalation: 100–300
ng/kg/min
Similar to PGI2Similar to PGI2
Phosphodiesterase inhibitors
Sildenafil IV: loading 0.14 mg/kg/h for 3 h
followed by 0.07 mg/kg/h;
PO/NG: 0.5–2 mg/kg/dose q 6 h
Inhibitor of phosphodiesterase
enzyme type V (responsible for
cGMP degradation)
• Itmaypotentiatenitricoxide
• Safeandeasytoadminister
• Mayworsenoxygenationdue
to vasodilation of unventilated
areas
(Continued)
t0 010
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Section
**********To Come**********
| IV |
ISBN: 978-81-312-4998-7; PII: B978-81-312-4998-7.00024-3; Author: VIDYASAGARENGLISH; Document ID: 00024; Chapter ID: c0120
To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s),
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property of the publisher and is confidential until formal publication.
pulmonary blood flow can worsen the VQ match and oxy-
genation. Aerosolized PG given into the lungs can overcome
these limitations; however, their penetration to alveolar and
vascular compartments is uneven due to the deposition of
droplets in ET tube or upper airway, resulting in variable
responses. For these reasons, they are not currently used as
the primary agents in PPHN, but can be important alternate
agents when PPHN infants fail to respond to the combina-
tion of mechanical ventilation, surfactant, and iNO. In our
experience, prostaglandins have been more effective in neo-
nates with PPHN secondary to CDH or alveolar capillary
dysplasia. There are three different prostacyclin analogs that
are currently available and their use and route of adminis-
tration in neonates is discussed in following sections, with
the manufacturer given names in the parentheses.
Epoprostenol (Flolan, Veletri)
Epoprostenol can be given either through IV or aerosol route.
It is one of the most commonly prescribed vasodilators for
pulmonary hypertension. The effects of epoprostenol last
only a few minutes; consequently, it requires continuous IV
infusion or continuous aerosol administration. In one retro-
spective study in neonatal PPHN, it was initiated at 1–2 ng/
kg/min and subsequently titrated up by 0.5–2 ng/kg/min,
intravenously [78,83]. Eronen et al. reported starting it at a
higher dose of 20 ng/kg/min IV, which was later increased
stepwise to a mean dose of 60 ng/kg/min (30–120 ng/
kg/min) [84]. Systemic hypotension was noted in some
patients, which required volume expansion and inotropic
support. There are currently no RCTs to determine its effi-
cacy, optimum dose, or frequency of side effects in neonates
with PPHN. Aerosol administration of epoprostenol has
been shown to improve oxygenation in pilot studies and
in case reports [85–87]. Bindl et al. reported that a dose of
20–30 ng/kg/min of continuous aerosolized PGI2 adminis-
tration has improved oxygenation in one term infant with
PPHN but was less effective in another infant [88]. Kelly
et al. reported that continuous epoprostenol aerosol admin-
istration has improved oxygenation in four infants with
PPHN unresponsive to iNO [86]. They administered the
drug by continuous nebulization at a dose of 50 ng/kg/min,
diluted into a volume of 8 mL/h. One concern with inhaled
epoprostenol treatment is that the diluent buffer has an
alkaline pH of 10. Kelly et al. reported no adverse effects in
their pilot study; however, no data on the potential impact
of high pH on the neonatal lungs are available.
Iloprost (Ventavis)
Iloprost is a synthetic PGI2 analog with a half-life of 20–30
min and can be given by inhaled route up to 6–9 times
a day through a nebulizer or can be also given intrave-
nously. A retrospective study compared inhaled iloprost
with oral sildenafil in term infants with PPHN in a setting
where iNO, ECMO, and HFV were not available. This study
observed better responses in the Iloprost treatment group
[89]. The dose for inhaled Iloprost was 1–2.5 µg/kg every
2–4 h through the endotracheal tube via a nebulizer [88]. In
another retrospective study, 15 premature infants who were
treated with surfactant and ventilator support continued to
have OI above 25 with suspected PPHN. Inhaled Iloprost
was given at a dose of 0.5–1.0 µg/kg/day. The mean maxi-
mal OI decreased from 38 to 8 by the end of the treatment.
Drugs Administration route/dose Mechanism of action Use in PPHN
Tadalafil [68] PO/NG: 1 mg/kg/day once daily Similar to sildenafil Similar to sildenafil
Milrinone Term:
IV: loading: 50 µg/kg over 60 min;
maintenance: 0.25–0.75 µg/kg/
min or continuous infusion only
at 0.25-0.75 µg/kg/min [100]
GA <30 weeks:
IV: loading: 50 µg/kg over 3 h;
maintenance: 0.2 µg/kg/min
Inhibitor of the
phosphodiesterase enzyme type
III (responsible for degradation of
cAMP)
• Maypotentiatetheactionof
prostaglandins
• Improvesrightcardiacoutput
by reducing afterload
Dipyridamole
[46,81]
IV: 0.3–0.6 mg/kg Nonspecific PDE inhibition Use together with iNO to prevent
rebound vasoconstriction
Endothelin receptor inhibitor
Bosentan Oral: 1–2 mg/kg twice daily Nonspecific antagonist A and B
endothelin receptors
Seldom used in newborns due to
the potential for damage to liver
function
Table 21.1 Vasodilators in PPHN management (cont.)
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ISBN: 978-81-312-4998-7; PII: B978-81-312-4998-7.00024-3; Author: VIDYASAGARENGLISH; Document ID: 00024; Chapter ID: c0120
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No cessation of treatment was needed for side effects in
this report [90]. There were a few other case reports using
Iloprost nebulization at doses 2 µg/kg in extremely prema-
ture infants with PPHN [91] or a total dose of 20 µg/kg/
day in term infants [92]. For intravenous administration,
a starting dose of 0.5–3.0 ng/kg/min with maintenance
doses of 1–10 ng/kg/min of Iloprost was reported in severe
PPHN [93]. The dosage was then titrated up by the clinical
response and was adjusted by 0.5–1 ng/kg/min increments
in this study [93]. We prefer to use agents, such as Iloprost
by aerosol route, to take advantage of the preferential pul-
monary vascular effects and avoidance of hypotension
(Fig. 21.7). Inhaled PG also overcomes the presence of right
to left extra-pulmonary shunts, which interfere with the
delivery of IV agents to pulmonary circulation (Fig. 21.7).
Treprostinil (Tyvaso, Remodulin and
Orenitram)
Treprostinil, a stable prostacyclin analog, was initially
approved by the FDA for subcutaneous use and subse-
quently approved for intravenous and inhaled use. Com-
pared to epoprostenol, treprostinil is [54] stable at room
temperature, [94] has longer half-life, [42] fewer side effects,
and [46] a smaller pump size as an option for continuous
infusion. Subcutaneous treprostinil offers the advantage of
not requiring a central venous catheter [95]. In our limited
experience and published case series, SC administration of
treprostinil is well tolerated by neonates with very few of
the local complications previously reported in older chil-
dren and adults. This route makes ambulatory administra-
tion feasible with appropriate training of the parents [96].
Our longest experience with SC treprostinil administration
in an ambulatory setting is 9 months in a premature infant
with BPD who had persistent elevation of PVR, despite oral
sildenafil therapy.
Prostaglandin E1 (Alprostadil)
Prostaglandin E1 (PGE1) has been used in infants with duc-
tus arteriosus–dependent congenital heart disease at doses
of 0.01–0.1 µg/kg/min as IV continuous infusion [97]. Once
ductal patency is established, the infusion can be titrated
down to the lowest effective dose (generally at 0.01 µg/kg/
min). PGE1 also can cause pulmonary vasodilation and has
been used for this indication in PPHN. PGE1 can improve
right ventricular function in CDH patients by providing pat-
ent ductus arteriosus as an outlet to decompress the stressed
right ventricle and to assist the systemic blood flow in the
presence of LV dysfunction. PGE1 can be also aerosolized
SVC
RA
LA
RV
LV
PA
PDA
AortaVentilated
alveolus
Non-ventilated
alveolus
Dilated pulmonary vessels
Constricted pulmonary vessels
Inhaled
vasodilator
No systemic
vasodilation
IVC
Satyan
Improved ventilation–perfusion match
Inactivation
of vasodilator
in circulation
Fig. 21.7 Benefits of Inhaled Vasodilators in Neonates with PPHN Secondary to Parenchymal Lung Disease. Inhaled
vasodilators, iNO, and prostacyclin are preferentially distributed to ventilated segments of the lung, where they dilate the
adjacent pulmonary vessels. They do not reach the atelectatic segments of the lung where pulmonary vessels remain constricted.
This property improves the matching of ventilation with perfusion. In case of inhaled NO, inactivation of NO by Hb limits the
vasodilation to pulmonary circulation, leading to highly selective effect on the lung. Inhaled vasodilators also are not affected by
presence of right to left extra-pulmonary shunts at PFO and PDA, which reduce the delivery of IV agents to pulmonary circulation.
Copyright: Satyan Lakshminrusimha.
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**********To Come**********
| IV |
ISBN: 978-81-312-4998-7; PII: B978-81-312-4998-7.00024-3; Author: VIDYASAGARENGLISH; Document ID: 00024; Chapter ID: c0120
To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s),
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and administered into the lung, similar to epoprostenol.
Sood et al. reported that a safe and effective dose of inhaled
PGE1 is 150–300 ng/kg/min in their phase I/II open label
clinical trial [98]. However, a planned RCT of PGE1 for
PPHN was terminated early due to low enrollment.
Phosphodiesterase-3 inhibitors
Milrinone (Primacor)
Milrinone is the only available PDE-3 inhibitor which has
been used in PPHN treatment. Milrinone increases the
bioavailability of cAMP and may indirectly also increase
cGMP levels through some inhibitory effect on PDE-5 [99].
McNamara et al. reported an open label trial of milrinone
in 11 term neonates with PPHN. Milrinone was given in a
loading dose of 50 µg/kg over 30–60 min, followed by a
maintenance infusion at 0.33–0.99 µg/kg/min for 24–72 h
[100]. They observed improvement in PaO2 and sustained
reductions in FiO2, OI, mean airway pressure, and iNO
dose. They also demonstrated decreases in PA pressure and
right to left shunts and improvement in LV and RV output
by echocardiography. Although hypotension was observed,
they noted an improvement in base deficit and reduction
in blood lactate levels. Bassler et al. reported their experi-
ence with milrinone in four neonates with severe PPHN
unresponsive to iNO, with mean OI of 40 ± 12. They
observed an improvement in oxygenation, with a reduc-
tion in OI to 28 ± 16 followed by extubation and survival
of all four infants. However, two infants developed severe
IVH and one other infant had a small IVH. Since this is
not an RCT, it is unclear whether the IVH was secondary
to severe underlying illness or to milrinone administration
[79]. We currently use milrinone in neonates with CDH,
where its combination of pulmonary vasodilator and ino-
tropic effects are beneficial in some infants with PPHN and
poor LV function. However, RCTs are needed to define its
indications, efficacy, and potential side effects. We advise
against using both sildenafil and milrinone simultaneously
in the same infant due to the potential for severe hypo-
tension associated with blocking both PDE isoforms in the
vascular smooth muscle.
Endothelin receptor antagonist
There are three oral medications (bosentan, ambrisentan,
and macitentan) in the endothelin receptor antagonist
(ERA) class. These medications block the endothelin recep-
tors, thereby reducing the vasoconstrictor effects of endo-
thelin. Bosentan is the first ERA available to treat PPHN,
and it blocks both type A and type B receptors. Ambrisen-
tan is another oral ERA that preferentially blocks the ETA
receptor, and is a pill which is taken once daily. Macitentan
is the most recently approved once daily pill that blocks
both the type A and the type B ET receptors. Bosentan is the
only one studied in neonates with PPHN. It is a competi-
tive antagonist of ET-1 at both ETA and ETB receptors with
slightly higher affinity for ETA than ETB [101 ] . Nakwan
et al. have previously reported the benefits of bosentan in
neonates with PPHN [102]. An RCT in PPHN infants less
than 7 days of age, in a setting where iNO and ECMO were
not available, showed an 88% response rate with improved
oxygenation in the treatment group, compared to 20%
response rate in the placebo group [103]. The dose used in
that study was 1–2 mg/kg twice daily, via nasogastric tube.
No detectable side effect was observed in this report, but
liver injury has been reported in adult patients with pul-
monary arterial hypertension. A recent randomized trial of
Bosentan in a group of neonates already on iNO therapy
for respiratory failure [104] was stopped early due to slow
recruitment. Bosentan was found to be safe, but no signifi-
cant improvement in oxygenation, time to wean from iNO,
or ventilator support was noted in the Bosentan-treated
group compared to placebo. Although systemic blood pres-
sure and hepatic transaminases were not different between
the groups, more infants treated with Bosentan had anemia
and peripheral edema. The study also found low serum lev-
els of the drug for the first 5 days after beginning nasogas-
tric administration, possibly due to poor absorption from
the gut in these ill neonates. Based on this limited evidence
and the availability of agents that are more widely stud-
ied, bosentan is not recommended as first or second line
therapy and should be reserved for occasions where iNO,
PDE inhibitors, and prostacyclin analogs failed to provide
improvement or are unavailable in PPHN.
Other vasodilators tested in PPHN
Magnesium sulfate
Magnesium sulfate was previously used to treat PPHN in
settings where inhaled NO and PDE-5 inhibitors were not
available [72,94,105]. The reported doses of MgSO4 were
20–100 mg/kg/h, following a loading dose of 200 mg/
kg over 30 min. Magnesium is believed to inhibit NMDA
receptors in the central nervous system [106] to offer pro-
tection to the brain and to induce muscle relaxation by
blocking the neuromuscular junction [73]. Magnesium
antagonizes calcium in the smooth muscle cells, which
leads to muscle relaxation. However, only observational
studies are available in newborn infants. Magnesium sul-
fate should be only rarely used in PPHN since it can be
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Pulmonary Vasodilators
| 21 |
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associated with systemic hypotension. Owing to the lack
of adequate RCTs and the availability of more effective pul-
monary vasodilators, we currently do not recommend the
use of MgSO4 in this setting.
Adenosine
Adenosine is a purine nucleoside and vasodilator of sys-
temic and pulmonary vasculature in both fetal and neo-
natal vessels [107,108]. Adenosine causes vasodilatation
by activation of endothelial A2a adenosine receptors and
subsequent release of NO [78]. From a randomized, pla-
cebo-controlled trial of 18 infants, Konduri et al. showed
an improvement in oxygenation in 45% of term infants
with PPHN [109]. The dosage used was 25–50 µg/kg/min
given as continuous infusion. This study did not report any
systemic side effects, presumably due to the rapid metabo-
lism of adenosine at these doses by pulmonary vascular
endothelial cells, as previously shown in the lamb model
of neonatal pulmonary hypertension [108]. However, the
improvement in oxygenation was not sustained and it did
not decrease the need for ECMO or mortality in neonatal
PPHN [109]. In a single-center prospective observation
study, nine infants on mechanical ventilation and receiv-
ing iNO at 20 ppm were given continuous intravenous
infusion of adenosine at 50 µg/kg/min; six of these infants
responded favorably with improved oxygenation [110].
Owing to its extremely short half-life, adenosine should be
given through continuous infusion, preferably in the upper
part of the body, since SVC flow is less likely to be shunted
across the PFO.
Steroids
A randomized controlled study showed benefit to the use of
glucocorticoids in managing PPHN caused by meconium
aspiration [ 111 ] . Improved oxygenation was also shown
with antenatal betamethasone or postnatal hydrocortisone
in a sheep model of PPHN [112–114]. The possible mecha-
nisms include increase in eNOS expression and function in
the endothelial cells or normalization of PDE-5 activity in
pulmonary artery smooth muscle cells [114]. Although ste-
roids are commonly used in neonatal intensive care unit to
manage systemic hypotension, its efficacy in relaxing pul-
monary arteries in PPHN remains to be determined. There
are currently no RCTs of this therapy in PPHN. Based on
the studies in premature infants, there is a concern of pos-
sible neurodevelopmental effects when they are adminis-
tered early in life.
Conclusions
PPHN occurs in 2/1000 live births and the affected infants
are often the sickest in the neonatal intensive care units.
The introduction of iNO therapy led to dramatic improve-
ments in the outcomes for the neonates with PPHN [115].
However, about 20%–30% of these infants do not improve
their oxygenation sufficiently with iNO, creating a need for
alternate agents to manage refractory PPHN. The incidence
of PPHN remains high and the survival rate for affected
infants remains low in the resource-constrained areas of the
world where surfactant, HFV, and iNO therapy are not read-
ily available. The use of alternate agents like oral sildenafil
or inhaled prostaglandins may offer benefit in these areas
(Table 21.1). However, many of these alternate vasodila-
tors lack high quality RCTs to establish their efficacy. Some
newer agents showed promising effects in animal studies,
but no human experience is available [16]. In future, con-
ducting these trials specifically in the settings where iNO
is not available, may provide important evidence to define
their indications, appropriate dose, and weaning strategies.
Adaptive trial designs with crossover component need to
be developed as alternatives to 1:1 randomization tradi-
tionally used in RCTs to allow the benefit of potentially
useful therapies in the affected infants with PPHN in these
settings. Finally, future studies need to explore the genetic
factors that contribute to the development of PPHN and
variability in the response to different vasodilators.
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**********To Come**********
| IV |
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editor(s), reviewer(s), Elsevier and typesetter Thomson Digital. It is not allowed to publish this proof online or in print. This proof copy is the copyright
property of the publisher and is confidential until formal publication.
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Pulmonary Vasodilators
| 21 |
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To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s),
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property of the publisher and is confidential until formal publication.
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Section
**********To Come**********
| IV |
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19
Chapter
Pulmonary Vasodilators
| 21 |
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To protect the rights of the author(s) and publisher we inform you that this PDF is an uncorrected proof for internal business use only by the author(s),
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Article
Full-text available
Background Persistent pulmonary hypertension of the newborn (PPHN) occurs in post-term neonates with an incidence of 1 in 500 - 1,500 live births. The survival rate is approximately 69% after conventional management of infants suffering from PPHN. Extracorporeal membrane oxygenation (ECMO) therapy improves survival up to 86%. Methods A total of 32 neonates with PPHN participated in this study. These neonates were randomly assigned into two 16-case groups: group A received tadalafil while group B received sildenafil. A random simple sampling method was used for the selection of subjects. The severity of tricuspid regurgitation (TR), main pulmonary artery (MPA) diameter, mean pulmonary artery pressure (MPAP), and right ventricular end-diastolic diameter (RVEDD) were assessed by echocardiography before and 6 months after treatment. Results MPAP decreased after treatment in both groups, but the mean of changes in PAP in the two groups was not significantly different (P = 0.48). Both tadalafil and sildenafil significantly reduced the TR severity, RVEDD, and MPA diameter (P < 0.05), but the mean of the changes in TR, RVEDD, and MPA in both groups was similar (P = 0.05). Conclusions Tadalafil and sildenafil can similarly reduce MPAP, TR severity, RVEDD, and MPA diameter.
Article
Background: Inhaled nitric oxide (iNO) cannot be recommended for the routine treatment of respiratory failure in premature neonates, but it has been suggested that the effectiveness of iNO therapy should be further studied in more select preterm infants, such as those with persistent pulmonary hypertension of the newborn (PPHN). Objective: To evaluate the frequency of PPHN in very preterm infants with severe respiratory distress syndrome (RDS), to assess the effectiveness of iNO in these patients, and to individuate possible predictive factors for the response to iNO in preterm infants with RDS. Study design: We retrospectively studied infants <30 weeks of gestational age or birth weight <1250 g, who were affected by severe RDS and treated with iNO during the first week of life. Clinical characteristics of infants with or without echocardiographic diagnosis of PPHN were compared, as well as those of responder or no responder to iNO therapy. Effectiveness of iNO was evaluated by recording changes of MAP, FiO2 , SpO2 /FiO2 ratio, and oxygenation index (OI) before, and 3 ± 1, 6 ± 1, 12 ± 3, 24 ± 6, 48 ± 6, and 72 ± 12 h after beginning therapy. Results: We studied 42 (4.6%) infants, of whom 28 (67%) had PPHN and 14 (33%) did not. iNO therapy was associated with improved oxygenation in both the groups but it was quicker in the PPHN than in the no PPHN group. Multivariate analysis showed that FiO2 >0.65, diagnosis of PPHN, and birth weight >750 g independently predicts effectiveness of iNO in very preterm infants with RDS. Conclusion: We found that PPHN is a frequent complication of severe RDS in very preterm infants and iNO therapy can improve their oxygenation earlier than in infants without PPHN. iNO therapy is not recommended for the routinely treatment of RDS in premature neonates but in cases of concurrent diagnosis of PPHN it should be considered carefully.
Article
Background: Therapy with inhaled nitric oxide (iNO) is effective in the management of pulmonary hypertension and severe hypoxemia. However, these benefits have not been demonstrated in preterm infants (<34 weeks). The objective of this report is to present the experience of eight cases of preterm neonates with respiratory distress syndrome (RDS) and refractory hypoxemia, with oligohydramnios history. Methods: We evaluated the clinical feature of 8 preterm neonates with severe hypoxemia who had maternal antecedents of oligoamnios, mainly due to premature rupture of membranes. They were treatment with conventional management, with poor clinical response. These neonates were treated with iNO, for avoid their dead. iNO has been used with a dosage of 5 - 10 ppm. An echocardiogram was performed to determine the presence of structural malformations or persistent ductus arteriosus. Results: All the infants showed improvement in oxygenation. The neonates had signs of low flow pulmonary, confirmed by echocardiogram. Five preterm infants survived without complications associated with the therapy. Two died from pulmonary bleeding secondary to ductus arteriosus and another for pneumotorax. Conclusion: iNO therapy can be useful in a subgroup of preterm infants with a high risk of death secondary to hypoxemia. Although this report is based on a small number of cases, it follows the directions of other studies that suggest that iNO therapy can benefit preterm neonates, particularly those exposed to oligohydramnios.
Article
Objective: To describe short-term and long-term outcomes of preterm neonates with severe acute pulmonary hypertension (aPHT) in relation to response to rescue inhaled nitric oxide (iNO) therapy. Design: Retrospective cohort studyover a 6 year period. Setting: Tertiary neonatal intensive care unit. Patients: 89 neonates <35 weeks gestational age (GA) who received rescue iNO for aPHT, including 62 treated at ≤3 days of age (early aPHT). Interventions: iNO ≥ 1 hour. Main outcome measures: Positive responders (reduction in fraction of inspired oxygen (FiO2) ≥0.20 within 1 hour of iNO) were compared with non-responders. Primary outcome was survival without moderate-to-severe disability at 18 months of age. Results: Mean (SD) GA and birth weight was 27.7 (3.0) weeks and 1077 (473) gm, respectively. Median (IQR) pre-iNO FiO2 was 1.0 (1.0, 1.0). Positive response rate to iNO was 46%. Responders showed improved survival without disability (51% vs 15%; p<0.01), lower mortality (34% vs 71%; p<0.01) and disability among survivors (17% vs 50%; p=0.06). Higher GA (adjusted OR: 1.44 (95% CI 1.10 to 1.89)), aPHT in context of preterm prolonged rupture of membranes (6.26 (95% CI 1.44 to 27.20)) and positive response to rescue iNO (5.81 (95% CI 1.29 to, 26.18)) were independently associated with the primary outcome. Compared with late cases (>3 days of age), early aPHT had a higher response rate to iNO (61% vs 11%; p<0.01) and lower mortality (43% vs 78%; p<0.01). Conclusion: A positive response to rescue iNO in preterm infants with aPHT is associated with survival benefit, which is not offset by long-term disability.
Article
Background and objectives: There are limited epidemiologic data on persistent pulmonary hypertension of the newborn (PPHN). We sought to describe the incidence and 1-year mortality of PPHN by its underlying cause, and to identify risk factors for PPHN in a contemporary population-based dataset. Methods: The California Office of Statewide Health Planning and Development maintains a database linking maternal and infant hospital discharges, readmissions, and birth and death certificates from 1 year before to 1 year after birth. We searched the database (2007-2011) for cases of PPHN (identified by International Classification of Diseases, Ninth Revision codes), including infants ≥34 weeks' gestational age without congenital heart disease. Multivariate Poisson regression was used to identify risk factors associated with PPHN; results are presented as risk ratios, 95% confidence intervals. Results: Incidence of PPHN was 0.18% (3277 cases/1 781 156 live births). Infection was the most common cause (30.0%). One-year mortality was 7.6%; infants with congenital anomalies of the respiratory tract had the highest mortality (32.0%). Risk factors independently associated with PPHN included gestational age <37 weeks, black race, large and small for gestational age, maternal preexisting and gestational diabetes, obesity, and advanced age. Female sex, Hispanic ethnicity, and multiple gestation were protective against PPHN. Conclusions: This risk factor profile will aid clinicians identifying infants at increased risk for PPHN, as they are at greater risk for rapid clinical deterioration.
Article
Objective: To evaluate the efficacy, safety, and pharmacokinetics of the endothelin receptor antagonist bosentan as adjunctive therapy for neonates with persistent pulmonary hypertension of the newborn (PPHN). Study design: This was a phase 3, multicenter, randomized, placebo-controlled exploratory trial (FUTURE-4). Eligible patients were >34 weeks gestation, <7 days old, receiving inhaled nitric oxide (iNO) treatment (≥4 hours), and had persistent respiratory failure (oxygenation index [OI] ≥12). After 2:1 randomization, bosentan 2 mg/kg or placebo was given by nasogastric tube twice daily for ≥48 hours and up to 1 day after iNO weaning. Results: Twenty-one neonates received a study drug (13 bosentan, 8 placebo). Compared with the placebo group, the group treated with bosentan had a higher median baseline OI and greater need for vasoactive agents. One treatment failure (need for extracorporeal membrane oxygenation) occurred in the group treated with bosentan. The time to weaning from iNO or mechanical ventilation was not different between the groups. Bosentan was well tolerated and did not adversely affect systemic blood pressure or hepatic transaminase levels. Anemia and edema were more frequent in patients receiving bosentan. Blood concentrations of bosentan were low and variable on day 1, and achieved steady state on day 5. Conclusion: Adjunctive bosentan was well tolerated, but did not improve oxygenation or other outcomes in our patients with PPHN. This effect may be related to delayed absorption of bosentan on treatment initiation in critically ill neonates or to more severe illness of the neonates who received bosentan. Trial registration: ClinicalTrials.gov:NCT01389856.
Article
Recent advances in our understanding of neonatal pulmonary circulation and the underlying pathophysiology of hypoxemic respiratory failure (HRF)/persistent pulmonary hypertension of the newborn (PPHN) have resulted in more effective management strategies. Results from animal studies demonstrate that low alveolar oxygen tension (PAO2) causes hypoxic pulmonary vasoconstriction, whereas an increase in oxygen tension to normoxic levels (preductal arterial partial pressure of oxygen (PaO2) between 60 and 80 mm Hg and/or preductal peripheral capillary oxygen saturation between 90% and 97%) results in effective pulmonary vasodilation. Hyperoxia (preductal PaO2 >80 mm Hg) does not cause further pulmonary vasodilation, and oxygen toxicity may occur when high concentrations of inspired oxygen are used. It is therefore important to avoid both hypoxemia and hyperoxemia in the management of PPHN. In addition to oxygen supplementation, therapeutic strategies used to manage HRF/PPHN in term and late preterm neonates may include lung recruitment with optimal mean airway pressure and surfactant, inhaled and intravenous vasodilators and ‘inodilators’. Clinical evidence suggests that administration of surfactant or inhaled nitric oxide (iNO) therapy at a lower acuity of illness can decrease the risk of extracorporeal membrane oxygenation/death, progression of HRF and duration of hospital stay. Milrinone may be beneficial as an inodilator and may have specific benefits following prolonged exposure to iNO plus oxygen owing to inhibition of phosphodiesterase (PDE)-3A. Additionally, sildenafil, and, in selected cases, hydrocortisone may be appropriate options after hyperoxia and oxidative stress owing to their effects on PDE-5 activity and expression. Continued investigation into these and other interventions is needed to optimize treatment and improve outcomes.