Archives of Cardiovascular Disease (2013) 106, 169—177

Available online at

www.sciencedirect.com

REVIEW

Pathophysiology of persistent pulmonary

hypertension of the newborn: Impact of the
perinatal environment
Physiopathologie de l’hypertension artérielle pulmonaire persistante du
nouveau-né : rôle de l’environnement périnatal

Laurent Storme a,b,∗, Estelle Aubry a,c,

Thameur Rakza a,b, Ali Houeijeh b,
Véronique Debarge a,b, Pierre Tourneux d,
Philippe Deruelle a,b, Thomas Pennaforte b ,
French Congenital Diaphragmatic Hernia Study Group

a
EA4489, Environnement Périnatal et Croissance, Faculté de Médecine, Université Lille-2,
Lille, France
b
Pôle Femme—Mère-Nouveau-né, Hôpital Jeanne-de-Flandre, CHRU de Lille, Lille, France
c
Pôle Enfant, Clinique de Chirurgie et Orthopédie de l’Enfant, CHRU de Lille, Lille, France
d
Pôle Mère—Enfant, CHU d’Amiens, Amiens, France

Received 26 July 2012; received in revised form 8 December 2012; accepted 11 December 2012
Available online 29 March 2013

KEYWORDS Summary The main cause of pulmonary hypertension in newborn babies results from the
Pulmonary failure of the pulmonary circulation to dilate at birth, termed ‘persistent pulmonary hyper-
hypertension; tension of the newborn’ (PPHN). This syndrome is characterized by sustained elevation of
Newborn; pulmonary vascular resistance, causing extrapulmonary right-to-left shunting of blood across
Inhaled NO; the ductus arteriosus and foramen ovale and severe hypoxaemia. It can also lead to life-
Hypoxaemia threatening circulatory failure. There are many controversial and unresolved issues regarding
the pathophysiology of PPHN, and these are discussed. PPHN is generally associated with factors

Abbreviations: CDH, congenital diaphragmatic hernia; cGMP, cyclic guanosine monophosphate; ECMO, extracorporeal oxygenation;
eNOS, endothelial nitric oxide synthase; iNO, inhaled nitric oxide; NO, nitric oxide; NOS, nitric oxide synthase; PaCO2 , partial pressure of
carbon dioxide in arterial blood; PO2 , oxygen pressure; PPHN, persistent pulmonary hypertension of the newborn; PUFA, polyunsaturated
fatty acid; PVR, pulmonary vascular resistance; SpO2 , saturation of peripheral oxygen; SSRI, selective serotonin reuptake inhibitor; VEGF,
vascular endothelial growth factor.
∗ Corresponding author. Pôle Femme—Mère-Nouveau-né, Hôpital Jeanne-de-Flandre, CHRU de Lille, 1, avenue Eugène-Avinée, 59035 Lille

cedex, France. Fax: +33 3 20 44 62 36.

E-mail address: lstorme@chru-lille.fr (L. Storme).

1875-2136/$ — see front matter © 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.acvd.2012.12.005
170 L. Storme et al.

such as congenital diaphragmatic hernia, birth asphyxia, sepsis, meconium aspiration and respi-
ratory distress syndrome. However, the perinatal environment—exposure to nicotine and certain
medications, maternal obesity and diabetes, epigenetics, painful stimuli and birth by Caesarean
section—may also affect the maladaptation of the lung circulation at birth. In infants with
PPHN, it is important to optimize circulatory function. Suggested management strategies for
PPHN include: avoidance of environmental factors that worsen PPHN (e.g. noxious stimuli, lung
overdistension); adequate lung recruitment and alveolar ventilation; inhaled nitric oxide (or
sildenafil, if inhaled nitric oxide is not available); haemodynamic assessment; appropriate fluid
and cardiovascular resuscitation and inotropic and vasoactive agents.
© 2013 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Résumé La principale cause d’hypertension pulmonaire du nouveau-né résulte d’une vaso-
Hypertension dilatation pulmonaire insuffisante à la naissance, appelée « hypertension artérielle pulmonaire
pulmonaire ; persistante du nouveau-né » (HTAPP). Ce syndrome est caractérisé par une élévation des résis-
Nouveau-né ; tances vasculaires pulmonaires, responsable d’un shunt droit-gauche par le foramen ovale
NO inhalé ; et le canal artériel et d’une profonde hypoxémie. L’HTAPP est à risque vital lorsque qu’elle
Hypoxémie s’accompagne d’une défaillance circulatoire. La prise en charge nécessite un recrutement pul-
monaire adéquat, l’inhalation de monoxyde d’azote et un support cardiovasculaire adapté.
Néanmoins, la physiopathologie et la prise en charge sont toujours l’objet de recherches inno-
vantes. Ainsi, de plus en plus d’arguments existent pour penser que l’environnement périnatal
joue un rôle déterminant dans la genèse et l’aggravation de ce syndrome.
© 2013 Elsevier Masson SAS. Tous droits réservés.

Background
Pulmonary hypertension in newborns results from the fail-
ure of the pulmonary circulation to dilate at birth. Termed
‘persistent pulmonary hypertension of the newborn’ (PPHN),
it occurs in an estimated 1—2 infants per 1000 live births
[1]. This syndrome is characterized by sustained elevation
of pulmonary vascular resistance (PVR), causing extrapul-
monary right-to-left shunting of blood across the ductus
arteriosus and foramen ovale and severe hypoxaemia [2,3]
(Fig. 1). PPHN is frequently associated with low systemic
pressure and low cardiac output because of increased
right ventricular afterload and myocardial dysfunction [2,4].
PPHN-induced circulatory failure is a life-threatening condi-
tion. Cardiac failure further impairs oxygen delivery to the
tissues and contributes to significant mortality and morbidity
in newborn infants with PPHN [2—4].
Management requires adequate lung recruitment and
alveolar ventilation, inhaled nitric oxide (iNO), and appro-
priate fluid and cardiovascular resuscitation [5]. Early
initiation of inotropic and vasoactive agents is commonly
used to increase cardiac output, maintain adequate blood
pressure and enhance oxygen delivery to the tissue [4,6].
Nevertheless, there are many controversial and unresolved
issues regarding the pathophysiology and the most effective
management of PPHN. Growing evidence is emerging that
indicates that the perinatal environment plays a key role in
this syndrome.
Figure 1. Schematic representation of the circulation in PPHN.
Sustained elevation of PVR contributes to low pulmonary blood flow
Pathophysiology and high pulmonary pressure, causing extrapulmonary right-to-left
shunting of blood across the ductus arteriosus and foramen ovale
Foetal circulation and severe hypoxaemia. LA: left atrium; LV: left ventricle; PPHN:
persistent pulmonary hypertension of the newborn; PV: pulmonary
The foetal pulmonary circulation is characterized by high vein; PVR: pulmonary vascular resistance; RA: right atrium; RV: right
PVR and low blood flow. Despite high pulmonary artery ventricle.
Impact of the perinatal environment on newborn persistent pulmonary hypertension
pressure, the lungs are perfused with less than 10% of
the combined ventricular output during late gestation [7].
Owing to high PVR in the foetus, most of the right ventricu-
lar output crosses the ductus arteriosus into the descending
aorta, thereby increasing umbilical—placental flow and gas
exchange.
Mechanisms that maintain high PVR in utero are incom-
pletely understood, but include low foetal oxygen pressure
(PO2 ) [7], lack of a gas—liquid interface [8] and pro-
duction of vasoconstrictor mediators such as endothelin-1
[9]. Nitric oxide (NO) production also modulates foetal
pulmonary vascular tone in response to diverse stimuli,
including acute changes in haemodynamic forces [8]. In
foetal lambs, acute compression of the ductus arteriosus
abruptly increases blood flow and pressure, and causes acute
pulmonary vasodilation through the shear stress-induced
release of NO [10—13]. However, despite maintenance of
constant pressure, pulmonary blood flow progressively falls
and PVR increases over time [14,15]. Therefore, the foetal
pulmonary circulation is characterized by an ability to
oppose vasodilation over time and to regulate its flow.
Pulmonary adaptation at birth
At birth, pulmonary blood flow increases dramatically, by
8—10-fold, and PVR drops immediately. Several stimuli,
including drainage and absorption of foetal lung liquid,
rhythmic distension of the lung, increased PO2 and altered
production of several vasoactive products, including NO,
are known to contribute to pulmonary vasodilation at birth
[8]. The effects of several birth-related stimuli, including
increased blood flow or shear stress, increased PO2 and ven-
tilation are partly dependent upon activation of nitric oxide
synthase (NOS) [8,10—13].
The increase in NO production accounts for nearly 50%
of the abrupt fall in PVR at birth in foetal lambs [8]. NO
mediates vasodilatation by stimulating soluble guanylate
cyclase-induced cyclic guanosine monophosphate (cGMP)
production [16]. cGMP is downregulated by phosphodieste-
rase 5 activity. Phosphodiesterase 5, which is abundantly
expressed in lung tissue, particularly during foetal life,
is a key regulator of perinatal pulmonary circulation [17]
(Fig. 2).
Maladaptation of the pulmonary circulation at
birth
PPHN is a clinical syndrome that is associated with
diverse neonatal cardiopulmonary diseases, including birth
asphyxia, sepsis, meconium aspiration and respiratory dis-
tress syndrome, or it can be idiopathic [1—3].
The usual clinical expression of PPHN consists of an
unstable refractory hypoxaemia with pre- and postductal
saturation of peripheral oxygen (SpO2 ) gradient. Pulmonary
hypertension can be associated with a systemic hypoten-
sion and symptoms of shock, termed ‘obstructive’ shock,
the clinical and biological signs of which are non-specific:
grey colour, tachycardia, refill capillary time more than
3 seconds, oliguria, systemic hypotension and lactic acido-
sis. Doppler echocardiography is required to determine the
main component of the shock. Management priority is not to
normalize postductal SpO2 , but to optimize the circulatory
171
Figure 2. NO/cGMP pathway. NO, produced by endothelial NOS,
diffuses towards the smooth muscle cell in which it stimulates sol-
uble guanylate cyclase to produce cGMP. The mechanism whereby
increased cGMP regulates pulmonary vascular tone includes acti-
vation of K+ channels, causing smooth muscle cell membrane
hyperpolarization and inactivation of VOCC. Closure of VOCC causes
a decrease in cytosolic Ca++ concentration and vasorelaxation.
Intracellular concentration of cGMP is downregulated by PDE5 activ-
ities. Ca++ : calcium; cGMP: cyclic guanosine monophosphate; eNOS:
endothelial nitric oxide synthase; GMP: guanosine monophosphate;
K+ : potassium; NO: nitric oxide; NOS: nitric oxide synthase; PDE
5: phosphodiesterase 5; SMC: smooth muscle cell; VOCC: voltage-
operated calcium channels.
function. A rigorous clinical and echocardiographic assess-
ment is required for early diagnosis of circulatory failure.
More relevant than changes in postductal SpO2 , reflecting
right-to-left ductus arteriosus shunting, the decrease in pre-
ductal SpO2 results from an increase in the right-to-left
shunting through the foramen ovale. It occurs when the
pulmonary venous return decreases (which reduces the left
atrial pressure) or in case of right cardiac failure (leading
to elevation of right atrial pressure). Both are markers for
potential circulatory failure. In most cases, low postductal
SpO2 alone (i.e. with normal preductal SpO2 ) does not cause
tissue hypoxia. In contrast, a drop in preductal SpO2 is usu-
ally associated with symptoms of shock and an increased
lactate concentration.
Experimental studies of chronic pulmonary hypertension
in newborn animals have demonstrated impaired endothelial
release of NO and increased production of vasoconstric-
tors (e.g. endothelin-1) [18]. In normal foetal lambs, acute
compression of the ductus arteriosus causes progressive
pulmonary vasodilation, which is blocked by NOS inhibi-
tion, suggesting that NO mediates shear stress-induced
vasodilation. After NOS inhibition, acute ductus arterio-
sus compression causes a marked pulmonary vasoconstrictor
response, suggesting that NOS blockade unmasks a potent
myogenic response in the normal foetal lung [14]. In con-
trast, exposure to chronic pulmonary hypertension for 2 days
impairs flow-induced vasodilation and enhances the myo-
genic response during acute ductus arteriosus compression
in the absence of NOS inhibition [19,20]. Therefore, with
prolonged pulmonary hypertension during the perinatal
period, pulmonary blood flow is autoregulated and indepen-
dent of pulmonary artery pressure. The most striking feature
of perinatal pulmonary hypertension is the loss of the normal
172
vasodilator response to birth-related stimuli causing a para-
doxical vasoconstriction to acute haemodynamic stress.
Several investigators have suggested that an increase
in PDE5 activity may contribute to this phenomenon. Lung
PDE5 activity increased by 150% in foetal lambs with
ductus arteriosus ligation for 8 days compared to control
lambs [21]. Sildenafil attenuates the progressive eleva-
tion of basal pulmonary vascular tone observed during
chronic pulmonary hypertension, and preserves, at least
in part, the physiological pulmonary vascular response to
vasodilators [22].
More recently, the role of vascular endothelial growth
factor (VEGF) in foetal lung development and the patho-
genesis of PPHN have been reported. VEGF is a potent
endothelial cell mitogen and regulator of angiogenesis.
In vivo inhibition of VEGF receptors in normal foetal
sheep results in impaired vascular growth and pul-
monary hypertension [23]. Impaired alveolarization and
vessel growth in chronic intrauterine pulmonary hyper-
tension are associated with decreased VEGF protein
expression [24].
Risk factors for PPHN: impact of the
environment
PPHN is usually associated with pulmonary parenchymal dis-
ease, such as meconium aspiration, pneumonia or hyaline
membrane disease; or with disease-related lung hypoplasia
including congenital diaphragmatic hernia (CDH) or prema-
ture rupture of the membrane-mediated oligohydramnios
[1—3]. However, growing evidence indicates that the foetal
environment plays a critical role in the maladaptation of the
lung circulation at birth. Evidence of a role for epigenetics in
the development of pulmonary arterial hypertension is also
emerging. Epigenetic mechanisms are involved in the reg-
ulation of gene expression, which are controlled, at least
in part, by environment. In newborn rats with pulmonary
hypertension, the increased expression of endothelial NOS is
associated with changes in epigenetic regulation [25]. In the
same way, pulmonary hypertension has been associated with
abnormal epigenetic regulation of superoxide dismutase and
hypoxia inducible factor [26].
Antenatal smoke exposure
Cotinine concentrations in cord blood — a biological marker
for nicotine exposure — have been found to be higher in
infants with PPHN than in healthy control newborn infants
[27]. Prenatal cigarette smoke has been found to increase
the risk of PPHN among premature infants less than 30 weeks
gestational age, suggesting a toxic effect on the pulmonary
vascular development and maturation [28]. Studies of lungs
exposed in utero to cigarette smoke have shown marked
structural and functional changes, such as decreased alve-
olar attachments to the airway wall and increased airways
responsiveness. Endothelial dysfunction in intrapulmonary
arteries has been found during exposure to tobacco smoke
contributing, at least in part, to vasoconstriction and smooth
muscle cell proliferation [29]. In an experimental model of
foetal lambs, we found that prenatal exposure to cigarette
L. Storme et al.
smoke causes a potent and sustained pulmonary vasocon-
striction in the foetus, and blunts the vasodilator response
to an increase in oxygen tension [30]. These effects are
associated with a marked decrease in foetal oxygenation.
As the postnatal circulatory adaptation is highly dependent
on the decrease in PVR and the vasodilator response to
birth-related stimuli, such as oxygen, we speculate that pre-
natal exposure to tobacco smoke increases the risk of PPHN
through failure of the pulmonary circulation to dilate at
birth.
Role of stress or pain
Corticosteroids and catecholamine are the main stress hor-
mones. Their effects on lung parenchyma maturation, lung
fluid clearance and surfactant release at birth have been
widely investigated. Evidence has emerged that the stress
hormones promote normal circulatory adaptation at birth.
Several experimental and clinical studies have shown that
norepinephrine improves circulation in the perinatal lung.
In foetal lambs, norepinephrine has been shown to increase
lung blood flow and reduce PVR [31]. Norepinephrine induces
an NO-dependent pulmonary vasodilation in the ovine foetus
through activation of ␣2 -adrenoceptors [32—35]. In a large
retrospective review of nearly 30,000 consecutive deliver-
ies over 7 years, the incidence of PPHN in newborn infants
delivered by elective Caesarean was almost five times higher
than among those delivered vaginally [36]. A likely hypoth-
esis for PPHN after Caesarean is that there might be an
advantage to labour and vaginal delivery for the pulmonary
vascular bed of the neonate. Mechanisms explaining the
increase in PPHN after Caesarean remain unclear. A surge
of catecholamines, especially norepinephrine, is observed
at birth. However, neonatal norepinephrine concentrations
are significantly lower after Caesarean section than after
vaginal delivery. Lower levels of circulating norepinephrine
after Caesarean section may explain, at least in part, the
high incidence of PPHN in newborn infants delivered by Cae-
sarean section [37].
In contrast, evidence exists that painful stimuli impair
normal adaptation at birth and promote PPHN. Hypox-
aemia is usually observed during stressful intensive care
procedures in newborn infants with respiratory failure,
the duration of which may be reduced by opioid anal-
gesia [38]. In foetal lambs, nociceptive stimuli increase
pulmonary artery pressure and PVR [39,40]. This vaso-
constrictive response is abolished by analgesia and by
␣1 -adrenoceptor blockade [41]. These results provide new
insights into the mechanisms by which stressful events may
worsen hypoxaemia in newborn infants with PPHN. Noci-
ceptive stimulation, through ␣1 -adrenoceptor activation,
may elevate pulmonary vascular tone leading to increased
right-to-left shunting through the ductus arteriosus and the
foramen ovale and to severe hypoxaemia.
Drug exposure
Drug administration during pregnancy may increase the risk
of maladaptation at birth.
The likelihood of PPHN increases after antenatal expo-
sure to aspirin or other non-steroidal anti-inflammatory
drugs [42]. Mechanisms of antenatal non-steroidal
Impact of the perinatal environment on newborn persistent pulmonary hypertension
anti-inflammatory-induced PPHN may include antena-
tal closure of the ductus arteriosus or decreased production
of vasodilator prostaglandins. Similar risks exist after birth:
ibuprofen administration has the potential to cause PPHN
in preterm infants with patent ductus arteriosus [43].
Selective serotonin reuptake inhibitors (SSRIs), used to
treat maternal depression, elevate the basal vascular tone
in the foetal lung [44]. Pulmonary vascular remodelling and
right ventricular hypertrophy have been observed in rat pups
after maternal exposure to fluoxetine [45]. A case-control
study to assess whether PPHN is associated with exposure to
SSRIs has been conducted during late pregnancy [46]. A total
of 377 women whose infants had PPHN and 836 matched con-
trol women were enrolled in the study. Fourteen infants with
PPHN had been exposed to antenatal SSRI, as compared with
six control infants (adjusted odds ratio 6.1, 95% confidence
interval 2.2—16.8) [46]. These data support an association
between the maternal use of SSRIs in late pregnancy and
PPHN in the offspring.
In case of severe respiratory failure, early initiation of
inotropic and vasoactive agents is warranted to increase
cardiac output, maintain adequate blood pressure and
enhance oxygen delivery to the tissue [47]. Dopamine is
the sympathomimetic amine most frequently used for sep-
tic shock in newborn infants. The ability of dopamine to
raise systemic blood pressure has been clearly documented.
However, dopamine has also been suggested to increase
pulmonary artery pressure and pulmonary/systemic mean
arterial pressure ratio in experimental models and in human
[31,48]. Caution should therefore be advocated in the use
of dopamine in newborn infants at risk of, or with, PPHN.
Perinatal nutrition
It has been well established that maternal obesity and
diabetes are associated with increased risks of maladapta-
tion at birth [49]. The exact mechanisms are unclear, but
include perinatal asphyxia, parenchymal disease and poly-
cythaemia. Studies have highlighted that infants with PPHN
are deficient in the amino acid, L-arginine, which is required
for NO synthesis [50]. Evidence exists that differential vas-
cular effects can be expected according to lipid intake.
Indeed, dietary fish oils have beneficial effects on cardiac
and vascular function, including effects on platelet/vessel
wall interactions, endothelial function and inhibition of
smooth muscle cell proliferation. The n3 polyunsaturated
fatty acids (PUFAs) are metabolized by several enzymes,
including cyclooxygenase, to produce prostaglandins (PGE3 ,
PGI3 ), which are known potential vasodilator mediators. In
addition, n3 PUFA competes with arachidonic acid (n6 PUFA)
for enzymatic conversion. This competition decreases for-
mation of vasoactive arachidonic acid metabolites such as
thromboxane A2, a potent pulmonary vasoconstrictor. Thus,
some evidence suggests that n3 PUFA may be beneficial in
conditions associated with pulmonary hypertension. Also, n3
PUFA induces a potent pulmonary vasodilatation in the peri-
natal lung [51]. This effect is abolished by cytochrome 450
epoxygenase, but not by NOS inhibitors. Our data provide
evidence for potential beneficial effects of n3 PUFA on the
pulmonary circulation through production of epoxides. n3
PUFA supplementation may help to prevent maladaptation
173
at birth, in particular in conditions with prolonged pul-
monary hypertension such as CDH or pulmonary hypoplasia.
Oxygen and hyperoxia
While oxygen stimulates endothelial nitric oxide synthase
(eNOS) and NO production and contributes to pulmonary
adaptation at birth [8], high concentrations of oxygen,
such as are used to treat PPHN, may produce reactive
oxygen species. For instance, hydrogen peroxide (H2 O2 )
could decrease eNOS promoter activity, associated with
an endothelin-1-mediated downregulation of eNOS expres-
sion [52]. Uncoupled eNOS has been shown to increase
superoxide radicals, which rapidly combine with NO to
form peroxynitrite, a potent pulmonary vasoconstrictor
and potential cellular toxin. Furthermore, hyperoxia may
blunt NO-mediated pulmonary vasodilation through increas-
ing phosphodiesterase 5 activity. In accordance with these
studies, recombinant human superoxide dismutase enhances
vasodilation after birth in experimental models of PPHN
[53].
Principles of management
Basic principles
In PPHN with right-to-left shunt through the ductus arterio-
sus, the contribution of hypoxaemia to tissue oxygenation
(low partial pressure of oxygen in arterial blood [PaO2 ]) is
likely to be modest, provided SpO2 in the preductal area
is greater than 80%, circulatory function is adequate and
haemoglobin concentration is normal. Similarly, hypoxaemia
during foetal life (SpO2 60—75%) or during cyanotic congen-
ital heart diseases is not associated with tissue hypoxia,
as long as cardiac function is normal. However, there is
some evidence to suggest that cardiac dysfunction may
play a major role in PPHN. Severe pulmonary hyperten-
sion increases right ventricular afterload that may result
in right ventricular failure. The resulting elevation of right
ventricular telediastolic pressure causes right-to-left shunt-
ing through the foramen ovale and worsens hypoxaemia.
Because of a high degree of interdependence between the
right and the left ventricles due to the presence of common
structures (the interventricular septum and the inextensible
pericardium), changes in the right ventricle size and geome-
try may alter the left ventricular function. This may explain
why PPHN is usually associated with low systemic pressure
and low cardiac output requiring the use of cardiac sup-
port [2—4]. Right ventricle failure occurs when the ductus
arteriosus is closed or restricted. In severe PPHN with right-
to-left shunting through the ductus arteriosus, both the left
and right ventricle contribute to systemic blood flow (Fig. 3).
Therefore, management of the newborn infant with PPHN
requires both lowering of PVR and support of cardiovascular
function (Table 1).
Environmental factors
First, exposure to environmental factors that worsen PPHN
should be avoided. Noxious stimuli, including tactile stimuli,
tracheal suction and heel pricks have to be limited as much
174 L. Storme et al.

Figure 3. Schematic representation of the circulation in PPHN. Because of elevated PVR, part of the right ventricular outflow is directed
towards the systemic circulation through the ductus arteriosus, contributing to systemic blood flow. Despite a right-to-left ductus arteriosus
shunting-mediating drop in postductal SpO2 , oxygen supply is usually adequate as long as the ductus arteriosus is widely patent. Both aortic
and pulmonary artery pressures are closely related when the ductus arteriosus is patent (low ductal resistance). Thus, aortic pressure plays
a critical role in pulmonary circulation. A drop in aortic pressure is associated with a decrease in pulmonary artery pressure, and since
pulmonary artery pressure is the driving force for lung blood flow, a decrease in aortic pressure-induced drop in pulmonary artery pressure
may worsen hypoxaemia and oxygen delivery. This electrical representation further highlights that a patent ductus arteriosus and normal
right ventricle function are required for sustaining systemic blood flow and oxygen supply. F(PAP): proportional to pulmonary artery pressure;
PA: pulmonary artery; PAP: pulmonary artery pressure; PPHN: persistent pulmonary hypertension of the newborn; PVR: pulmonary vascular
resistance; SVR: systemic vascular resistance.

as possible. A specific pain scale for newborns should be
used to titrate analgesia and optimize their environment
(reduce noise and light, ‘cocooning’). Overdistension of the
lungs contributes to a decrease in pulmonary blood flow and
should be prevented, in particular in conditions associated
with pulmonary hypoplasia (CDH and premature rupture of
the membranes). Polycythaemia-mediating increased blood
viscosity and increased pulmonary artery pressure should be
corrected.
Mechanical ventilation
Management requires adequate lung recruitment and
alveolar ventilation, appropriate fluid and cardiovascular
resuscitation and use of pulmonary vasodilators [5]. In
CDH, mask ventilation should be avoided during resus-
citation in the delivery room to prevent gut distension
located in the thoracic cavity. High airway pressures should
also be avoided, to prevent pulmonary barotraumas while
maintaining preductal oxygen saturation greater than 85%
and partial pressure of carbon dioxide in arterial blood
(PaCO2 ) of 40—55 mmHg. Centres with better-than-expected
CDH survival report the combination of establishing clini-
cal care guidelines that set limits on ventilatory pressures
to avoid lung overdistension and accepting adequate blood
gas rather than optimal PaCO2 and PaO2 , as long as
there is evidence of adequate cardiac output and organ
function [54].
Infants with significant right-to-left shunting require pul-
monary vasodilator therapy. Currently, iNO is recommended
for infants with PPHN [55]. This improves outcomes in hypox-
aemic term and near-term infants by reducing the incidence
of the combined endpoint of death or need for extracor-
poreal oxygenation (ECMO) [55]. Oxygenation improves in
approximately 50% of infants receiving iNO [55]. Improve-
ment in oxygenation has also been reported with the use of
iNO in newborns with CDH and PPHN [56]. However, early use
of iNO does not appear to improve the combined endpoint of
Impact of the perinatal environment on newborn persistent pulmonary hypertension
Table 1 Steps in the management of PPHN.
Step Action
1 Prevent exposure to environmental factors that
may worsen PPHN (e.g. stress, painful stimuli,
noise, excessive light, lung overdistension)
2 Provide adequate lung expansion and ventilation
3 Provide inhaled nitric oxide
4 Assess for haemodynamics (clinical examination,
chest X-ray, cardiothoracic index, Doppler
echocardiography)
5 Provide appropriate fluid expansion and
vasoactive support according to the main
component of the circulatory failure
(obstructive, hypovolaemic, distributive or
cardiogenic)
6 ECMO may be required in life-threatening
obstructive shock
ECMO: extracorporeal oxygenation; PPHN: persistent pulmonary
hypertension of the newborn.
death/ECMO in infants with CDH alone [57]. Usual concen-
trations of iNO for the treatment of PPHN are 5—20 ppm.
Supporting cardiovascular function
Early initiation of inotropic and vasoactive agents is warr-
anted to increase cardiac output, maintain adequate blood
pressure and enhance oxygen delivery to the tissues.
Systemic hypotension is usually poorly tolerated, with
worsening of hypoxia explained by:
• a decrease in left ventricle filling causing a decrease in
oxygen delivery to the tissue;
• a decrease in coronary flow;
• a drop in pulmonary pressure resulting in a decrease in
pulmonary blood flow.
Indeed, as the ductus arteriosus is usually patent in
newborns with PPHN, pulmonary artery pressure and aortic
pressure are closely related (Fig. 3). A decrease in systemic
pressure-mediated drop in pulmonary artery pressure causes
a decrease in pulmonary blood flow, as Flow = f(Pressure).
Therefore, careful assessment of haemodynamics (clini-
cal examination, chest X-ray, cardiothoracic index and
echocardiography) is required in PPHN to provide optimal
treatment.
Four types of shock, according to the main mechanism
responsible for the cardiocirculatory failure, can be distin-
guished in the newborn:
• hypovolaemic;
• vasoplegic;
• cardiogenic;
• obstructive.
Fluid resuscitation should only be used if there is evi-
dence for hypovolaemia. Cardiogenic shock — a rare event
in PPHN as long as the ductus arteriosus is widely patent —
may require inotropic drug infusion (dobutamine). The use
of vasoactive drug is usually warranted in vasoplegic or
obstructive shock.
175
ECMO
ECMO may be required to ensure effective oxygenation and
decarboxylation, to limit the baro-volotrauma of the lungs
and to improve right cardiac failure. ECMO is indicated when
hypoxaemia persists despite optimal medical management.
ECMO may be indicated based on the following criteria [1]:
• preductal SpO2 less than 80% despite peak inspiratory
pressure greater than 28 cmH2 O (or mean airway pres-
sure greater than 15 cmH2 O in high frequency oscillatory
ventilation);
• PPHN and circulatory failure resistant to adequate man-
agement;
• gestational age greater than 34 weeks;
• birth weight greater than 2 kg.
Pulmonary vasodilator drugs
There is limited experience in PPHN with other pharmaco-
logical pulmonary vasodilators.
Phosphodiesterase inhibitors reduce the degradation of
cGMP produced by endogenous or inhaled NO. Sildenafil has
been found to improve cardiac output and respiratory func-
tion by reducing pulmonary hypertension refractory to iNO in
seven newborns with CDH [58]. In chronic pulmonary hyper-
tension associated with CDH, sildenafil has been found to
improve pulmonary vascular function and promoted lung
growth [59]. Evidence exists that sildenafil is well tolerated
in the newborn infant with PPHN [60]. A meta-analysis of
three trials including 77 newborn infants with PPHN has indi-
cated that sildenafil may improve oxygenation and reduce
mortality [61]. The studies were performed in resource-
limited settings where iNO was not available. The results of
the meta-analysis suggest that sildenafil in the treatment
of PPHN has significant potential, especially in resource-
limited settings.
The use of prostacyclin and analogues is an established
therapy for children and adults with primary pulmonary
hypertension. In a recent population-based study, the use of
prostacyclin, along with various other measures, has been
associated with a high survival rate [62]. Subcutaneous tre-
prostinil has been found to improve functional symptoms in
young children with refractory pulmonary arterial hyperten-
sion [63]. However, its use in PPHN has not been reported.
Similarly, there is evidence to suggest that endothe-
lin receptor blockade may improve pulmonary blood flow
in PPHN. In an experimental model of foetal pulmonary
hypertension, intrauterine endothelin receptor blockade
decreased pulmonary artery pressure, decreased right ven-
tricular hypertrophy and distal muscularization of small
pulmonary arteries and increased the fall in PVR at deliv-
ery [64]. Bosentan is a non-specific endothelin-1 receptor
inhibitor that improves pulmonary hypertension in adult
patients. Although recent reports suggest that bosentan may
improve PPHN [65], there is still insufficient evidence to
support the use of bosentan in the management of PPHN.
Conclusions
Growing evidence indicates that the perinatal environment
plays a key role in the failure of cardiopulmonary transition
176
to adequate pulmonary circulation at birth. Reduction of
exposure to risk factors should be the first step in the pre-
vention of PPHN. New insights showing that PPHN may be
associated with epigenetic modifications suggest that novel
pharmacological interventions targeting modulation of epi-
genetic regulation may be beneficial.
PPHN causes hypoxaemia through extrapulmonary right-
to-left shunting. The management priority should be to
optimize circulatory function rather than normalize post-
ductal SpO2 , because PPHN-induced circulatory failure is a
life-threatening condition.
Management of PPHN requires adequate lung recruit-
ment and alveolar ventilation, iNO and appropriate fluid
and cardiovascular resuscitation. Early initiation of inotropic
and vasoactive agents is commonly used to increase car-
diac output, maintain adequate blood pressure and enhance
oxygen delivery to the tissue. However, a rigorous clinical
and echocardiographic assessment is required for optimal
management of PPHN-associated circulatory failure.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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