“Persistent Pulmonary Hypertension of the Newborn: Pathophysiology” by Andrea Moscatelli

“Persistent Pulmonary Hypertension of the Newborn: Pathophysiology” by Andrea Moscatelli


“Persistent Pulmonary
Hypertension of the Newborn– Pathophysiology,” by
Dr. Andrea Moscatelli. Hello. My name is Andrea
Moscatelli, and I’m Director of the Neonatal and
Pediatric Intensive Care Unit at Gaslini Children’s Hospital. In this video, we will
address the pathophysiology and the treatment of persistent
pulmonary hypertension of the newborn, or PPHN. We’ll start with a brief
review of the pathophysiology of transition
circulation and PPHN, because it is
extremely important to plan the treatment of a baby
with pulmonary hypertension. During fetal life, pulmonary
vascular resistance is high, and most of the oxygenated
blood coming from the placenta through the right atrium is
diverted towards the foramen ovale and the ductus arteriosus
into the systemic circulation. The features is low
content of oxygen in blood with a saturation which
is about 60 and a PaO2 of 20. Nevertheless, it
is able to maintain a good delivery of
oxygen to tissues, because both the ventricles
are working in parallel towards sustaining circulation. During the fetal life,
pulmonary vascular resistance is high because the
lungs are not ventilated, but also because there
is a relative excess of vasoconstricting agents,
like endothelin and thromboxane, respect to the
vasodilating agents. The main vasodilating agents are
nitric oxide and postracyclin. Nitric oxide increases
the levels of cGMP while the process cyclings
increase the level of cAMP into those smooth muscle cells. GMP is metabolized by the
phosphodiesterases type 5, while cAMP is metabolized by
phosphodiesterases type 3. And with increase
in cGMP and cAMP, the nitric oxide
and prostaglandins are able to relax the
pulmonary vasculature. During the transition
at birth, there is a rapid fall in pulmonary
vascular resistance, with an increase in
flow of 10 folds. This is due to the fact that
the lungs become distended, but also because the rhythmic
respiration, the increased oxygen tension in
blood, and the increase of flow through the lungs
with increase in shear stress would stimulate the
production of nitric oxide and prostaglandins. And they also activate
potassium channels, which have a direct
vasodilatory effect on the pulmonary vessels. During a normal transition,
we have an increase in flow to the lungs. And because the increase
in systemic pressure is after the separation
from the placenta, we have the closure
of the foramen ovale and the increase
in oxygen content in blood related
to the constriction of ductus arteriosus. So now, the delivery of oxygen
to the peripheral tissues is mainly dependent on the
oxygen content of blood, with respect to
the cardiac output. Because the right and
the left ventricle are now working in
series, and there is a slight decrease in
cardiac output of the newborn. The last step in
this adaptive process is vascular remodeling,
which takes place in the first week of life, with
a reduction in the thickness of the muscular layer of
the pulmonary vessels, with a further decrease in
pulmonary vascular resistance. In the PPHN, we
have the persistence of high pulmonary
vascular resistance, with a right-to-left shunt
towards the foramen ovale and the ductus arteriosus. So the baby enters this
vicious cycle of hypoxia, where hypoxia, hypercapnia,
acidosis, and cold are triggering pulmonary
vasoconstriction, with increase in the
pulmonary vascular resistance and right-to-life
shunt auto-maintaining hypoxia. PPHN is affecting two of
1,000 liveborn term infants, and it is complicating 10%
of neonatal respiratory failures at term, with
a 5% to 10% mortality despite adequate therapy. And 25% of newborns with
moderate to severe, impaired neurological development. The main cause of PPHN is
meconium aspiration syndrome, followed by primary PPHN,
RDS, and pneumonia/sepsis, and lung hypoplasia. So we might have an
abnormal constriction of normally developed vessels,
like in parenchymal diseases. But we can also have
a normal parenchyma with abnormal muscularization
of the pulmonary vessels, which happens to be the case of
idiopathic PPHN, which has been associated with the closure in
utero of the ductus arteriosus or with the maternal therapy
with serotonin reuptake inhibitors. The last cause of
pulmonary hypertension could be lung
hypoplasia and CDH, where we have a reduction
in the cross-sectional area of the pulmonary vessels. All these conditions
share a certain amount of vascular remodeling,
with an increase in thickness of the middle
layer of the pulmonary vessels and an extension of
the muscularization at an intra-acinar level. This is the case of
ideopathic PPHN, where the substrate of
pulmonary hypertension is related to
vascular anomalies. And it has also been described
in congenital diaphragmatic hernia, while in
parenchymal diseases the substrate for
pulmonary hypertension is mainly functional
and there is a less extent of pathologic
vascular remodeling and muscularization. We can have an increase
in the pulmonary pressure just because there is
an increase of flow through the lungs,
even if the vascular resistance of the pulmonary
vessels is normal. This can happen in cases of
pulmonary overflow, which we might see in patients with
VSD, large ventricular septal defects, or in babies
with a large pattern ductus arteriosus. Another cause of increase
in the pulmonary pressure is related to the
increase of the pressures in the left atrium, which
is usually associated to an obstruction to the
inflow of the left ventricle, like in mitral
stenosis, or can be associated with a dysfunction
of the left ventricle. In this case, the only way to
reduce the pulmonary pressure is to fix the mitral
stenosis or to sustain the contractile function
of the left ventricle. That does improving
its function. A condition that should
be always excluded in a baby with PPHN is an
obstructed total anomalous pulmonary venous return. Point of clarification. Total anomalous pulmonary
venous return, TAPVR, refers to heart defects in which
none of the pulmonary veins are connected to
the left atrium, instead connecting to
other systemic veins or chambers of the heart. In obstructive TAPVR,
pulmonary venous drainage is also obstructed or narrowed,
making it difficult for blood to return from the
lungs to the heart. Such babies, they
present at birth, in fraught, with pulmonary
edema with a right-to-left shunt towards the ductus arteriosus
and a severe pulmonary hypertension. And an obstructed TAPVR can be
excluded if we can demonstrate with cardiac echo the
presence of at least three of the venous returns
to the left atrium. So if we put
everything in practice, we can go through a real case. We have a 41 weeks
gestational age baby who was delivered by
caesarean section because of acute fetal
distress during labor. Amniotic fluid was
stained with meconium, and the baby has been
resuscitated at birth. On ICU admission, she was
extremely desaturated, with hypotension,
a capillary refill of more than seven seconds,
and a severe respiratory and metabolic acidosis. Taking into account
of the history and looking at the chest
X-ray, the admission impression is that of a meconium aspiration
syndrome, complicated by PPHN, which was demonstrated
by a differential saturation between
the pre-ductal and the post-ductal oximeter
probe of more than 20%. Point of clarification. A diagnosis of PPHN
is usually suggested by a sustained difference in
pre- and post-ductal oxygen saturation of greater than 10%. And there is also
right pneumothorax, which is a condition often
associated with meconium aspiration syndrome. When dealing with a baby
with pulmonary hypertension, it is extremely
important to have a careful cardiac
echo assessment. Usually we look to the shunt
towards the ductus arteriosus and the foramen ovale, which
could be bi-directional, but with a prominent
right-to-left component, or exclusively right to left. And if we have a short-axis
cut of the left ventricle, we would see a
V-shaped left ventricle because of the increase
in the pressures in the right ventricle which are
displacing the interventricular septum to the left. With the use of cardiac
echo, we can also calculate the pulmonary
systolic pressure. We can calculate the difference
between the right ventricular pressure and the
right atrial pressure with the application of the
modified Bernoulli equation. So this difference would be
given by four times the square of the peak velocity of the
tricuspid regurgitation jet, which we usually see in
severe cases of PPHN. If we added to this value the
right atrial pressure, which can be estimated by the
central venous pressure, we have the pulmonary systolic
pressure, which is usually iso- or supra-systemic. So the findings in
admission at echo are a normal anatomy with
normal pulmonary venous return. So there isn’t an
obstructed total anomalous pulmonary
venous return. The PDA is big, with
a right-to-left shunt. The right atrium is distended,
with a right-to-left shunt towards the foramen ovale. DRV is dilated with a moderate
tricuspid regurgitation. We have a D-shaped
left ventricle and isosystemic pulmonary
systolic pressure. So everything is saying
to us that this baby has a severe pulmonary
hypertension. The plan on admission is
to place a chest drain, to start mechanical
ventilation, to start therapy with a pulmonary
vasodilating, and to tailor the hemodynamic support
to the needs of the baby. Please help us improve the
content by providing us with some feedback.

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