"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.
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