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the right ventricular output crosses the ductus arteriosus Etiology and Pathophysiology of PPHN
to the aorta, and only approximately 8% to 10% of com- PPHN can be secondary to lung parenchymal diseases,
bined ventricular output in an ovine fetus and 13% to 21% such as meconium aspiration syndrome (with or without
in human fetuses perfuse the fetal lungs due to high PVR. asphyxia), respiratory distress syndrome (RDS), or pneu-
(3)(4) Mechanical factors such as fluid-filled lungs, hypoxic monia or sepsis (maladaptation of pulmonary vasculature);
pulmonary vasoconstriction, and circulating vasoconstric- remodeled pulmonary vasculature (maldevelopment) with
tors such as endothelin 1, and products of the prostaglan- normal lung parenchyma (primary or idiopathic); or lung
din pathway (ie, leukotriene and thromboxane) all play hypoplasia (underdevelopment) due to oligohydramnios
a significant role in maintaining high fetal PVR. (5) Seroto- or congenital diaphragmatic hernia (CDH) or intrinsic ob-
nin increases fetal PVR, and the use of selective serotonin struction (polycythemia with hyperviscosity). Disruption
reuptake inhibitors during the last half of pregnancy has of normal neonatal circulatory transition due to these fac-
been associated with an increased incidence of PPHN, al- tors results in failure to resolve fetal pulmonary hyperten-
though recent studies have questioned this association. sion and leads to the persistence of fetal pulmonary
A series of circulatory events take place at birth to en- hypertension or PPHN. High PVR decreases the blood
sure a smooth transition from fetal to extrauterine life. flow to the lungs because the blood takes the path of least
Clamping of the umbilical cord removes the low-resistance resistance, which is the systemic circulation. Ventilation-
placental circulation, increasing systemic arterial pressure. perfusion mismatch and extrapulmonary right-to-left
Various mechanisms operate simultaneously to rapidly shunting of deoxygenated blood across the patent fora-
reduce pulmonary resistance and increase pulmonary men ovale (PFO) and patent ductus arteriosus (PDA) re-
blood flow. The most important stimulus to promote pul- sult in cyanosis. Differential cyanosis (saturation in the
monary vasodilation appears to be ventilation of the lungs lower limb is >5%–10% lower than right upper limb) oc-
and an increase in oxygen tension. (5) An 8-fold increase in curs due to pulmonary artery to aorta shunt through the
pulmonary blood flow occurs, which raises left atrial PDA. If the PDA is closed and the shunt exclusively is at
pressure, closing the foramen ovale. Because PVR decreases the PFO level, the degree of cyanosis is similar in both
lower than systemic vascular resistance, flow reverses across the upper and lower limbs. Labile hypoxemia (marked
the ductus arteriosus (from the aorta to the pulmonary change in oxygen saturation with minimal or no change
artery or left to right). The increase in arterial oxygen in ventilator settings or fraction of inspired oxygen
saturation leads to closure of the ductus arteriosus and [FIO2]) is characteristic of PPHN and is due to change
ductus venosus. in the volume of right-to-left shunt secondary to subtle
changes in the delicate balance between PVR and sys-
temic vascular resistance. A few clinically important con-
Endothelium-Derived Mediators and ditions associated with PPHN are outlined below.
Circulatory Transition at Birth
Vascular endothelium releases several vasoactive products Malignant TTN
that play a primary role in cardiopulmonary transition at Transient tachypnea of newborn (TTN) has been associ-
birth. Pulmonary endothelial nitric oxide production in- ated with PPHN. For example, after elective cesarean de-
creases markedly at the time of birth. The shear stress that livery, newborns with TTN who have hypoxemia may be
results from increased pulmonary blood flow and in- given high concentrations of inspired oxygen (approxi-
creased oxygenation also induces endothelial nitric oxide mately 100%) by hood or nasal cannula (without any pos-
synthase (eNOS) expression, thus contributing to nitric itive pressure). In these cases, absorption atelectasis can
oxide–mediated pulmonary vasodilation after birth. (5) develop, resulting in increasing oxygen requirements
Nitric oxide exerts its action through soluble guanylate and respiratory failure (Fig 2). Furthermore, the forma-
cyclase and cyclic guanosine monophosphate (Fig 1). tion of reactive oxygen species from the high alveolar ox-
The arachidonic acid–prostacyclin pathway also plays ygen can lead to increased pulmonary vascular reactivity,
an important role; prostaglandins activate adenylate cy- thereby contributing to PPHN. (9)(10) The term malig-
clase to increase cyclic adenosine monophosphate con- nant TTN has been used to describe severe respiratory
centrations in vascular smooth muscle cells (Fig 1). morbidity and subsequent mortality in newborns deliv-
Inhibition of prostacyclin production by nonsteroidal ered by elective cesarean delivery who developed PPHN.
anti-inflammatory drugs during late pregnancy has been (11) One possible strategy when managing these new-
associated with PPHN, (7) although this association has borns (and to prevent malignant TTN) may be early
also been recently called into question. (8) use of distending pressure (such as continuous positive
Congenital Diaphragmatic
Hernia
CDH is a developmental defect in
the diaphragm that separates the
thorax and the abdomen and is the
Figure 1. Endothelium-derived mediators: the vasodilators prostacyclin (PGI2) and nitric oxide
(NO) and the vasoconstrictor endothelin (ET-1). Cyclooxygenase (COX) and prostacyclin most important cause of pulmonary
synthase (PGIS) are involved in the production of prostacyclin. Prostacyclin acts on its receptor hypoplasia resulting in PPHN. CDH
(IP) in the smooth muscle cell and stimulates adenylate cyclase (AC) to produce cyclic aden- has a mortality rate of 20% to 30%,
osine monophosphate (cAMP). cAMP is broken down by phosphodiesterase 3A (PDE3A). and the degree of associated pulmo-
Milrinone inhibits PDE3A and increases cAMP levels in arterial smooth muscle cells and car- nary hypoplasia and the severity
diac myocytes. Endothelin acts on ET-A receptors causing vasoconstriction. A second endothelin of pulmonary hypertension remain
receptor (ET-B) on the endothelial cell stimulates NO release and vasodilation. Endothelial nitric the major determinants of survival.
oxide synthase (eNOS) produces NO, which stimulates soluble guanylate cyclase (sGC) enzyme to Despite marked improvement in
produce cyclic guanosine monophosphate (cGMP). cGMP is broken down by PDE5 enzyme. survival of PPHN resulting from
Sildenafil inhibits PDE5 and increases cGMP levels in pulmonary arterial smooth muscle cells.
other causes, the mortality and need
cAMP and cGMP reduce cytosolic ionic calcium concentrations and induce smooth muscle cell
for extracorporeal membrane oxy-
relaxation and pulmonary vasodilation. NO is a free radical and can avidly combine with su-
peroxide anions to form the toxic vasoconstrictor peroxynitrite. Medications used in PPHN are genation (ECMO) remain high in
shown in black boxes. Modified from Sharma et al. (6) Copyright Satyan Lakshminrusimha. infants with CDH.
airway pressure when FIO2 exceeds 0.5–0.6) to inflate and Alveolar Capillary Dysplasia
recruit the lungs vs merely administering high amounts of Alveolar capillary dysplasia is generally associated with
oxygen without positive pressure. malalignment of the pulmonary veins. It presents with re-
spiratory failure and unremitting PPHN early in life and
Pulmonary Hypertension in Premature Infants carries a mortality rate that approaches 100%. (14) His-
Although PPHN is traditionally considered a disease of- tologic examination of lung tissue remains the gold stan-
term and late preterm infants, it is increasingly being dard for diagnosis. A lung biopsy to rule out alveolar
diagnosed in extremely preterm infants. Some preterm capillary dysplasia should be considered for neonates
infants with RDS present with PPHN in the first who do not respond to conventional medical manage-
few days after birth, (12) whereas preterm infants with ment or fail attempts at ECMO decannulation.
bronchopulmonary dysplasia (BPD) may be diagnosed
as having pulmonary hypertension later in the hospital
course or after discharge from the NICU. Pulmonary ar- Diagnosis
tery hypertension complicating BPD is a process some- In a hypoxemic neonate, differentiating cyanotic congenital
what distinct from PPHN and tends to run a much heart disease from PPHN is of paramount importance. The
Figure 4. Echocardiographic evaluation of neonatal hypoxemia based on ductal (black bar) and atrial (blue bar) shunts. Left-to-right
shunt at the ductal and atrial level is considered normal but can also be seen in the presence of parenchymal lung disease, resulting in
hypoxemia in the absence of persistent pulmonary hypertension of the newborn (PPHN) (lower left quadrant). The presence of right-to-
left shunt at the atrial and ductal levels is associated with PPHN (upper right quadrant). Right-to-left shunt at the ductal level but a left-
to-right shunt at the atrial level is associated with left ventricular dysfunction, pulmonary venous hypertension, and ductal-dependent
systemic circulation (lower right quadrant) and is a contraindication for inhaled pulmonary vasodilators, such as inhaled nitric oxide. In
patients with right-sided obstruction (such as critical pulmonary stenosis [PS]), right atrial blood flows to the left atrium through the PFO.
Pulmonary circulation is dependent on a left-to-right shunt at the patent ductus arteriosus (PDA) (upper left quadrant).
Ao[aorta; LA[left atrium; LV[left ventricle; PA[pulmonary artery; PGE1[prostaglandin E1; RA[right atrium; RV[right ventricle; Rx[treatment; TR[tricuspid
regurgitation.
Modified from Nair and Lakshminrusimha. (15) Copyright Satyan Lakshminrusimha.
studies reveal benefit, but a review of the CDH registry iNO is a potent and selective pulmonary vasodilator
did not support the use of surfactant. (26) We recom- without a significant decrease in systemic blood pressure
mend administration of surfactant only in the presence (selective effect of iNO). iNO is also preferentially distrib-
of clinical, radiologic, or biochemical evidence of surfac- uted to the ventilated segments of the lung, resulting in
tant deficiency in CDH and administer only 50% of the increased perfusion of the ventilated segments, optimizing
dose because of pulmonary hypoplasia. ventilation-perfusion match (microselective effect of iNO).
Studies have found that iNO therapy causes marked im-
Pulmonary Vasodilator Therapy provement in oxygenation in term newborns with PPHN.
After achieving lung recruitment with and without surfac- (27) Multicenter randomized clinical studies subsequently
tant therapy, further management should be based on ox- confirmed that iNO therapy reduces the need for ECMO
ygenation status, systemic blood pressure, and cardiac and in term neonates with hypoxemic respiratory failure. (28)
ventricular function on echocardiography (Fig 6). Various (29)(30) iNO therapy is the only therapy approved by the
therapeutic strategies outlined in this figure are described US Food and Drug Administration for clinical use in term
below. or near-term newborn infants (>34 weeks’ gestation) with
Pao2/FIO2 ratio of 20 mm Hg or
more (20-20-20 rule for initiation of
iNO). Methemoglobin levels are mon-
itored at 2 hours, 8 hours after initi-
ation of iNO, and then once a day
for the duration of iNO therapy.
Some centers stop checking methe-
moglobin levels after the first couple
of days if levels are low (<2%) and
iNO dose remains less than 20 ppm.
Weaning iNO is a gradual pro-
cess to minimize the risk of rebound
vasoconstriction and resultant pul-
monary hypertension associated with
abrupt withdrawal. Weaning in steps
from 20 ppm gradually for a period
before its discontinuation prevents
the rebound effect. (33) If there is
oxygenation response, inspired oxygen
concentration is first weaned below
60%, and then iNO is weaned only if
PaO2 can be maintained at 60 mm
Hg or higher (or preductal oxygen
Figure 5. Management of acute persistent pulmonary hypertension of the newborn (PPHN)
saturation as measured by pulse oxi-
(suggested guidelines as recommended by the authors are shown in this figure): (1) minimal
stimulation with the use of eye covers and ear muffs; (2) sedation and analgesia with metry ‡90%) for 60 minutes (60-
a narcotic agent and a benzodiazepine (avoid muscle paralysis if possible); (3) maintain 60-60 rule of weaning iNO). Our
preductal oxygen saturation in the low to mid-90s and postductal saturations above 70% practice is to wean iNO at a rate of
as long as metabolic acidosis, lactic acidosis, and/or oliguria are not present; (4) lung 5 ppm every 4 hours. Once iNO dose
recruitment with adequate positive end-expiratory pressure (PEEP) or mean airway pressure is 5 ppm, gradual weaning by 1 ppm
and/or surfactant to maintain 8- to 9-rib expansion during inspiration; and (5) maintain every 2 to 4 hours is performed. Con-
adequate blood pressure and avoid supraphysiological systemic pressure. See text for details. tinuing iNO in infants unresponsive
HFOV[high frequency oscillatory ventilation; MAS[meconium aspiration syndrome; OI[oxygenation index;
to iNO or failure to wean iNO can
PIP[peak inspiratory pressure.
potentially lead to prolonged depen-
Modified from Nair and Lakshminrusimha. (15) Copyright Satyan Lakshminrusimha.
dence on iNO due to suppression of
endogenous eNOS. (34)(35)
PPHN. Konduri et al initially found that earlier initiation If iNO is not effective or not available and if hyp-
of iNO with an oxygenation index (OI) of 15 to 25 did oxemia persists, further management is based on sys-
not reduce the need for ECMO but may have a tendency temic blood pressure and ventricular function on
to reduce the risk of progression to severe hypoxemic re-
echocardiography:
spiratory failure. (31) Post hoc analysis of the same study
suggested that the use of surfactant before randomization 1. If blood pressure is relatively stable but hypoxemia
and enrollment (and use of iNO) at an OI of 20 or less was persists, consider the use of phosphodiesterase (PDE)
associated with reduced incidence of ECMO or death. 5 inhibitors, especially in the presence of a right-to-left
(25) A dose of 20 ppm results in improved oxygenation shunt at the PFO and/or PDA levels with good ven-
and the most optimal decrease in pulmonary to systemic tricular function (Fig 4). Sildenafil, administered by
arterial pressure ratio (32) and is the typical starting dose. intravenous (preferred) or oral route, is usually the first-
Higher doses are not recommended because they are as- line agent. Sildenafil is metabolized by the liver, and
sociated with increased levels of nitrogen dioxide and met- severe hepatic dysfunction may impair its metabolism.
hemoglobin. (27) To summarize, we recommend initiation On the basis of pharmacokinetic data in neonates with
of iNO if the OI is approximately 20 at a dose of 20 ppm. PPHN, intravenous sildenafil is administered as a load
A complete response to iNO is defined as an increase in of 0.42 mg/kg for 3 hours (0.14 mg/kg per hour)
should precipitate cannulation for ECMO (or immediate reflect the severity of the underlying illnesses experienced
transfer to an ECMO center). by these infants rather than complications of iNO or
ECMO.
Chronic Pulmonary Hypertension in Neonates
Neonates with CDH and BPD can have pulmonary hy- Conclusion
pertension lasting for weeks or months. In the hospital The management of PPHN has significantly improved
setting, these patients are often managed with supplemen- during the last 2 decades. The emphasis has shifted from
tal oxygen, iNO (sometimes through a nasal cannula), and hyperoxygenation-hyperventilation-alkalosis to improved
oral pulmonary vasodilators, such as sildenafil or bosentan. gentle ventilation strategies to optimize lung recruitment
Because of its high cost, long-term therapy with iNO is and minimize oxygen toxic effects and permissive hyper-
cost prohibitive, and most patients can be successfully tran- capnia paired with the therapeutic use of surfactant and
sitioned to sildenafil after a few days. iNO. These changes have led to a substantial decrease
Bosentan is an endothelin 1 receptor blocker (Fig 1) in the number of neonatal PPHN patients requiring
that may be beneficial in the management of PPHN. (45) ECMO for respiratory disorders. Two remaining chal-
However, the results of a multicenter, randomized, double- lenges where large knowledge gaps persist include man-
blind, placebo-controlled exploratory trial of bosentan agement of pulmonary hypoplasia and pulmonary
(2 mg/kg per dose twice daily) did not have any hypertension in CDH and BPD-associated pulmonary hy-
additive effect on the top of iNO in term neonates with pertension in the premature infant. Newer pulmonary vas-
PPHN. (46) odilators, such as antioxidants (superoxide dismutase),
ECMO is a modified cardiopulmonary bypass used for soluble guanylate cyclase activators, and rho-kinase inhib-
a prolonged period to support heart and lung function. itors, are currently under investigation. At the same time,
The use of neonatal ECMO has decreased from a peak many nurseries around the world cannot afford proven but
of more than 1,500 cases per year in the early 1990s to expensive therapies such as iNO and ECMO. Further re-
approximately 750 cases per year. This decline is likely search to develop appropriate cost-effective strategies to
due to improvements in both perinatal care and availability ameliorate pulmonary vascular disease associated with con-
of advanced therapies for neonatal hypoxemic respiratory ditions such as pneumonia and asphyxia and meconium as-
failure, including high-frequency ventilators, surfactant, piration, common in developing countries, is warranted.
and iNO. Generally accepted criteria to start ECMO are
persistent hypoxemia (with an OI of >40 or alveolar-arterial
gradient >600 despite aggressive medical management American Board of Pediatrics Neonatal-Perinatal
of PPHN with mechanical ventilation and iNO) and Content Specifications
the presence of hemodynamic instability (Fig 6). • Know the pathogenesis, pathophysiology,
pathologic features, and risk factors for
persistent pulmonary hypertension.
Neurodevelopmental Outcome in NICU • Recognize the clinical features and
Graduates With Severe PPHN differential diagnosis of persistent
The infants with PPHN who survive and are discharged pulmonary hypertension.
• Recognize the laboratory, imaging, and other diagnostic
from the NICU have long-term consequences, such as neu- features of persistent pulmonary hypertension.
rodevelopmental, cognitive, and hearing abnormalities. • Know the management of persistent pulmonary hypertension
(47)(48)(49) Thus, it is essential to provide long-term including assisted ventilation, pharmacologic approaches,
multidisciplinary follow-up after discharge. In their and ECMO.
long-term follow-up of infants randomized to early
iNO in PPHN, Konduri et al noted neurodevelopmental
impairment in approximately 25% of infants and hear- References
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1. A male infant cries soon after spontaneous vaginal delivery. He is vigorous and has good tone. He is initially
cyanotic, but gradually his skin turns pink. Which of the following statements regarding transitional
physiology for the healthy term infant is correct?
A. Clamping of the umbilical cord causes a decrease in the infant’s systemic arterial pressure.
B. Pulmonary blood flow doubles compared with fetal circulation.
C. The flow across the ductus arteriosus switches from left to right to right to left.
D. Approximately 25% to 35% of combined ventricular output in the fetus will perfuse the fetal lungs.
E. Ventilation of the lungs and an increase in oxygen tension lead to pulmonary vasodilation.
2. A 1-hour-old term female infant is having respiratory distress. She was born in meconium-stained amniotic
fluid. Her oxygen saturation is low, and the saturation in the lower limb is 10% lower than the saturation
measured in the right wrist. You suspect possible persistent pulmonary hypertension of the newborn (PPHN).
Which of the following statements correctly describes the pathophysiology of PPHN?
A. In PPHN, there is an excess induction of endothelial nitric oxide synthase, leading to an abundance of nitric
oxide in the pulmonary vasculature.
B. In PPHN, high pulmonary vascular resistance decreases the blood flow to the lungs, and there is preferential
blood flow to the systemic circulation, which is the path of least resistance.
C. In PPHN, there will be excessive shunting of deoxygenated blood that flows from the aorta to the
pulmonary arteries.
D. In PPHN, the oxygen saturation is likely to remain at a consistent, stable level with very little change.
E. The foramen ovale must be closed for PPHN to have clinical manifestations in the newborn.
3. The same infant is in the neonatal intensive care unit (NICU) undergoing evaluation and treatment. Part of the
initial evaluation includes chest radiography and arterial blood gas analysis. Echocardiography is also ordered.
Which of the following statements concerning diagnosis of PPHN and the consideration of congenital heart
disease is correct?
A. A fixed hypoxemia that is not labile would lead to a higher suspicion of PPHN rather than cyanotic
congenital heart disease.
B. Even when echocardiography is readily available, the best way to distinguish between PPHN and cyanotic
heart disease is to induce a moderate hyperoxia combined with hyperventilation.
C. On echocardiography, flattening or left deviation of the interventricular septum is one sign that provides
an indication of right-sided pressures.
D. Chest radiography in patients with PPHN typically reveals severe parenchymal disease, usually more than
one would expect considering the degree of hypoxemia.
E. Infants who have coarctation of the aorta will have a reverse pattern of differential cyanosis than infants
with PPHN, with the lower limbs having saturation approximately 10% higher than the right upper limb.
4. After diagnostic evaluation, the patient is diagnosed as having PPHN, and congenital heart disease has been
ruled out. She is receiving mechanical ventilation and intravenous fluids. Which of the following treatments
would be most appropriate for this patient?
5. The patient continues to have hypoxemia and appears to be worsening despite various adjustments in
mechanical ventilation strategies. The respiratory therapist has brought out the inhaled nitric oxide (iNO)
delivery system next to the ventilator. Which of the following statements regarding the use of iNO for PPHN is
correct?
A. iNO is a potent and selective pulmonary vasodilator that does not cause a significant decrease in systemic
blood pressure.
B. iNO is preferentially distributed to the parts of the lung that are not well ventilated.
C. Although it is widely used in NICU practice as an off-label drug, the US Food and Drug Administration has
not approved iNO specifically for clinical use in term infants with PPHN or any kind of respiratory failure.
D. iNO works better for term infants with PPHN when surfactant is not given.
E. The current recommended practice is to begin iNO in this type of scenario at 1 ppm and titrate up to desired
effect.
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