Persistent Pulmonary Hypertension

of the Newborn (Persistent Fetal

Circulation)

Shawn K. Ahlfeld

Keywords

persistent pulmonary hypertension of the newborn

PPHN

persistent fetal circulation

extracorporeal membrane oxygenation

ECMO

inhaled nitric oxide

iNO

sildenafil

high-frequency oscillatory ventilation

HFOV

alveolocapillary dysplasia

ACD

Persistent pulmonary hypertension of the newborn (PPHN ) occurs

in term and

postterm infants most often. Predisposing factors include birth asphyxia, MAS,

early-onset sepsis, RDS, hypoglycemia, polycythemia, maternal use of

nonsteroidal antiinflammatory drugs with in utero constriction of the

ductus

arteriosus, maternal late trimester use of selective serotonin

reuptake inhibitors,

and pulmonary hypoplasia caused by diaphragmatic hernia, amniotic fluid

leak,

oligohydramnios, or pleural effusions. PPHN is often idiopathic. Some

patients

with PPHN have low plasma arginine and NO metabolite concentrations

and
polymorphisms of the carbamoyl phosphate synthase gene, findings
suggestive

of a possible subtle defect in NO production. The incidence

is 1 in 500-1,500

live births, with a wide variation among clinical centers. Regardless

of etiology

of PPHN, profound hypoxemia from right-to-left shunting and normal

or

elevated PaCO

are present (Fig. 122.9 ).

FIG. 122.9 Cardiopulmonary interactions in persistent pulmonary

hypertension of the

newborn (PPHN). FO, Foramen ovale; L V , left ventricular; PDA, patent

ductus arteriosus;

PVR, pulmonary vascular resistance; RV , right ventricular; SVR,

systemic vascular

resistance. (From Kinsella JP , Abman SH: Recent developments in the

pathophysiology

and treatment of persistent pulmonary hypertension of the

newborn, J Pediatr 126:853–

864, 1995.)

Pathophysiology

Persistence of the fetal circulatory pattern of right-to-left shunting

throughthe

PDA and foramen ovale after birth is a result of excessively

high pulmonary

vascular resistance (PVR). Fetal PVR is usually elevated relative to

fetal

systemic or postnatal pulmonary pressure. This fetal state

normally permits

shunting of oxygenated umbilical venous blood to the left atrium

(and brain)
throughthe foramen ovale, from which it bypasses the lungs through
the ductus

arteriosus and passes to the descending aorta. After birth, PVR

normally declines

rapidly as a consequence of vasodilation secondary to lung

inflation, a rise in

postnatal PaO

, a reduction in PaCO

, increased pH, and release of vasoactive

substances. Increased neonatal PVR may be (1) maladaptive from

an acute

injury (not demonstrating normal vasodilation in response to increased

O

and

other changes after birth); (2) the result of increased pulmonary

artery medial

muscle thickness and extension of smooth muscle layers into the usually

nonmuscular , more peripheral pulmonary arterioles in response to

chronic fetal

hypoxia; (3) a consequence of pulmonary hypoplasia (diaphragmatic

hernia,

Potter syndrome); or (4) obstructive as a result of polycythemia,

total

anomalous pulmonary venous return (T APVR), or congenital diffuse

development disorders of acinar lung development.

Clinical Manifestations

PPHN usually manifests in the deliveryroom or within the 1st 12

hr after birth.

Idiopathic PPHN or PPHN related to polycythemia, hypoglycemia, hypothermia,

or asphyxia may result in severe cyanosis and respiratory
distress. In some cases,

however , initial signs of respiratory distress may be minimal. Infants

who have

PPHN associated with meconium aspiration, group B streptococcal

pneumonia,

diaphragmatic hernia, or pulmonary hypoplasia usually exhibit cyanosis,

grunting, flaring, retractions, tachycardia, and shock. Multiorgan involvement

may be present (see T able 1 19.2 ). Myocardial ischemia, papillary

muscle

dysfunction with mitral and tricuspid regurgitation, and biventricular

dysfunction

produce cardiogenic shock with decreases in pulmonary blood flow ,

tissue

perfusion, and O

delivery .

Hypoxemia is often labile and out of proportion to the findings

on chest

radiographs. In asphyxia-associated and idiopathic PPHN, chest x-ray findings

are often normal, whereas in PPHN associated with pneumonia and

diaphragmatic hernia , parenchymal opacification and bowel/liver in the

chest,

respectively , are seen.

Diagnosis

Independent of the prenatal history , PPHN should be suspected

in all term

infants who have cyanosis. Hypoxemia is universal and intermittently

unresponsive to 100% O

given by oxygen hood. A transient improvement may

occur in response to hyperoxic hyperventilation administered by
positive

pressure ventilation. A PaO

or SaO

gradient between a preductal (right radial

artery) and a postductal (umbilical artery) site of blood sampling

suggests right-

to-left shunting throughthe ductus arteriosus. Intracardiac shunting through

the

patent foramen ovale does not lead to a PaO

or SaO

gradient.

Real-time echocardiography combined with Dopplerflow imagingis very

helpful in evaluating PPHN. Systolic flattening of the interventricular septum

as

the right ventricular systolic pressure approaches the left ventricular

systolic

pressure can be used to estimate the degree of pulmonary

hypertension. The

peak velocity of the tricuspid valve regurgitation jet, when present,

yields a

quantitative estimate of the right ventricular systolic pressure.

Likewise, the

direction and velocity of a shunt across the PDA provides a

quantitative

comparison between the aortic and pulmonary artery pressures. In

advanced

cases, right-to-left or bidirectional shunting across a PDA and a

patent foramen
ovale can be observed.

The differential diagnosis of PPHN includes cyanotic heart disease

(especially

obstructed T APVR), idiopathic pulmonary vein stenosis, congenital

surfactant

deficiency syndromes, pulmonary artery thrombosis, and congenital diffuse

development disorders of acinar lung development (acinar dysplasia,

congenital

alveolardysplasia, and alveolarcapillary dysplasia with misalignment of

the

pulmonary veins).

Alveolocapillary dysplasia (ACD) is a rare, highly lethal autosomal

recessive

disorder of distal lung development characterized by immature lobular

development and reduced capillary density . Infants with ACD present

with

idiopathic PPHN, demonstrating little or no parenchymal lung disease and

profound hypoxemia. Over 60% of infants with ACD manifest

hypoxemia and

respiratory failure within 48 hr of birth, while some with milder disease

present

beyond 6 mo of age. The diagnosis is made on autopsyin

90% of cases, and the

constellation of findingsinclude thickened alveolarsepta, increased

muscularization of the pulmonary arterioles, a reduced numberof

capillaries,

with the remaining capillaries demonstrating abnormal apposition to

the air

interface, and misalignment of the intrapulmonary veins. In up to

80% of cases,

extrapulmonarymalformations of the genitourinary , gastrointestinal, or

cardiovascular system are present. Mutations in the transcription factor

gene
FOXFI have been identified in up to 40% of cases, but the
diagnosis continues to

rest on clinical and histopathologic features. ACD is uniformly lethal

and should

be suspected in infants with idiopathic PPHN who fail to

respond to maximal

medicaltherapy , or when symptoms recur after successful weaning

from ECMO.

In a United Kingdom ECMO report, up to 14% of infants who

failed ECMO

ultimately were diagnosed with ACD. Regardless of the timing of

presentation,

ACD is uniformly fatal, and lung transplantation remainsthe sole,

experimental

therapy .