1. Department of Child Health University of Sumatera Utara
PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN) = PERSISTENT FETAL CIRCULATION
MUHAMMAD ALI
Cardiology Division
Department of Child Health
University of Sumatera Utara

2. Prevalence
PPHN (or persistence of the fetal circulation) occurs in approximately 1 in 1500 live births.
Pathology and Pathophysiology
This neonatal condition is characterized by persistence of pulmonary hypertension, which in turn causes a varying degree of cyanosis from a right-to-left shunt through the PDA or patent foramen ovale (PFO). No underlying congenital heart defect is present.

3. Various causes have been identified, but they can be divided into three groups by the anatomy of the pulmonary vascular bed.
Intense pulmonary vasoconstriction in the presence of a normally developed pulmonary vascular bed.
* perinatal asphyxia, meconium aspiration, ventricular
dysfunction, group B streptococcal pneumonia,
hyperviscosity syndrome, and hypoglycemia
* Alveolar hypoxia and acidosis
* Thromboxane, vasoconstrictor prostaglandins, leukotrienes,
and endothelin
Hypertrophy (of the medial layer) of the pulmonary arterioles. Chronic intrauterine hypoxia and maternal ingestion of nonsteroidal anti-inflammatory agents may be important causes of pulmonary arteriolar hypertrophy.

4. Developmentally abnormal pulmonary arterioles with decreased cross-sectional area of the pulmonary vascular bed.
*Congenital diaphragmatic hernia and primary pulmonary hypoplasia.
In general, pulmonary hypertension caused by the first group is relatively easy to reverse, and that caused by the second group is more difficult to reverse than that caused by the first group. Pulmonary hypertension caused by the third group is most difficult or impossible to reverse.
Varying degrees of myocardial dysfunction often occur in association with PPHN, manifested by a global decrease in contractility or TR. These abnormalities are caused by global or subendocardial ischemia and are aggravated by hypoglycemia and hypocalcemia.

6. Clinical Manifestations
Symptoms begin 6 to 12 hours after birth, with cyanosis and respiratory difficulties. The idiopathic form usually affects full-term or post-term neonates. The patient usually has a history of meconium staining or birth asphyxia. A history of maternal ingestion of nonsteroidal anti-inflammatory drugs (in the third trimester) may be elicited.
Varying degrees of cyanosis and is tachypneic with retraction and grunting.
A prominent RV impulse and a single and loud S2 are usually found. Occasional gallop rhythm (from myocardial dysfunction) and a soft regurgitant systolic murmur of TR may be audible..
Arterial desaturation is found in blood samples obtained from an umbilical artery catheter.

7. The ECG usually is normal for age, but RVH or T-wave abnormalities may suggest myocardial dysfunction.
Chest x-rays may reveal a varying degree of cardiomegaly. The lung fields may be free of abnormal findings or may show hyperinflation or atelectasis. The PVM may appear normal, increased, or decreased.
Echo and Doppler studies are indicated to rule out CHDs and to identify patients with myocardial dysfunction. Patients with PPHN have no evidence of cyanotic defect. The only structural abnormality is the presence of a large PDA with a right-to-left or bidirectional shunt, with or without an interatrial communication, usually a PFO.
Cardiac catheterization usually is not indicated and considered if the diagnosis is unclear or the patient does not respond to therapy.

8. Management
The goals of therapy are:
(1) to lower the pulmonary vascular resistance and pulmonary artery (PA) pressure through the administration of oxygen, the induction of respiratory alkalosis, and the use of pulmonary vasodilators
(2) to correct myocardial dysfunction
(3) to stabilize the patient and treat associated conditions.
General supportive therapy: monitoring o2 saturation; detecting and treating hypoglycemia, hypocalcemia, hypomagnesemia, and polycythemia; and maintaining body temperature between 98°F and 99°F (36.6°C and 37.2°C)

9. To achieve arterial PO2 of 100 mm Hg, 100% oxygen is administered, initially without intubation. If this is not successful, intubation plus continuous positive airway pressure at 2 to 10 cm of water may be effective.
Mechanical ventilation using a fractional inspired oxygen concentration of 1.0 is intended to improve oxygenation and produce respiratory alkalosis if the previous measures are not successful. The patient usually is paralyzed with pancuronium (Pavulon) at 0.1 mg/kg intravenously. When relative normoxemia has been achieved for 12 to 24 hours, careful weaning can be begun, one ventilator setting at a time.

10. Tolazoline (Priscoline)
- Loading dose of 0.5 to 1.0 mg/kg by slow IV administration, followed by IV infusion of 2 to 4 mg/kg per hour.
- Tolazoline is not a specific pulmonary vasodilator, and it lowers systemic vascular resistance as well, resulting in systemic hypotension.
- Carefully monitor BP and maintain adequate circulating blood volume. Systemic hypotension is treated with volume expanders and dopamine infusion.
- Side effects: hypotension, increased gastric secretion, gastrointestinal bleeding, decreased platelet counts, and decreased urine output.
- Cimetidine (a histamine H2 -receptor antagonist) is not recommended because histamine may be important in dilating pulmonary vasculature.

11. For myocardial dysfunction, the following therapy is provided:
A. Dopamine with tolazoline improve cardiac output.
Dose: 10 μg/kg per minute by IV infusion.
B. Dobutamine (a β-adrenergic agent) used if signs of CHF are
present. Dose: 5 to 8 μg/kg per minute by continuous IV
infusion.
C. Correction of acidosis, hypocalcemia, and hypoglycemia helps
improve myocardial function.
D. Diuretics may be included in the regimen. For chronic
myocardial dysfunction, digoxin may be added at a later stage
E. A high-frequency oscillatory ventilator is effective in patients
with severe PPHN. Through the use of this device, about 40%
of patients who would be candidates for ECMO can avoid this
procedure.

12. A high-frequency oscillatory ventilator is effective in patients with severe PPHN. Through the use of this device, about 40% of patients who would be candidates for extracorporeal membrane oxygenation can avoid this procedure
Inhaled nitric oxide (NO) is a promising therapy for PPHN.
Prolonged low-dose NO therapy (6 parts per million) has caused sustained improvement in oxygenation, without systemic hypotension.
When administered by inhalation, NO diffuses to vascular smooth muscle, stimulating the production of cyclic guanosine monophosphate and causing vasodilatation.
Randomized trials of NO in PPHN confirmed that inhaled NO causes a rapid improvement in oxygenation and thereby decreases the need for extracorporeal membrane oxygenation.
. ECMO has been shown to be effective in the management of selected patients with severe PPHN. However, this treatment may require ligation of a carotid artery and the jugular vein, and cerebrovascular accidents have been reported.

13. Prognosis
Prognosis generally is good for neonates with mild PPHN who respond quickly to therapy. Most of these neonates recover without permanent lung damage or neurologic impairment.
For those requiring a maximal ventilator setting for a prolonged time, the chance of survival is smaller, and many survivors develop bronchopulmonary dysplasia and other complications.
Patients with developmental decreases in cross-sectional areas of the pulmonary vascular bed usually do not respond to therapy, and their prognosis is poor.
Neurodevelopmental abnormalities may manifest. Patients have a high incidence of hearing loss (up to 50%), positively related to the degree of alkalosis, the duration of ventilator support, and possibly the use of furosemide and aminoglycosides. An abnormal EEG (up to 80%) and cerebral infarction (45%) have been reported.

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