What is the treatment approach for persistent pulmonary hypertension of the newborn (PPHN)?

Persistent Pulmonary Hypertension of the Newborn (PPHN): Pathophysiology and Treatment

Pathophysiology

PPHN is a syndrome characterized by sustained elevation of pulmonary vascular resistance after birth, resulting in right-to-left shunting through the patent ductus arteriosus and foramen ovale, leading to severe hypoxemia. 1, 2

The condition represents a failure of the normal postnatal transition where pulmonary vascular resistance should decrease dramatically at birth. 1 The underlying mechanisms involve:

• Impaired endothelium-dependent vasodilation due to absolute or relative deficiency of endogenous nitric oxide 1
• Pulmonary vasoconstriction and vascular remodeling as the two cornerstones of increased pulmonary vascular resistance 3
• Elevated circulating endothelin-1 levels contributing to vasoconstriction 1

PPHN can be classified into three etiologic categories: (1) abnormally constricted pulmonary vasculature secondary to parenchymal diseases like meconium aspiration syndrome, pneumonia, or sepsis; (2) hypoplastic pulmonary vasculature as seen in congenital diaphragmatic hernia; and (3) idiopathic PPHN with normal parenchyma but remodeled pulmonary vasculature. 4

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Treatment Algorithm

Initial Assessment and Stabilization

Confirm the diagnosis with echocardiography to exclude congenital heart disease, assess left ventricular function, and document pulmonary hypertension severity. 2

• Optimize lung recruitment through appropriate ventilation strategies to improve efficacy of pulmonary vasodilators 2
• Maintain normal systemic blood pressure with volume expansion and inotropic support to reduce ventricular dysfunction and enhance systemic oxygen delivery 2
• Avoid supraphysiological blood pressure elevation solely to drive left-to-right shunting across the ductus arteriosus, as this does not reduce pulmonary vascular resistance 2
• Avoid extreme hyperoxia (FiO₂ >0.6) as it may be ineffective due to extrapulmonary shunting and can aggravate lung injury 2

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First-Line Therapy: Inhaled Nitric Oxide

Inhaled nitric oxide (iNO) at 10-20 ppm is the first-line therapy indicated to reduce the need for ECMO in term and near-term infants with PPHN. 1, 2, 5

• Start with 10-20 ppm as the initial dose, as doses exceeding 20 ppm do not enhance oxygenation and increase the risk of methemoglobinemia 2, 5
• Monitor methemoglobin levels, which typically remain below 1% at therapeutic doses but can reach 5% at 80 ppm 5
• iNO works by selectively dilating pulmonary vessels in well-ventilated lung regions, redistributing blood flow to areas with normal ventilation/perfusion ratios 5

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Lung Recruitment Strategies

Implement aggressive lung recruitment strategies, particularly in PPHN associated with parenchymal lung disease, as this significantly improves iNO efficacy. 1, 2

• Consider high-frequency ventilation for poor lung compliance and inadequate gas exchange, while avoiding lung over-expansion 2
• Exogenous surfactant may be considered for infants with severe parenchymal lung disease and poor lung recruitment, though it did not reduce ECMO use in idiopathic PPHN 2

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Management of iNO-Resistant PPHN (30-40% of cases)

For infants refractory to iNO, particularly those with an oxygenation index exceeding 25, sildenafil is the most reasonable adjunctive therapy. 1, 2, 6, 3

The oxygenation index is calculated as: (mean airway pressure × FiO₂ × 100) / PaO₂ 2

Adjunctive Pharmacologic Options (in order of evidence strength):

1. Sildenafil (0.5-2 mg/kg three times daily) - reasonable adjunctive therapy with moderate evidence 1, 2, 6
2. Inhaled prostacyclin analogs - may be considered as adjunctive therapy with moderate evidence 1, 2
3. Intravenous milrinone - reasonable specifically for infants with signs of left ventricular dysfunction 1, 2

Approximately 30-40% of infants fail to respond to iNO, making these adjunctive therapies clinically important. 6, 3

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ECMO Indications

ECMO support is indicated for term and near-term infants with PPHN when the oxygenation index exceeds 25. 1, 2

• ECMO is also indicated for severe pulmonary hypertension or hypoxemia refractory to iNO and optimization of respiratory and cardiac function 1, 2
• An oxygenation index >40 is a critical threshold for ECMO referral 2
• ECMO has improved survival but carries significant morbidity including hemorrhagic and neurologic complications 1

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Special Considerations and Pitfalls

Evaluate for disorders of lung development (alveolar capillary dysplasia, genetic surfactant protein diseases) in infants with severe PPHN who fail to improve after vasodilator therapy, lung recruitment, or ECMO. 1, 2

Common pitfalls to avoid:

• Do not abruptly discontinue iNO, as this can cause rebound pulmonary hypertension 5
• For congenital diaphragmatic hernia with PPHN, minimize peak inspiratory pressure and avoid large tidal volumes to reduce ventilator-associated lung injury 2
• Use iNO cautiously in congenital diaphragmatic hernia with suspected left ventricular dysfunction 2
• Methemoglobin levels >7% should prompt dose reduction or discontinuation of iNO, and can be treated with intravenous vitamin C, methylene blue, or blood transfusion 5

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Prognosis

Despite advances in treatment, PPHN continues to have a mortality rate of approximately 10-20%, with 7-20% of survivors developing long-term impairments including hearing deficits, chronic lung disease, and intracranial hemorrhage. 1, 4