What is the treatment for Persistent Pulmonary Hypertension of the Newborn (PPHN)?

Treatment of Persistent Pulmonary Hypertension of the Newborn (PPHN)

Inhaled nitric oxide (iNO) at 10-20 ppm is the first-line therapy for term and near-term infants with PPHN when the oxygenation index exceeds 25, as it reduces the need for ECMO support. 1

Diagnostic Confirmation

• Confirm PPHN diagnosis with echocardiography to document extrapulmonary right-to-left shunting across the patent ductus arteriosus or foramen ovale, exclude congenital heart disease, and assess for left ventricular dysfunction before initiating therapy. 1, 2

• Calculate the oxygenation index (OI) using the formula: (mean airway pressure × FiO₂ × 100) / PaO₂ to gauge disease severity and guide treatment escalation. 1, 2

Initial Supportive Management

• Optimize lung recruitment through appropriate ventilation strategies, as adequate lung volume is essential for iNO efficacy, particularly in infants with parenchymal lung disease like meconium aspiration syndrome. 1, 2

• Consider exogenous surfactant only for infants with severe parenchymal lung disease and poor lung recruitment, though it carries risk of acute airway obstruction and did not reduce ECMO use in idiopathic PPHN. 1, 2

• Use high-frequency oscillatory ventilation when conventional ventilation provides inadequate gas exchange, but avoid lung over-expansion which can worsen pulmonary vascular resistance. 2

• Maintain normal systemic blood pressure with volume and inotropic support to reduce ventricular dysfunction and enhance oxygen delivery, but avoid supraphysiological pressures 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. 1, 2

• Avoid forced alkalosis through hyperventilation or sodium bicarbonate infusion, as prolonged alkalosis may worsen pulmonary vascular tone and cause cerebral vasoconstriction with worse neurodevelopmental outcomes. 1

First-Line Pharmacologic Therapy: Inhaled Nitric Oxide

• Initiate iNO at 10-20 ppm when OI exceeds 25 in term and near-term infants with echocardiographically confirmed PPHN. 1, 2, 3

• Do not exceed 20 ppm, as higher doses do not enhance oxygenation and increase the risk of methemoglobinemia and other complications. 1, 3

• Wean iNO relatively rapidly to 5 ppm once oxygenation improves, then to 1 ppm before discontinuation to prevent rebound pulmonary hypertension, which can cause life-threatening elevations in pulmonary vascular resistance. 1

• Discontinue iNO within 5 days in most cases; infants requiring iNO beyond 5 days likely have underlying disorders such as alveolar capillary dysplasia, severe lung hypoplasia, or progressive lung injury. 1

• Monitor methemoglobin levels, particularly if using doses approaching 20 ppm, as levels >7% require dose reduction or discontinuation. 3

Adjunctive Therapies for iNO-Refractory PPHN

When infants fail to respond adequately to iNO (30-40% of cases), consider the following adjunctive therapies:

• Sildenafil is a reasonable adjunctive therapy for infants refractory to iNO, especially with OI exceeding 25, though evidence is moderate. 1, 2

• Inhaled prostacyclin analogs may be considered as adjunctive therapy for iNO-refractory PPHN with OI exceeding 25, though evidence is limited. 1, 2

• Intravenous milrinone is reasonable specifically for infants with PPHN and echocardiographic signs of left ventricular dysfunction. 1, 2

ECMO Indications

• ECMO support is indicated for term and near-term neonates with severe pulmonary hypertension or hypoxemia refractory to iNO and optimization of respiratory and cardiac function. 1

• Consider ECMO referral when OI exceeds 40, as this indicates severe disease with high mortality risk. 1, 2

Special Considerations and Pitfalls

• Evaluate for underlying 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 strategies, or ECMO. 1

• In congenital diaphragmatic hernia with PPHN, iNO may not be effective and can worsen outcomes, as lowering pulmonary vascular resistance may increase preload to a dysfunctional left ventricle that cannot accommodate increased stroke volume. 1

• Response to iNO is disease-specific: excellent response occurs in idiopathic PPHN and respiratory distress syndrome, moderate response in meconium aspiration syndrome, and poor response in congenital diaphragmatic hernia. 4

• Early initiation of iNO (OI 15-25) does not improve outcomes compared to waiting until OI exceeds 25, but delaying until OI exceeds 40 may increase time on oxygen. 1