What is the management of persistent pulmonary hypertension of the newborn (PPHN)?

Management of Persistent Pulmonary Hypertension of the Newborn (PPHN)

The management of PPHN requires a stepwise approach starting with inhaled nitric oxide (iNO) as first-line therapy, followed by lung recruitment strategies, and escalation to ECMO for severe cases with an oxygenation index exceeding 25. 1

Initial Assessment and General Management

• Diagnosis requires echocardiography to exclude congenital heart disease and confirm PPHN, as well as to evaluate for left ventricular dysfunction which could affect treatment decisions 1
• Optimize lung volume and function through appropriate ventilation strategies to improve efficacy of pulmonary vasodilators 1
• Maintain normal systemic blood pressure with volume and cardiotonic therapy to reduce both left and right ventricular dysfunction and enhance systemic oxygen transport 1
• Avoid increasing blood pressure to supraphysiological levels solely to drive left-to-right shunting across the patent ductus arteriosus, as this may transiently improve oxygenation but will not reduce pulmonary vascular resistance 1
• Avoid extreme hyperoxia (FiO₂ >0.6) as it may be ineffective due to extrapulmonary shunt and may aggravate lung injury 1

First-Line Therapy

• Inhaled nitric oxide (iNO) is indicated as first-line therapy to reduce the need for extracorporeal membrane oxygenation in term and near-term infants 1, 2
• The recommended initial dose is 10-20 ppm, as doses >20 ppm do not enhance oxygenation and increase the risk of methemoglobinemia 1, 2
• iNO works by selectively dilating the pulmonary vasculature through activation of guanylate cyclase, increasing intracellular cyclic guanosine monophosphate levels 2
• Monitor methemoglobin levels, as concentrations can increase during the first 8 hours of nitric oxide exposure 2

Lung Recruitment Strategies

• Implement lung recruitment strategies to improve the efficacy of iNO therapy, particularly in patients with PPHN associated with parenchymal lung disease 1
• Consider high-frequency ventilation for poor lung compliance and inadequate gas exchange, but avoid lung over-expansion 1
• 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 1
• Avoid forced alkalosis through hyperventilation or sodium bicarbonate infusion, as it may worsen pulmonary vascular tone and reduce cerebral blood flow 1

Adjunctive Therapies for iNO-Resistant PPHN

• Sildenafil is a reasonable adjunctive therapy for infants with PPHN who are refractory to iNO, especially with an oxygenation index exceeding 25 1, 3
• Inhaled prostacyclin analogs may be considered as adjunctive therapy for infants with PPHN who are refractory to iNO and have an oxygenation index exceeding 25 1, 3
• Intravenous milrinone is reasonable in infants with PPHN and signs of left ventricular dysfunction 1, 3
• Up to 30-40% of infants do not achieve sustained improvement in oxygenation with iNO, necessitating consideration of these alternative therapies 1, 4

ECMO Indications and Considerations

• ECMO support is indicated for term and near-term infants with PPHN who have an oxygenation index exceeding 25 1
• ECMO is also indicated for neonates with severe pulmonary hypertension or hypoxemia refractory to iNO and optimization of respiratory and cardiac function 1
• The oxygenation index (calculated as: mean airway pressure × FiO₂ × 100 / PaO₂) is a useful gauge for judging disease severity, with an index >40 indicating consideration for ECMO referral 1
• Infants with sustained hypoxemia or compromised hemodynamic function should be transferred to a center equipped with appropriate ECMO equipment and experienced personnel 1

Special Considerations

• Evaluate for disorders of lung development such as alveolar capillary dysplasia and genetic surfactant protein diseases in infants with severe PPHN who fail to improve after vasodilator, lung recruitment, or ECMO therapy 1
• For infants with congenital diaphragmatic hernia and PPHN, minimize peak inspiratory pressure and avoid large tidal volumes to reduce ventilator-associated acute lung injury 1
• Use iNO cautiously in infants with congenital diaphragmatic hernia who have suspected left ventricular dysfunction 1
• Long-term follow-up is essential as 14-46% of survivors develop impairments such as hearing deficits, chronic lung disease, cerebral palsy, and other neurodevelopmental disabilities 5

Management Algorithm for PPHN

1. Confirm diagnosis with echocardiography 1
2. Optimize ventilation and maintain normal systemic blood pressure 1
3. Initiate iNO at 10-20 ppm 1, 2
4. If inadequate response to iNO:
   • Implement lung recruitment strategies 1
   • Consider adjunctive therapies (sildenafil, inhaled prostacyclin, milrinone) based on clinical presentation 1, 3
5. Calculate oxygenation index regularly; if exceeds 25-40, consider ECMO 1
6. Monitor for complications and provide appropriate long-term follow-up 5