What is the recommended treatment for persistent pulmonary hypertension (PPHN) in a neonate using inhaled nitric oxide (iNO)?

Inhaled Nitric Oxide Therapy for Persistent Pulmonary Hypertension in Neonates

Inhaled nitric oxide (iNO) is indicated as first-line therapy for term and near-term neonates (>34 weeks gestation) with persistent pulmonary hypertension of the newborn (PPHN) to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO). 1, 2

Initial Treatment Protocol

• iNO therapy should be initiated in term and near-term neonates with PPHN who have hypoxic respiratory failure with clinical or echocardiographic evidence of pulmonary hypertension 1
• Lung recruitment strategies should be performed before and during iNO therapy to optimize efficacy, particularly in patients with PPHN associated with parenchymal lung disease 2
• Failure to optimize lung inflation significantly reduces iNO efficacy 3
• The FDA-approved indication for iNO is for term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension 1

Dosing and Administration

• Low-dose iNO (6-20 ppm) has been shown to cause sustained clinical improvement in severe PPHN 4, 5
• Starting with subtherapeutic doses (2 ppm) may attenuate the clinical response to subsequent higher doses of iNO 6
• Abrupt discontinuation of iNO can cause life-threatening rebound pulmonary hypertension; always wean gradually to 1 ppm before discontinuation 3
• Monitor methemoglobin levels and nitrogen dioxide (NO2) concentrations during therapy; if NO2 reaches 3 ppm, the delivery system should be assessed 1

Monitoring and Response Assessment

• Response to iNO therapy should be assessed by improvement in oxygenation (increased PaO2 or decreased oxygenation index) 7, 4
• Patients with extrapulmonary shunting, clear chest radiographs, and adequate lung volume tend to have better responses to iNO 8
• If there is no improvement in oxygenation after initiation of iNO, consider escalation to combination therapy or ECMO 2

Refractory Cases and Adjunctive Therapies

• ECMO support is indicated for term and near-term neonates with severe PH or hypoxemia that is refractory to iNO and optimization of respiratory and cardiac function 2
• For infants with PPHN refractory to iNO, especially with an oxygenation index exceeding 25, consider the following adjunctive therapies:
  • Sildenafil is a reasonable adjunctive therapy 2
  • Inhaled prostacyclin analogs may be considered 2
  • Intravenous milrinone is reasonable in infants with PPHN and signs of left ventricular dysfunction 2
• Combination of high-frequency oscillatory ventilation (HFOV) with iNO may be more effective than either therapy alone in severe PPHN 7

Special Considerations

• In patients with congenital diaphragmatic hernia (CDH), iNO should be used cautiously in subjects with suspected left ventricular dysfunction as it may worsen pulmonary edema 2, 3
• Patients with left ventricular dysfunction treated with iNO may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia, and cardiac arrest 1
• Evaluation for disorders of lung development such as alveolar capillary dysplasia and genetic surfactant protein diseases is reasonable for infants with severe PPHN who fail to improve after vasodilator, lung recruitment, or ECMO therapy 2

Disease-Specific Response Patterns

• Response to iNO varies by underlying disease; patients with respiratory distress syndrome and meconium aspiration syndrome may respond better to combination therapy with HFOV plus iNO than to either treatment alone 7
• Patients with congenital diaphragmatic hernia, severe sepsis, and alveolar capillary dysplasia are more likely to have poor responses to iNO therapy 8

Common Pitfalls to Avoid

• Initiating iNO without optimizing lung recruitment first 3
• Abrupt discontinuation of iNO therapy (always wean gradually) 3
• Using iNO in patients with left ventricular dysfunction without careful monitoring 1
• Starting with subtherapeutic doses (2 ppm) which may diminish subsequent response to therapeutic doses 6
• Failure to consider combination therapy (iNO + HFOV) in severe cases 7