What is the recommended dosing for inhaled nitric oxide (iNO) therapy?

Inhaled Nitric Oxide Therapy Dosing Guidelines

The recommended dose of inhaled nitric oxide (iNO) for term and near-term neonates with persistent pulmonary hypertension of the newborn (PPHN) is 20 ppm, maintained for up to 14 days or until the underlying oxygen desaturation has resolved. 1

Indications and Initial Dosing

• iNO is FDA-approved for term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension 1
• Initiation criteria:
  • Oxygenation index >25 (calculated as: mean airway pressure × FiO₂ × 100 / PaO₂) 2
  • Confirmed diagnosis of PPHN with extrapulmonary right-to-left shunting established by echocardiography 2

Dosing Protocol

1. Initial dose: 20 ppm for term and near-term neonates with PPHN 2, 1

   • Doses greater than 20 ppm do not enhance oxygenation or improve outcomes 2
   • Higher doses increase risk of methemoglobinemia and other complications 1

2. Monitoring requirements:

   • Measure methemoglobin within 4-8 hours after initiation and periodically throughout treatment 1
   • Monitor PaO₂ and inspired NO₂ levels during administration 1
   • Assess oxygenation response within 30-60 minutes (approximately 50% of infants show improvement) 3

3. Expected response:

   • Successful response typically shows decreased oxygenation index by approximately 15 points within 30-60 minutes 3
   • PaO₂ increases by approximately 53 mmHg in responders 3

Weaning and Discontinuation

• Avoid abrupt discontinuation of iNO therapy to prevent rebound pulmonary hypertension 1
• Weaning protocol:
  1. Once oxygenation improves, wean relatively rapidly to 5 ppm 2
  2. Further wean to 1 ppm before discontinuation to prevent rebound pulmonary hypertension 2
  3. Pause several hours at each weaning step to monitor for hypoxemia 1
  4. An oxygenation index <5 cm H₂O/torr predicts successful withdrawal (75% sensitivity, 89% specificity) 4

Special Considerations

• Duration of therapy: Treatment should be maintained up to 14 days or until underlying oxygen desaturation resolves 1
• Rebound prevention: When iNO is stopped abruptly, rebound pulmonary hypertension may develop even if no initial improvement in oxygenation was observed 2
• Non-responders: Up to 30-40% of infants do not achieve sustained improvement in oxygenation with iNO 2
• Prolonged therapy: Infants who remain hypoxemic with evidence of PPHN beyond 5 days may have underlying conditions such as alveolar capillary dysplasia, severe lung hypoplasia, or progressive lung injury 2

Adjunctive Therapies

• Lung recruitment strategies should be performed in patients with PPHN associated with parenchymal lung disease to improve iNO efficacy 2
• For patients refractory to iNO:
  • Consider sildenafil, especially with an oxygenation index >25 2
  • Consider inhaled prostacyclin analogs with an oxygenation index >25 2
  • Consider intravenous milrinone in infants with PPHN and signs of left ventricular dysfunction 2
  • ECMO is indicated for term and near-term neonates with severe PH or hypoxemia refractory to iNO and optimization of respiratory and cardiac function 2

Potential Complications

• Methemoglobinemia (especially with doses >20 ppm) 2, 1
• Nitrogen dioxide formation causing airway inflammation 1
• Rebound pulmonary hypertension during abrupt discontinuation 1
• Signs of rebound include hypoxemia, systemic hypotension, bradycardia, and decreased cardiac output 1

By following these evidence-based dosing guidelines for iNO therapy, clinicians can optimize outcomes for neonates with PPHN while minimizing potential complications.