What are the indications and treatment effects of inhaled nitric oxide (iNO) in patients with pulmonary hypertension and impaired oxygenation?

Indications for Inhaled Nitric Oxide (iNO): Mechanism of Action and Treatment Effects

Inhaled nitric oxide (iNO) is primarily indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO) in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension. 1

Mechanism of Action

• iNO is a potent signaling molecule that acts as a selective pulmonary vasodilator, decreasing pulmonary vascular resistance without causing systemic hypotension 2
• It works by diffusing across the alveolar-capillary membrane and binding to hemoglobin in pulmonary vessels, activating guanylate cyclase, which increases cyclic GMP and causes smooth muscle relaxation 2
• Beyond vasodilation, iNO has multiple regulatory effects throughout the body, including stimulating angiogenesis, augmenting alveolarization, improving surfactant function, and inhibiting abnormal smooth muscle proliferation in animal models 2
• iNO improves ventilation-perfusion matching by selectively dilating vessels in ventilated lung regions 3

Primary Clinical Indications

1. Persistent Pulmonary Hypertension of the Newborn (PPHN)

• iNO is indicated as first-line therapy for term and near-term infants with PPHN who have an oxygenation index exceeding 25 2
• It significantly improves oxygenation in 60-70% of patients with PPHN and reduces the need for ECMO 4, 5
• The recommended dose is 20 ppm, with treatment maintained up to 14 days or until the underlying oxygen desaturation resolves 1

2. Congenital Diaphragmatic Hernia (CDH) with Pulmonary Hypertension

• iNO should not be used routinely in CDH but reserved for specific cases 2
• Its use should be limited to patients with suprasystemic pulmonary vascular resistance with right-to-left shunting across the oval foramen causing critical preductal hypoxemia 2
• iNO should only be administered after optimal lung inflation and adequate left ventricular performance are established 2

3. Bronchopulmonary Dysplasia (BPD) with Pulmonary Hypertension

• iNO may be considered in infants with established BPD and pulmonary hypertension after optimization of respiratory support and treatment of underlying lung disease 2
• Evaluation and treatment of lung disease, including assessments for hypoxemia, aspiration, and structural airway disease, should be completed before initiating iNO therapy 2

4. Preterm Infants with Severe Hypoxemia

• iNO can be beneficial for preterm infants with severe hypoxemia primarily due to PPHN 2
• However, routine use in preterm infants <34 weeks gestation is not supported by evidence 2

Adjunctive Therapies and Optimization Strategies

• Lung recruitment strategies significantly improve the efficacy of iNO therapy and should be performed in patients with PPHN associated with parenchymal lung disease 2
• High-frequency oscillatory ventilation (HFOV) combined with iNO often provides better outcomes than either therapy alone in severe PPHN, particularly in respiratory distress syndrome and meconium aspiration syndrome 6, 7
• For patients who fail to respond to iNO, additional therapies include:
  • Sildenafil as adjunctive therapy for infants with PPHN refractory to iNO 2
  • Inhaled prostacyclin analogs for infants with PPHN refractory to iNO 2
  • Intravenous milrinone for infants with PPHN and signs of left ventricular dysfunction 2

Important Considerations and Monitoring

• Methemoglobin levels should be monitored within 4-8 hours after initiating iNO therapy and periodically throughout treatment 1
• Avoid abrupt discontinuation of iNO as it can lead to rebound pulmonary hypertension syndrome with worsening oxygenation and increasing pulmonary artery pressure 1
• To wean iNO, gradually downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia 1
• iNO is contraindicated in neonates dependent on right-to-left shunting of blood 1

Clinical Pitfalls to Avoid

• Using doses greater than 20 ppm does not enhance oxygenation or improve outcomes and increases the risk of methemoglobinemia 1
• Failure to optimize lung inflation before or during iNO administration significantly reduces its efficacy 2, 7
• Abrupt discontinuation can cause life-threatening rebound pulmonary hypertension; always wean gradually to 1 ppm before discontinuation 2, 1
• In CDH, iNO may worsen pulmonary edema if left ventricular dysfunction is present due to increased preload to an abnormal left ventricle 2