Is nebulized nitric oxide (NO) a first-line treatment for pulmonary hypertension?

Nebulized Nitric Oxide for Pulmonary Hypertension

Inhaled nitric oxide (iNO) is not a first-line treatment for chronic pulmonary hypertension but is considered a standard therapy for acute postoperative pulmonary hypertension and pulmonary hypertensive crises. 1

Indications for Inhaled Nitric Oxide

Acute Settings (First-Line)

• Postoperative pulmonary hypertension after cardiac surgery, particularly in children 1
• Pulmonary hypertensive crises requiring immediate intervention 1
• Persistent pulmonary hypertension of the newborn (PPHN) in near-term and term infants 1
• Acute right heart failure requiring ICU management 1

Chronic Pulmonary Hypertension (Not First-Line)

For chronic pulmonary arterial hypertension (PAH), the first-line therapies depend on functional class:

• Class III patients: Oral endothelin receptor antagonists (e.g., bosentan), prostanoid analogues, or PDE5 inhibitors 1
• Class IV patients: IV epoprostenol is the preferred first-line therapy due to demonstrated survival benefit 1

Advantages of Inhaled Nitric Oxide

• Selective pulmonary vasodilation without affecting systemic vascular resistance 1
• Rapid onset of action 1
• Improves ventilation-perfusion matching 1
• Decreases intrapulmonary shunt fraction 1
• Often improves systemic arterial oxygenation 1

Dosing Considerations

• Acute postoperative PH: 2-20 ppm is typical range 1
• PPHN: Doses >20 ppm do not enhance outcomes and increase risk of methemoglobinemia 1
• ICU setting: 20 ppm is commonly used for hypotensive PH patients 1

Important Cautions and Complications

Rebound Pulmonary Hypertension

• Occurs upon abrupt withdrawal of iNO 2, 3, 4, 5
• Characterized by:
  • Increase in pulmonary artery pressure by >20% 1
  • Decreased cardiac output 2
  • Hypotension 1
  • Systemic desaturation 1

Prevention of Rebound

• Gradual weaning of iNO to doses <1-5 ppm before discontinuation 1
• Consider transitioning to oral sildenafil before withdrawal 1
• Dipyridamole may also attenuate rebound 1

Mechanism of Rebound Phenomenon

• iNO increases plasma endothelin-1 (ET-1) levels during therapy 3
• ET-1 levels decrease rapidly upon iNO discontinuation 3
• ET-1 induces superoxide production, which can form peroxynitrite with NO 4
• Peroxynitrite reduces endogenous nitric oxide synthase activity 4

Algorithm for Management

1. For acute postoperative PH or pulmonary hypertensive crisis:

   • Start iNO at 10-20 ppm 1
   • Monitor for improvement in oxygenation and hemodynamics
   • Adjust dose based on response (rarely exceed 20 ppm)

2. For chronic PAH:

   • Start with appropriate oral therapy based on functional class
   • Reserve iNO for acute decompensation or perioperative management
   • Consider ETA receptor antagonists for long-term management 1

3. When discontinuing iNO:

   • Wean gradually to <5 ppm 1
   • Consider starting oral sildenafil before complete withdrawal 1
   • Monitor closely for signs of rebound (increased PAP, decreased cardiac output)
   • Be prepared to reinstitute iNO if significant rebound occurs 1

Conclusion

While inhaled nitric oxide is an important tool in the management of pulmonary hypertension, particularly in acute and crisis settings, it is not considered a first-line therapy for chronic pulmonary hypertension management. The risk of rebound pulmonary hypertension upon withdrawal requires careful weaning strategies and consideration of transition to other pulmonary vasodilators.