What are the direct indications for inhaled nitric oxide (iNO) in critically ill patients, including neonates and adults with severe respiratory distress or pulmonary hypertension?

Direct Indications for Inhaled Nitric Oxide

Inhaled nitric oxide is FDA-approved for term and near-term neonates (>34 weeks gestation) with hypoxic respiratory failure and pulmonary hypertension, and should be considered as a rescue therapy in critically ill adults with severe pulmonary hypertension causing acute right ventricular failure or in severe ARDS with refractory hypoxemia despite optimization of ventilation. 1

FDA-Approved Indication

• The only FDA-approved indication is for term and near-term neonates (>34 weeks gestation) with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, used in conjunction with ventilatory support to improve oxygenation and reduce the need for extracorporeal membrane oxygenation (ECMO). 1

• iNO is specifically indicated when the oxygenation index exceeds 25 in this neonatal population. 2

• The FDA explicitly states that nitric oxide is not indicated for use in the adult population as a routine therapy. 1

Off-Label Critical Care Applications in Adults

Acute Pulmonary Hypertension with Right Ventricular Failure

• In critically ill adults with pulmonary arterial hypertension (PAH) who are hypotensive with acute right ventricular failure, iNO at 20 parts per million should be routinely employed in the ICU setting. 3

• iNO acutely decreases pulmonary vascular resistance (PVR) and improves cardiac output in pulmonary hypertension, particularly in patients post-coronary bypass surgery or valve replacement. 3

• The critical advantage in this population is that iNO has no detrimental effect on systemic vascular resistance (SVR), which is essential when maintaining the principle that SVR must remain greater than PVR to prevent right ventricular ischemia. 3

• iNO has a short half-life and rapid onset of action, allowing it to unload an acutely failing right ventricle while improving oxygenation through enhanced ventilation-perfusion matching. 3

Severe ARDS with Refractory Hypoxemia

• In mechanically ventilated adults with COVID-19 (or other causes of) severe ARDS and hypoxemia despite optimizing ventilation and other rescue strategies, a trial of inhaled pulmonary vasodilator should be used as rescue therapy; if no rapid improvement in oxygenation is observed, the treatment should be tapered off. 3

• The routine use of iNO in mechanically ventilated adults with COVID-19 ARDS is not recommended. 3

• iNO should only be considered after optimization of mechanical ventilation (low tidal volume 4-8 mL/kg, plateau pressure <30 cmH2O, higher PEEP strategy, prone positioning for 12-16 hours) and when hypoxemia persists. 3

Pediatric Applications Beyond Neonates

• In infants and children at high risk of pulmonary hypertensive crises, inhaled nitric oxide or aerosolized prostacyclin or analogues to reduce pulmonary vascular resistance should be considered. 3

• iNO may be considered in infants with established bronchopulmonary dysplasia (BPD) and pulmonary hypertension after optimization of respiratory support and treatment of underlying lung disease. 2

• For preterm infants with severe hypoxemia primarily due to persistent pulmonary hypertension of the newborn (PPHN), iNO can be beneficial, but routine use in preterm infants <34 weeks gestation is not supported by evidence. 2

Dosing Considerations

• The typical starting dose in critically ill adults with PAH is 20 ppm. 3

• In ARDS patients, the optimal dose for improving oxygenation ranges from 1-20 ppm, with 64% of responders showing benefit at 1 ppm and 36% at 5 ppm. 4

• Doses above 20 ppm may worsen oxygenation in ARDS patients and should be avoided. 4

• The dose required for decreasing mean pulmonary artery pressure may range from 1-40 ppm, which is higher than that needed for oxygenation improvement. 4

Critical Pitfalls and Contraindications

Rebound Pulmonary Hypertension

• Abrupt discontinuation of iNO can cause life-threatening rebound pulmonary hypertension; always wean gradually and start or restart a phosphodiesterase inhibitor (such as sildenafil) as replacement therapy before complete discontinuation. 3, 2

Left Ventricular Dysfunction

• Patients with left ventricular dysfunction treated with iNO may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening left ventricular dysfunction, systemic hypotension, bradycardia, and cardiac arrest. 1

• In congenital diaphragmatic hernia (CDH), iNO may worsen pulmonary edema if left ventricular dysfunction is present due to increased preload to an abnormal left ventricle. 2

• Discontinue iNO immediately while providing symptomatic care if these complications develop. 1

Methemoglobinemia and Nitrogen Dioxide Toxicity

• iNO can cause methemoglobinemia, though usually only at sustained high doses. 3

• Nitrogen dioxide (NO2) levels >3 ppm or methemoglobin levels >7% require dose reduction or discontinuation of iNO. 1

• Methemoglobinemia that does not resolve after discontinuation can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion. 1

Optimization Requirements

• Failure to optimize lung inflation before or during iNO administration significantly reduces its efficacy. 2

• Lung recruitment strategies must be employed to improve the efficacy of iNO therapy in patients with PPHN associated with parenchymal lung disease. 2

Adjunctive Therapies

• Sildenafil may be used as adjunctive therapy for infants with PPHN refractory to iNO. 2

• Inhaled prostacyclin analogs may be used for infants with PPHN refractory to iNO. 2

• Intravenous milrinone may be used for infants with PPHN and signs of left ventricular dysfunction. 2

Transport Considerations

• Starting iNO at a referring hospital at the start of neonatal transport decreases length of hospital stay in surviving neonates with PPHN not requiring ECMO, compared to starting iNO only at the receiving facility. 5