What is the role of inhaled Nitric Oxide (NO) in the treatment of Acute Respiratory Distress Syndrome (ARDS)?

Inhaled Nitric Oxide in ARDS: Reserve for Salvage Therapy Only

Inhaled nitric oxide should NOT be used routinely in ARDS and should be restricted to salvage therapy only in patients with severe ARDS and life-threatening hypoxemia after all other evidence-based, mortality-reducing interventions have failed. 1

Primary Recommendation

The evidence is unequivocal: while inhaled nitric oxide consistently improves oxygenation parameters, it does not reduce mortality in adult ARDS patients. 1, 2, 3 The 2024 American Thoracic Society guidelines and Society of Critical Care Medicine both recommend against routine use, as multiple randomized controlled trials have failed to demonstrate any survival benefit. 1

• The FDA label explicitly states that inhaled nitric oxide is "ineffective in Adult Respiratory Distress Syndrome (ARDS)" based on a large randomized trial of 385 patients where, despite acute improvements in oxygenation, there was no effect on days alive and off ventilator support. 2

• A comprehensive Cochrane review of all RCTs found no mortality benefit at longest follow-up (RR 1.04,95% CI 0.9-1.19) or at 28 days (RR 1.08,95% CI 0.92-1.27), with moderate quality evidence. 3

When to Consider (Only After All Else Fails)

Inhaled nitric oxide may be considered exclusively after optimizing and failing ALL of the following proven mortality-reducing interventions: 1

1. Lung-protective ventilation: Tidal volumes 4-8 mL/kg predicted body weight with plateau pressures <30 cm H₂O 1

2. Higher PEEP strategies: PEEP ≥15 cm H₂O in moderate-severe ARDS 1

3. Prone positioning: >12 hours daily in severe ARDS 1

4. Neuromuscular blockade: Cisatracurium when plateau pressures exceed 30-35 cm H₂O 1

Physiological Effects vs Clinical Outcomes

The disconnect between physiology and outcomes is critical to understand:

• Inhaled nitric oxide significantly improves PaO₂/FiO₂ ratio at 24 hours (MD 15.91 mmHg, 95% CI 8.25-23.56) and oxygenation index (MD -2.31,95% CI -2.73 to -1.89). 3

• However, this oxygenation improvement is transient and does not translate to increased ventilator-free days (MD -0.57 days, 95% CI -1.82 to 0.69). 3

• In COVID-19 ARDS specifically, a multicenter cohort found that while 45.7% of patients responded with improved oxygenation at 6 hours, there was no mortality benefit, and iNO use was associated with longer ICU stays, fewer ventilator-free days, and higher odds of acute kidney injury (OR 2.35) and hospital-acquired pneumonia (OR 3.2). 4

Critical Harms to Consider

Inhaled nitric oxide may cause harm:

• Renal impairment: Statistically significant increase in renal failure (RR 1.59,95% CI 1.17-2.16) with high quality evidence. 3

• In COVID-19 patients, iNO was associated with significantly higher odds of acute kidney injury and ventilator-associated pneumonia. 4

Potential Role in Right Ventricular Failure

The 2016 Intensive Care Medicine expert consensus suggests inhaled nitric oxide (5-10 ppm) may improve right ventricular function by reducing pulmonary vascular resistance without inducing systemic hypotension. 5 However, this has not been rigorously tested as a specific indication in ARDS, and both inhaled nitric oxide and inhaled prostacyclin appear comparable in improving oxygenation without evidence for improved clinical outcomes. 5

Dosing When Used as Salvage

When used as rescue therapy, typical dosing is 5-10 ppm. 5 The FDA label notes that in neonatal studies, doses of 20 ppm were used, with no additional benefit observed at 80 ppm. 2 However, these neonatal data cannot be extrapolated to adult ARDS.

ECMO vs Prolonged Nitric Oxide

The American Thoracic Society provides a conditional recommendation for VV-ECMO in highly selected severe ARDS patients at experienced centers, suggesting this should be considered rather than prolonged nitric oxide therapy. 1 This reflects the lack of mortality benefit with iNO versus the potential (though still uncertain) benefit of ECMO in refractory cases.

Bottom Line for Clinical Practice

Inhaled nitric oxide improves oxygenation but not survival in adult ARDS and should be reserved exclusively for salvage therapy in life-threatening hypoxemia after all evidence-based, mortality-reducing interventions have been exhausted. 1 The transient physiological improvement does not justify routine use given the lack of mortality benefit, potential for renal harm, and increased healthcare resource utilization. 3, 4