What is the role of nitric oxide in acute respiratory distress syndrome (ARDS)?

Nitric Oxide in Acute Respiratory Distress Syndrome (ARDS)

Primary Recommendation

Inhaled nitric oxide should NOT be used routinely in adults with ARDS, as it consistently improves oxygenation but does not reduce mortality and may cause renal impairment; reserve it exclusively for salvage therapy in life-threatening hypoxemia after all evidence-based, mortality-reducing interventions have failed. 1, 2, 3

When to Consider Nitric Oxide (Salvage Therapy Only)

Inhaled nitric oxide may be considered ONLY after optimizing and failing ALL of the following interventions first 1:

• Lung-protective ventilation: Tidal volumes 4-8 ml/kg predicted body weight with plateau pressures <30 cm H₂O 1
• Higher PEEP strategies: PEEP ≥15 cm H₂O in moderate-severe ARDS 1
• Prone positioning: >12 hours daily in severe ARDS (PaO₂/FiO₂ <150 mmHg) 1
• Neuromuscular blockade: Cisatracurium when plateau pressures exceed 30-35 cm H₂O 1

The critical pitfall is using nitric oxide before exhausting these proven mortality-reducing interventions. 1

Dosing Strategy for Salvage Use

When used as rescue therapy, start at 5-10 ppm 4, 1:

• The typical salvage dose is 5-10 ppm based on expert consensus 4, 1
• In research studies, 65-69% of ARDS patients responded to nitric oxide, with 64% responding at just 1 ppm 5, 6
• Higher doses (>20 ppm) may paradoxically worsen oxygenation 7, 6
• Long-term use at constant doses (e.g., 10 ppm continuously) leads to enhanced sensitivity after several days, potentially causing overdosing and deterioration of oxygenation 7
• Do not escalate beyond 20 ppm, as oxygenation worsens at higher concentrations 6

Physiological Effects and Evidence

Nitric oxide improves oxygenation transiently but does not improve survival:

• A Cochrane systematic review of 1,243 patients showed no mortality benefit (38.2% deaths with nitric oxide vs. 37.5% control; RR 1.04,95% CI 0.9-1.19) 3
• PaO₂/FiO₂ ratio improved significantly at 24 hours (mean difference 15.91,95% CI 8.25-23.56) but this effect diminished over time 3
• The FDA label confirms that despite acute improvements in oxygenation in ARDS trials, there was no effect on days alive and off ventilator support 2

Mechanism of benefit: Nitric oxide reduces pulmonary vascular resistance and improves ventilation/perfusion matching without inducing systemic hypotension, as it acts locally on well-ventilated alveoli and is rapidly inactivated in the bloodstream 4, 8

Specific Role in Right Ventricular Failure

Inhaled nitric oxide (5-10 ppm) may improve right ventricular function by reducing pulmonary vascular resistance without systemic hypotension in ARDS patients with acute cor pulmonale 4, 9:

• This represents a potential secondary indication beyond oxygenation alone 4
• However, this has not been rigorously tested as a specific indication in ARDS 4

Critical Safety Concerns

Renal impairment risk: Nitric oxide increases the risk of renal impairment (RR 1.59,95% CI 1.17-2.16) 3

Monitoring requirements:

• Monitor for methemoglobinemia at sustained high doses 9, 2
• In the FDA-approved neonatal trials, 2% of patients were withdrawn due to methemoglobin levels >4% 2
• Be aware of potential tachyphylaxis with prolonged use 9

Weaning considerations: Rebound pulmonary hypertension can occur when discontinuing nitric oxide 9

Comparison to Other Therapies

Inhaled prostacyclin (20-30 ng/kg/min) has comparable efficacy to nitric oxide for improving oxygenation, with no evidence that either improves clinical outcomes 4

VV-ECMO should be considered at experienced centers rather than prolonged nitric oxide therapy in highly selected severe ARDS patients, though evidence certainty remains low 1

Systemic vasodilators should never be used in ARDS, as they worsen ventilation/perfusion matching by inhibiting hypoxic pulmonary vasoconstriction and can cause systemic hypotension 4, 8

Bottom Line for Clinical Practice

Nitric oxide improves oxygenation transiently but does not reduce mortality, increases renal impairment risk, and should only be used as a last resort in life-threatening hypoxemia after all evidence-based therapies have been exhausted. 1, 2, 3 Do not use it routinely or before optimizing lung-protective ventilation, prone positioning, and neuromuscular blockade. 1