What is the updated treatment protocol for Acute Respiratory Distress Syndrome (ARDS) using milrinone (phosphodiesterase 3 inhibitor)?

Milrinone is NOT Recommended for ARDS Treatment

Milrinone should not be used as a treatment for ARDS, as it has failed to demonstrate efficacy in improving oxygenation and is not included in any current evidence-based ARDS management guidelines. The most recent 2024 American Thoracic Society guidelines make no mention of milrinone or other phosphodiesterase-3 inhibitors as therapeutic options for ARDS 1.

Evidence Against Milrinone Use

The only available clinical trial data directly examining inhaled milrinone in ARDS showed:

• No significant improvement in oxygenation: Median PaO₂ increase was only 6 mmHg (not statistically significant) compared to baseline 2
• Inferior to inhaled nitric oxide: When directly compared, only inhaled NO significantly improved oxygenation, while milrinone did not 2
• No hemodynamic benefit: Milrinone had no impact on systemic hemodynamics in ARDS patients 2

This 2017 prospective crossover study in 15 ARDS patients concluded that "inhaled milrinone appeared safe but failed to improve oxygenation in ARDS" 2.

Current Evidence-Based ARDS Management (2024 Guidelines)

Instead of milrinone, the American Thoracic Society recommends the following proven interventions:

Core Ventilation Strategy

• Lung-protective ventilation with tidal volumes 4-8 mL/kg predicted body weight and plateau pressures <30 cmH₂O (strong recommendation) 1
• Higher PEEP without prolonged lung recruitment maneuvers for moderate to severe ARDS (conditional recommendation) 1
• Strong recommendation against prolonged lung recruitment maneuvers due to hemodynamic harm 1

Adjunctive Therapies for Severe ARDS

• Prone positioning for >12 hours daily in severe ARDS (PaO₂/FiO₂ <100 mmHg) - proven mortality reduction 1, 3
• Corticosteroids for ARDS patients (conditional recommendation, moderate certainty) 1
• Neuromuscular blockers in early severe ARDS (conditional recommendation, low certainty) 1
• VV-ECMO in selected patients with severe ARDS at experienced centers (conditional recommendation, low certainty) 1

Fluid Management

• Conservative fluid strategy to minimize pulmonary edema while maintaining organ perfusion 3, 4

Alternative Pulmonary Vasodilators

While milrinone is not effective, other pulmonary vasodilators have limited roles:

• Inhaled nitric oxide showed statistically significant oxygenation improvement in the same study where milrinone failed 2
• However, current guidelines suggest against routine use of inhaled nitric oxide in ARDS 5
• These agents may be considered as rescue therapy only in refractory severe hypoxemia, but should be discontinued if no rapid improvement occurs 4

Why Milrinone Was Investigated (But Failed)

Milrinone was theoretically attractive because:

• It has pulmonary vasodilator properties through phosphodiesterase-3 inhibition
• Related agent levosimendan showed some benefit for right ventricular afterload in ARDS patients with septic shock 6

However, the clinical trial data demonstrated that theoretical mechanisms do not translate to clinical benefit in ARDS 2.

Critical Implementation Points

The priority in ARDS management is implementing proven interventions that reduce mortality 1:

1. Immediate lung-protective ventilation (the only intervention proven to improve survival) 3, 4
2. Higher PEEP strategy in moderate-severe ARDS 1
3. Prone positioning in severe ARDS (significantly underutilized despite mortality benefit) 3, 4
4. Conservative fluid management 3, 4

Common pitfall: Underutilization of evidence-based strategies like prone positioning and lung-protective ventilation is associated with increased mortality 3, 4.