What is the role of milrinone (phosphodiesterase 3 inhibitor) in the management of patients with aneurysmal subarachnoid hemorrhage?

Milrinone in Aneurysmal Subarachnoid Hemorrhage

Primary Recommendation

Milrinone can be used as an adjunctive inotropic agent to offset decreased venous return from higher PEEP in patients with concurrent severe ARDS and high-grade aSAH, particularly during the delayed cerebral ischemia period, though it is not mentioned in major guideline recommendations for routine vasospasm management. 1

Context and Evidence Base

The most recent AHA/ASA guidelines (2023) do not include milrinone in their formal recommendations for cerebral vasospasm or delayed cerebral ischemia (DCI) management 1. The guidelines focus on:

• Enteral nimodipine (60 mg every 4 hours for 21 days) as the only Class I recommendation for preventing DCI and improving functional outcomes 1, 2
• Maintenance of euvolemia rather than hypervolemia 1
• Blood pressure augmentation for symptomatic vasospasm (Class IIa recommendation) 1
• Intra-arterial vasodilators and cerebral angioplasty for severe vasospasm (Class IIb recommendations) 1

Specific Clinical Scenario Where Milrinone May Be Considered

High-Grade aSAH with Concurrent Severe ARDS

The only guideline-level mention of milrinone appears in the context of managing the challenging scenario of preventing DCI while treating concurrent severe ARDS 1. In this specific situation:

• Higher PEEP levels may decrease cerebral blood flow 1
• Simultaneous use of inotropic agents such as milrinone may offset the decreased venous return from higher PEEPs 1
• These patients should have advanced intracranial monitoring with PbtO2 to allow nuanced ventilator titration 1

Mechanism and Rationale

Milrinone is a phosphodiesterase III inhibitor that:

• Provides inotropic support without significantly affecting heart rate or blood pressure 3
• Acts as both a cardiac inotrope and vasodilator 3
• May improve microcirculation 4

Research Evidence (Not Guideline-Supported)

While not incorporated into major guidelines, research studies have explored milrinone:

Intravenous Administration

• A case series of 88 patients using IV milrinone (mean 9.8 days) showed 75% achieved good functional outcome (mRS ≤2) with no significant side effects 4
• This protocol emphasized maintenance of homeostasis rather than triple-H therapy 4

Intra-arterial Administration

• Small case series show vessel dilation and increased cerebral blood flow with intra-arterial milrinone (2.5-15 mg) 5
• Higher doses (up to 24 mg per session) have been used for refractory vasospasm 6
• Combined intra-arterial milrinone and nimodipine has been reported as rescue therapy 6, 7

Critical Limitations and Caveats

These research findings have not been validated in randomized controlled trials and are not incorporated into any major society guidelines 1. The 2023 AHA/ASA guidelines specifically recommend against:

• Prophylactic hemodynamic augmentation (Class III: Harm) to reduce iatrogenic patient harm 1
• Routine statin therapy (Class III: No benefit) 1
• Routine IV magnesium (Class III: No benefit) 1

Algorithmic Approach to Vasospasm Management (Guideline-Based)

Prevention Phase (All Patients)

1. Start enteral nimodipine 60 mg every 4 hours within 96 hours of hemorrhage, continue for 21 days 1, 2
2. Maintain euvolemia with goal-directed fluid management 1
3. Avoid prophylactic hypervolemia (associated with worse outcomes) 1

Treatment of Symptomatic Vasospasm/DCI

1. First-line: Elevate systolic blood pressure (unless already elevated or cardiac contraindications exist) 1
2. Second-line (severe vasospasm): Consider intra-arterial vasodilators (Class IIb) 1
3. Third-line (severe vasospasm): Consider cerebral angioplasty (Class IIb) 1

Special Circumstance: Concurrent Severe ARDS

• Use ARDS protocol ventilation with higher PEEP if early in bleed course and aneurysm secured 1
• Implement intracranial pressure monitoring, especially PbtO2 monitoring 1
• Consider inotropic agents such as milrinone to offset decreased venous return from PEEP 1
• Consider spontaneous ventilation modes (APRV) to lower sedation requirements 1

Common Pitfalls to Avoid

• Do not use prophylactic hypervolemia – it increases complications without improving outcomes 1
• Do not discontinue nimodipine due to hypotension – use vasopressors to maintain blood pressure instead 2
• Do not use milrinone as routine prophylaxis – no guideline support exists for this indication 1
• Do not delay aneurysm securing – early treatment allows more aggressive vasospasm management 1

Bottom Line

Milrinone is not a guideline-recommended therapy for routine vasospasm management in aSAH. Its only guideline-level mention is as a potential adjunctive inotrope in the highly specific scenario of high-grade aSAH with concurrent severe ARDS requiring high PEEP 1. Standard management remains nimodipine, euvolemia, and blood pressure augmentation for symptomatic vasospasm 1. Any use of milrinone beyond this narrow indication represents off-guideline practice based on limited case series data 4, 5.