Milrinone in Subarachnoid Hemorrhage
Direct Answer
Milrinone should be administered as a continuous intravenous infusion at 0.5 μg/kg/min for 5-7 days (up to day 14 post-bleed) when cerebral vasospasm is refractory to nimodipine, euvolemia, and induced hypertension, with close monitoring for hypotension and electrolyte disturbances. 1
Clinical Context and Guideline Framework
Current American Heart Association/American Stroke Association guidelines do not specifically address milrinone, but classify intra-arterial vasodilator therapy as Class IIb, Level of Evidence B—meaning it may be reasonable as an alternative or adjunct when medical management fails. 2 The fundamental limitation is that angiographic improvement does not equal proven clinical benefit in terms of morbidity, mortality, or quality of life. 2
However, the most recent high-quality evidence (2021 MILRISPASM study) demonstrates that IV milrinone is independently associated with:
- Lower 6-month functional disability (adjusted OR 0.28,95% CI 0.10-0.77) 1
- Reduced vasospasm-related brain infarction (adjusted OR 0.19,95% CI 0.04-0.94) 1
- Decreased need for endovascular angioplasty (15% vs 53%, adjusted OR 0.12) 1
Dosing and Administration Protocol
Intravenous Route (Preferred First-Line)
The continuous IV infusion protocol is as effective as combined intra-arterial plus IV therapy and should be considered the first-line approach. 3
- Dose: 0.5 μg/kg/min continuous infusion 1
- Duration: Median 5 days (range 2-8 days), continuing up to day 14 post-hemorrhage 1, 4
- Initiation: Start when vasospasm becomes symptomatic despite maximal medical management 1
Intra-Arterial Route (Rescue Therapy)
For refractory vasospasm requiring ≥3 endovascular interventions: 5
- Infusion rate: 0.25 mg/min via catheter 4
- Total dose per territory: Maximum 10-16 mg 5
- Maximum per session: 24 mg 5
- Maximum per day: 42 mg 5
- Technique: Infusion through cervical catheter is reasonable, with intracranial microcatheter placement reserved for severe cases 2
Combined intra-arterial milrinone plus nimodipine can be used as rescue therapy in exceptional refractory cases. 5
Monitoring Requirements
Hemodynamic Monitoring
- Mean arterial pressure: Target ≥100 mmHg with concurrent induced hypertension 1
- Norepinephrine support: May require up to 1.5 μg/kg/min to maintain blood pressure goals 1
- Cardiac output: Consider advanced hemodynamic monitoring with transpulmonary thermodilution 6
Laboratory Monitoring
- Creatinine clearance: Expect polyuria with clearance ~191 ml/min 1
- Electrolytes: Monitor closely for hyponatremia and hypokalemia (common complications) 1
- Magnesium: Correct hypomagnesemia when present 7
Neurological Monitoring
- Intracranial pressure: Monitor if available, especially during intra-arterial infusion 6
- Brain tissue oxygenation (PbtO2): Ideal for patients with concurrent ARDS requiring higher PEEP 6
- Transcranial Doppler: Serial monitoring for vasospasm severity 3
Expected Clinical Response
Angiographic Response
- Vessel diameter increase: Occurs in all patients receiving intra-arterial milrinone 4
- Reversion rate: 64-71% of vasospastic arterial segments reverse within first week 3
Clinical Response
- Cerebral blood flow: Increases in all treated patients 4
- Symptom prevention: IV infusion prevents recurrence of symptomatic vasospasm in 57% of patients 4
Contraindications and Discontinuation Criteria
Absolute Contraindications
- Inability to maintain mean arterial pressure ≥100 mmHg despite 1.5 μg/kg/min norepinephrine 1
- Severe thrombocytopenia (though infrequent with milrinone) 1
Relative Contraindications
- Active myocardial ischemia (monitor closely, though arrhythmia and ischemia are infrequent) 1
- Severe electrolyte disturbances that cannot be corrected 1
Discontinuation Rate
Expect premature discontinuation in 29% of patients due to poor tolerance, most commonly (24%) for inability to achieve induced hypertension targets. 1 This is similar to control patients not receiving milrinone (21%), suggesting the issue relates to vasospasm severity rather than milrinone itself. 1
Alternative and Adjunctive Rescue Options
Endovascular Mechanical Therapy
- Balloon angioplasty: Superior to vasodilators in terms of durability and efficacy for large vessels 6
- Timing: Early therapy at <2 hours may promote sustained clinical improvement 6, 2
- Mortality benefit: 16% reduction in in-hospital death at institutions with angioplasty capability 6, 2
Other Intra-Arterial Vasodilators
- Verapamil: Increasingly used with excellent anecdotal results, appears safer than papaverine 6, 2
- Papaverine: Generally avoided due to neurotoxicity risk; utility not established 2
- Nimodipine (intra-arterial): Not available in all regions; evidence remains observational 2
Combination Therapy
Intra-arterial infusions can be used with angioplasty to access the entire vasculature for diffuse spasm. 2 Balloon angioplasty demonstrates greater durability compared to vasodilator therapy alone. 2
Critical Pitfalls and Caveats
Foundational Medical Management Must Continue
- Oral nimodipine 60 mg every 4 hours for 21 days remains the ONLY Class I, Level of Evidence A recommendation and must be continued even when adding milrinone 6, 7, 2
- Euvolemia (not hypervolemia) must be maintained throughout treatment 6, 7
- Avoid prophylactic hypervolemia and triple-H therapy as they increase complications without improving outcomes 6, 7
Hypotension Management
The primary complication is systemic hypotension requiring aggressive vasopressor support. 2 This can be controlled with:
- Norepinephrine titration up to 1.5 μg/kg/min 1
- Brief hyperventilation if intracranial pressure rises 6, 2
- Mannitol, barbiturate therapy, or ventricular drainage as needed 6, 2
Evidence Quality Limitations
No randomized controlled trials demonstrate that milrinone improves functional outcomes, morbidity, or mortality—the current evidence is observational. 2 The 2021 MILRISPASM study is the highest quality evidence available but is a controlled before-after study, not an RCT. 1
Institutional Expertise Matters
Outcomes are significantly better at institutions with endovascular capability and experience. 2 Consider early transfer if your institution lacks this expertise.