Abstract

BACKGROUND

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurological condition that can be complicated by delayed cerebral ischemia (DCI), a leading cause of secondary brain injury. Milrinone, a phosphodiesterase-3 inhibitor with vasodilatory and anti-inflammatory properties, has been proposed as a potential therapeutic agent to mitigate DCI, yet its clinical utility remains uncertain. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of milrinone infusion in patients with aSAH.

METHODS

We systematically searched PubMed, Embase, and Cochrane Library databases from inception through June 1, 2025. Eligible studies included randomized and observational trials comparing outcomes between patients treated with and without milrinone infusion following aSAH. This analysis used aggregate study-level data; individual patient-level data were not available. Primary outcomes included incidence of DCI, good functional outcome (modified Rankin Scale score 0-2), and mortality. Cardiovascular adverse events were also assessed. Data were pooled using a random-effects model, and heterogeneity was evaluated using the I 2 statistic.

RESULTS

Seven studies comprising 1,045 patients across all routes of milrinone administration were included, of whom 529 (50.6%) received milrinone. In the primary analysis restricted to intravenous milrinone, treatment was associated with lower odds of vasospasm-related DCI (OR 0.45, 95% CI 0.23-0.90; p = 0.02). However, this association was not robust to leave-one-out sensitivity analysis. Intravenous milrinone was not associated with significantly better functional outcomes (OR 1.47, 95% CI 0.84-2.56; p = 0.17) or reduced mortality (OR 0.95, 95% CI 0.48-1.88; p = 0.88). Cardiovascular adverse events were numerically more frequent with intravenous milrinone, although the difference was not statistically significant (OR 1.63, 95% CI 0.86-3.08; p = 0.13).

CONCLUSION

Milrinone administration in patients with aSAH is associated with a lower incidence of delayed cerebral ischemia, with a trend toward increased cardiovascular adverse events. However, this did not translate into improved functional outcomes or reduced mortality. Further large-scale randomized controlled trials are needed.

MeSH

Mortality, Safety, Hemorrhage, Incidence, Subarachnoid Hemorrhage, Milrinone, Drug-Related Side Effects And Adverse Reactions, Therapeutics, Ischemia