Efeitos do milrinone venoso na recuperação clínica e reversão do vasoespasmo cerebral secundário à hemorragia subaracnoide: revisão sistemática e meta-análise

Abstract

Introduction: Non-traumatic subarachnoid hemorrhage (SAH) is a prevalent condition among young patients. Although mortality has significantly decreased over the past three decades, SAH remains a major public health issue, with an estimated global mortality ranging between 15% nd 35%. Additionally, about one-third of survivors experience a significant reduction in quality of life. Adverse complications of SAH include primary brain injury caused by bleeding and delayed cerebral ischemia (DCI), often associated with cerebral vasospasm (CVS). CVS is a common and severe complication of SAH that negatively impacts prognosis due to its relationship with DCI. Together, these conditions affect approximately one-third of patients, with DCI resulting in severe functional impairment and dependence on daily living activities in 8% to 20% of cases. Objectives: This study aims to evaluate the efficacy of intravenous milrinone as an adjunct therapy to standard treatment for cerebral vasospasm secondary to aneurysmal SAH. Although milrinone is widely used in clinical practice, robust evidence confirming its benefits and evaluating its potential adverse effects remains scarce. The exclusive intravenous administration was chosen due to its ease of application and potential to expand treatment access, especially in medical centers lacking endovascular resources for intra-arterial administration. Methods: A systematic review was conducted through searches in PubMed, Cochrane Library, and SciSpace (https://typeset.io/) between September 1, 2024, and November 23, 2024. Studies evaluating exclusive intravenous administration of milrinone for treating cerebral vasospasm secondary to SAH were selected, including experimental, observational, and clinical trials, with no language or date restrictions. Article selection was conducted independently by two reviewers experienced in SAH management, following predefined inclusion and exclusion criteria: studies describing patients treated with standard CVS therapy associated with exclusive intravenous milrinone were included, while studies evaluating endovascular treatment or combining other parenteral vasodilators with milrinone were excluded. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies and the Risk of Bias Tool (RoB 2) for clinical trials. Publication bias was evaluated using funnel plots complemented by Egger's test for asymmetry analysis. A random-effects meta-analysis was performed, comparing milrinone use with clinical improvement and angiographic reversal of vasospasm, with heterogeneity among studies assessed using the I² statistic (95% CI), derived from Cochran’s Q test. Data were analyzed in R Studio (version 1.1.463), using R language (version 4.0.1) and the metaviz and metafor packages. Results: A total of 1,421 records were screened, from which 26 were selected for full-text review, resulting in 6 studies included in the systematic review and 3 in the meta-analysis, encompassing 343 patients, predominantly severe cases with high risk for cerebral vasospasm. Milrinone demonstrated efficacy in significantly reducing cerebral blood flow velocity, improving clinical outcomes, and reducing the need for endovascular angioplasty. The meta-analysis showed a favorable association between milrinone use and functional improvement (HR 1.80 [1.35–2.39]), as well as a trend toward angiographic vasospasm reversal (HR 1.18 [1.00–1.39]). Although generally well tolerated, milrinone was associated with hypotension requiring vasopressors and isolated supraventricular arrhythmias, without increased mortality. Conclusions: Our meta-analysis is the first to quantitatively demonstrate the positive impact of milrinone on angiographic vasospasm reversal and the Modified Rankin Scale. Despite methodological limitations and heterogeneity among included studies, the results highlight the need for randomized clinical trials to validate its efficacy and address the current lack of robust safety data.