Efficacy of phosphodiesterase-3 (PDE-3) inhibitors for the treatment of cerebral vasospasm in patients with aneurysmal subarachnoid haemorrhage (aSAH) admitted to the intensive care unit (ICU): a systematic review and meta-analysis protocol

Introduction Aneurysmal subarachnoid haemorrhage (aSAH) complicated by cerebral vasospasm is a major contributor to delayed cerebral ischaemia (DCI), long-term neurological disability and mortality. Phosphodiesterase-3 (PDE3) inhibitors, such as milrinone and cilostazol, have shown potential to improve cerebral perfusion by reducing cerebral arterial vasoconstriction. However, there has been no systematic comparison of their effects in patients with aSAH. This review aims to assess the efficacy of PDE3 inhibitors, milrinone and cilostazol, in preventing and treating cerebral vasospasm in adult patients with aSAH. Methods and analysis A systematic review and meta-analysis will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook. An initial search was conducted in July 2023 across MEDLINE, Embase, Web of Science and Scopus, with an updated search in August 2025. Eligible studies will include randomised controlled trials and observational studies with >15 patients evaluating the utility of milrinone or cilostazol in aSAH patients. Primary outcomes will be the incidence of and/or effect on cerebral vasospasm and DCI. Secondary outcomes will include mortality, neurological outcomes, intensive care unit and hospital length of stay, ventilator-free days, duration of vasopressor therapy and adverse events. Risk of bias will be assessed using the Cochrane RoB 2.0 tool, Risk Of Bias In Non-randomised Studies of Interventions tool and the Joanna Briggs Institute (JBI) checklist. Data will be synthesised using RevMan Web. The overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. Ethics and dissemination This systematic review does not require ethical approval as it synthesises previously published data. Findings will be submitted for publication in a peer-reviewed journal and disseminated at relevant conferences. Systematic review registration The protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42023444369.