{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T11:10:09Z","timestamp":1788952209151,"version":"build-2803163510"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\u2013level data were not available. Primary outcomes included incidence of DCI, good functional outcome (modified Rankin Scale score 0\u20132), and mortality. Cardiovascular adverse events were also assessed. Data were pooled using a random-effects model, and heterogeneity was evaluated using the\n                      <jats:italic>I<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      statistic.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u20130.90;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.02). 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\u20132.56;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.17) or reduced mortality (OR 0.95, 95% CI 0.48\u20131.88;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.88). Cardiovascular adverse events were numerically more frequent with intravenous milrinone, although the difference was not statistically significant (OR 1.63, 95% CI 0.86\u20133.08;\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.13).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1872442","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:15:39Z","timestamp":1788948939000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy and safety of milrinone infusion in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Khaled","family":"Gharaibeh","sequence":"first","affiliation":[{"name":"College of Medicine and Life Sciences, University of Toledo","place":["Toledo, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aizaz","family":"Ali","sequence":"additional","affiliation":[{"name":"College of Medicine and Life Sciences, University of Toledo","place":["Toledo, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nameer","family":"Aladamat","sequence":"additional","affiliation":[{"name":"College of Medicine and Life Sciences, University of Toledo","place":["Toledo, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashfaq","family":"Shuaib","sequence":"additional","affiliation":[{"name":"University of Alberta","place":["Edmonton, AB, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed F.","family":"Zaidi","sequence":"additional","affiliation":[{"name":"College of Medicine and Life Sciences, University of Toledo","place":["Toledo, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mouhammad A.","family":"Jumaa","sequence":"additional","affiliation":[{"name":"College of Medicine and Life Sciences, University of Toledo","place":["Toledo, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1161\/STROKEAHA.115.009288","article-title":"Long-term excess mortality after aneurysmal subarachnoid hemorrhage: patients with multiple aneurysms at risk","volume":"46","author":"Huhtakangas","year":"2015","journal-title":"Stroke"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3171\/jns.1990.73.1.0018","article-title":"The international cooperative study on the timing of aneurysm surgery: part 1: overall management results","volume":"73","author":"Kassell","year":"1990","journal-title":"J Neurosurg"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1587091","DOI":"10.3389\/fneur.2025.1587091","article-title":"Pathophysiological mechanisms underlying early brain injury and delayed cerebral ischemia in the aftermath of aneurysmal subarachnoid 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strategies","volume":"163","author":"Labeyrie","year":"2021","journal-title":"Acta Neurochir"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e285","DOI":"10.1016\/j.wneu.2022.06.150","article-title":"Role of nimodipine and milrinone in delayed cerebral ischemia","volume":"166","author":"Kotwal","year":"2022","journal-title":"World Neurosurg"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1007\/s12028-021-01331-z","article-title":"Intravenous milrinone for cerebral vasospasm in subarachnoid hemorrhage: the MILRISPASM controlled before-after study","volume":"35","author":"Lakhal","year":"2021","journal-title":"Neurocrit Care"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.bjan.2018.09.005","article-title":"Effect of magnesium sulphate and milrinone on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a randomized study","volume":"69","author":"Soliman","year":"2019","journal-title":"Braz J 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A retrospective analysis","volume":"13","author":"Jentzsch","year":"2022","journal-title":"Front Neurol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s12028-025-02260-x","article-title":"Treatment effect of early intravenous milrinone for cerebral vasospasm or delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage","volume":"43","author":"Baang","year":"2025","journal-title":"Neurocrit Care"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"717","DOI":"10.3171\/2016.10.JNS162227","article-title":"Effect of intrathecal milrinone injection via lumbar catheter on delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage","volume":"128","author":"Koyanagi","year":"2018","journal-title":"J Neurosurg"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1097\/ANA.0000000000000755","article-title":"Treatment of subarachnoid Hemorrhage-associated delayed cerebral ischemia with milrinone: a review and proposal","volume":"33","author":"Bernier","year":"2021","journal-title":"J Neurosurg Anesthesiol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"971","DOI":"10.3171\/2020.1.JNS193107","article-title":"Milrinone for refractory cerebral vasospasm with delayed cerebral ischemia","volume":"134","author":"Abulhasan","year":"2021","journal-title":"J Neurosurg"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"32","DOI":"10.3390\/neurolint17030032","article-title":"Evidence-based approach to cerebral vasospasm and delayed cerebral ischemia: milrinone as a therapeutic option-a narrative literature review and algorithm treatment proposition","volume":"17","author":"Batarda Sena","year":"2025","journal-title":"Neurol Int"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1212\/WNL.50.4.876","article-title":"Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review","volume":"50","author":"Feigin","year":"1998","journal-title":"Neurology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1227\/neu.0000000000002601","article-title":"Efficacy and safety of clazosentan after aneurysmal subarachnoid hemorrhage: an updated meta-analysis","volume":"93","author":"Pontes","year":"2023","journal-title":"Neurosurgery"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"154807","DOI":"10.1016\/j.jcrc.2024.154807","article-title":"Systemic tolerance of intravenous milrinone administration for cerebral vasospasm secondary to non-traumatic subarachnoid hemorrhage","volume":"82","author":"Julian","year":"2024","journal-title":"J Crit Care"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1872442\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:15:40Z","timestamp":1788948940000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1872442\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":21,"alternative-id":["10.3389\/fneur.2026.1872442"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1872442","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"article-number":"1872442"}}