{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:24:40Z","timestamp":1791836680260,"version":"4.3.4"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T00:00:00Z","timestamp":1713398400000},"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. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Methylene blue is an interesting approach in reducing fluid overload and vasoactive drug administration in vasodilatory shock. The inhibition of guanylate cyclase induced by methylene blue infusion reduces nitric oxide production and improves vasoconstriction. This systematic review and meta-analysis aimed to assess the effects of methylene blue administration compared to placebo on the hemodynamic status and clinical outcomes in patients with sepsis and septic shock.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The authors specifically included randomized controlled trials that compared the use of methylene blue with placebo in adult patients with sepsis and septic shock. The outcomes were length of intensive care unit stay, hemodynamic parameters [vasopressor use], and days on mechanical ventilation. We also evaluated the abnormal levels of methemoglobinemia. This systematic review and meta-analysis were recorded in PROSPERO with the ID CRD42023423470.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During the initial search, a total of 1,014 records were identified, out of which 393 were duplicates. Fourteen citations were selected for detailed reading, and three were selected for inclusion. The studies enrolled 141 patients, with 70 of them in the methylene blue group and 71 of them in the control group. Methylene blue treatment was associated with a lower length of intensive care unit stay (MD \u22121.58; 95%CI \u22122.97, \u22120.20; <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u200925%; <jats:italic>p<\/jats:italic>\u2009=\u20090.03), decreased days on mechanical ventilation (MD \u22120.72; 95%CI \u22121.26, \u22120.17; <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090%; <jats:italic>p<\/jats:italic>\u2009=\u20090.010), and a shorter time to vasopressor discontinuation (MD \u221231.49; 95%CI \u221246.02, \u221216.96; <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090%; <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.0001). No association was found with methemoglobinemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Administering methylene blue to patients with sepsis and septic shock leads to reduced time to vasopressor discontinuation, length of intensive care unit stay, and days on mechanical ventilation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic review registration<\/jats:title><jats:p><jats:ext-link>https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?ID=CRD42023423470<\/jats:ext-link>, CRD42023423470.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2024.1366062","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T04:42:10Z","timestamp":1713415330000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Methylene blue in sepsis and septic shock: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"11","author":[{"given":"Raquel Sim\u00f5es","family":"Ballarin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taline","family":"Lazzarin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Zornoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula Schmidt","family":"Azevedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipe Welson Leal","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana Erico","family":"Tanni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos Ferreira","family":"Minicucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for Sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1213\/ANE.0000000000001045","article-title":"Methylene blue: magic bullet for Vasoplegia?","volume":"122","author":"Hosseinian","year":"2016","journal-title":"Anesth Analg"},{"key":"ref3","first-page":"77","article-title":"Evidence of increased nitric oxide production in patients with the sepsis syndrome","volume":"41","author":"Evans","year":"1993","journal-title":"Circ Shock"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1056\/NEJMoa010307","article-title":"Early goal-directed therapy in the treatment of severe Sepsis and septic shock","volume":"345","author":"Rivers","year":"2001","journal-title":"N Engl J Med"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"3692","DOI":"10.1007\/s12325-020-01422-x","article-title":"Vasopressor-sparing action of methylene blue in severe Sepsis and shock: a narrative review","volume":"37","author":"Puntillo","year":"2020","journal-title":"Adv Ther"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e1063","DOI":"10.1097\/CCM.0000000000005337","article-title":"Surviving Sepsis campaign: international guidelines for Management of Sepsis and Septic Shock 2021","volume":"49","author":"Evans","year":"2021","journal-title":"Crit Care Med"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1177\/0885066609340519","article-title":"Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress","volume":"24","author":"D\u00fcnser","year":"2009","journal-title":"J Intensive Care Med"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1007\/s00134-012-2531-2","article-title":"Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study","volume":"38","author":"Schmittinger","year":"2012","journal-title":"Intensive Care Med"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1007\/s00134-019-05801-z","article-title":"Vasopressor therapy in critically ill patients with shock","volume":"45","author":"Russell","year":"2019","journal-title":"Intensive Care Med"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s13054-024-04839-w","article-title":"Administration of methylene blue in septic shock: pros and cons","volume":"28","author":"Arias-Ortiz","year":"2024","journal-title":"Crit Care"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1164\/rccm.202002-0339OC","article-title":"Norepinephrine dysregulates the immune response and compromises host defense during Sepsis","volume":"202","author":"Stolk","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e0142605","DOI":"10.1371\/journal.pone.0142605","article-title":"Non-adrenergic vasopressors in patients with or at risk for vasodilatory shock. A systematic review and Meta-analysis of randomized trials","volume":"10","author":"Belletti","year":"2015","journal-title":"PLoS One"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s13613-019-0498-7","article-title":"Current use of vasopressors in septic shock","volume":"9","author":"Scheeren","year":"2019","journal-title":"Ann Intensive Care"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1186\/s13054-016-1488-x","article-title":"Decatecholaminisation during sepsis","volume":"20","author":"Rudiger","year":"2016","journal-title":"Crit Care"},{"key":"ref15","article-title":"Methylene blue effectiveness as contributory treatment in patients with septic shock. Intensive care med Exp [internet]. 2016;4((Aguilar Arzapalo M.F.) SSA UADY, M\u00e9rida, Mexico)","year":"2016"},{"key":"ref16","first-page":"214","article-title":"Methylene blue for the management of septic shock refractory to vasopressors","volume":"33","author":"Carrillo-Esper","year":"2010","journal-title":"Rev Mex Anestesiol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/s13054-023-04397-7","article-title":"Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial","volume":"27","author":"Ibarra-Estrada","year":"2023","journal-title":"Crit Care"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"g7647","DOI":"10.1136\/bmj.g7647","article-title":"Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation","volume":"349","author":"Shamseer","year":"2015","journal-title":"BMJ"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1378\/chest.101.6.1644","article-title":"Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP\/SCCM consensus conference committee. American College of Chest Physicians\/Society of Critical Care Medicine","volume":"101","author":"Bone","year":"1992","journal-title":"Chest"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan\u2014a web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst Rev"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/1471-2288-14-135","article-title":"Estimating the sample mean and standard deviation from the sample size, median, range and\/or interquartile range","volume":"14","author":"Wan","year":"2014","journal-title":"BMC Med Res Methodol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1785","DOI":"10.1177\/0962280216669183","article-title":"Optimally estimating the sample mean from the sample size, median, mid-range, and\/or mid-quartile range","volume":"27","author":"Luo","year":"2018","journal-title":"Stat Methods Med Res"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.jclinepi.2010.04.026","article-title":"GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables","volume":"64","author":"Guyatt","year":"2011","journal-title":"J Clin Epidemiol"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1177\/0310057X0203000606","article-title":"The influence of methylene blue infusion on cytokine levels during severe sepsis","volume":"30","author":"Memis","year":"2002","journal-title":"Anaesth Intensive Care"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1860","DOI":"10.1097\/00003246-200110000-00002","article-title":"Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study","volume":"29","author":"Kirov","year":"2001","journal-title":"Crit Care Med"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1177\/0885066606290671","article-title":"Use of methylene blue in sepsis: a systematic review","volume":"21","author":"Kwok","year":"2006","journal-title":"J Intensive Care Med"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"950596","DOI":"10.3389\/fmed.2022.950596","article-title":"Efficacy and safety of methylene blue in patients with vasodilatory shock: a systematic review and meta-analysis","volume":"9","author":"Zhao","year":"","journal-title":"Front Med (Lausanne)"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1014276","DOI":"10.3389\/fmed.2022.1014276","article-title":"Methylene blue dosing strategies in critically ill adults with shock\u2014a retrospective cohort study","volume":"9","author":"Sari-Yavuz","year":"2022","journal-title":"Front Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1366062\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T04:42:13Z","timestamp":1713415333000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1366062\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,18]]},"references-count":29,"alternative-id":["10.3389\/fmed.2024.1366062"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2024.1366062","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,18]]},"article-number":"1366062"}}