METHYLENE BLUE IN REFRACTORY SEPTIC SHOCK: AN INTEGRATIVE REVIEW OF THE EVIDENCE ON HEMODYNAMIC EFFICACY AND CLINICAL IMPACT

Abstract

Refractory septic shock remains associated with high mortality despite early fluid resuscitation, appropriate antimicrobial therapy, and stepwise vasopressor support. Exaggerated activation of the nitric oxide–cGMP pathway constitutes a central mechanism of septic vasoplegia, providing the pathophysiological rationale for the use of methylene blue as a guanylate cyclase inhibitor. Recent evidence suggests hemodynamic benefit; however, uncertainties persist regarding its impact on robust clinical outcomes. This integrative review critically analyzed the evidence published over the last decade concerning the efficacy, safety, and administration strategies of methylene blue as adjunctive therapy in refractory septic shock. The review was conducted according to the framework proposed by Whittemore and Knafl, with a systematic search performed in PubMed/MEDLINE, SciELO, and ScienceDirect databases covering the period from 2014 to 2024. Randomized controlled trials demonstrated a significant reduction in vasopressor duration and increased mean arterial pressure with early administration of methylene blue. Recent meta-analyses reported a possible reduction in short-term mortality, as well as decreased vasopressor exposure and lower serum lactate levels, although with low certainty of evidence due to methodological heterogeneity and limited sample size. Observational evidence supports hemodynamic improvement in extreme refractory settings, although variability in dosing regimens and lack of therapeutic standardization remain relevant limitations. In conclusion, methylene blue demonstrates consistent hemodynamic benefit in refractory septic shock; however, despite signals suggesting short-term mortality reduction, the overall quality of evidence remains low to moderate, and routine clinical incorporation depends on large, multicenter randomized controlled trials with standardized protocols and long-term outcome assessment.