The Effectiveness of Methylene Blue in Adult Shock: A Systematic Review, Meta-Analysis, and Trial Sequential Analysis of Randomized Controlled Trials.

Background/

Objectives

Methylene blue (MB) has re-emerged as an adjunctive vasopressor-sparing therapy in vasoplegic shock states, with emerging evidence supporting its hemodynamic benefits; however, its effect on mortality remains uncertain. We systematically evaluated the effectiveness of MB versus standard therapy in adults with circulatory shock.

Methods

We performed a systematic review and meta-analysis of randomized controlled trials registered in PROSPERO (CRD420261326534) and reported according to PRISMA. MEDLINE, Embase, and the Cochrane Library were searched through February 2026. An additional AI-assisted supplementary search was conducted to minimize the risk of missing eligible studies. Eligible studies enrolled adults with shock and compared MB with standard therapy or placebo. The primary outcome was 28-30-day all-cause mortality. Secondary outcomes were renal replacement therapy (RRT), hospital length of stay, and intensive care unit (ICU) length of stay. Risk of bias was assessed with RoB 2.

Results

Nine randomized trials involving 535 participants met the eligibility criteria; most evaluated septic shock, while one trial included post-cardiac surgery vasoplegic shock. Eight trials contributed to the quantitative synthesis of mortality. MB was not associated with a statistically significant reduction in short-term mortality. Secondary analyses also did not demonstrate significant pooled effects for RRT, hospital length of stay, or ICU length of stay, although several individual trials reported faster hemodynamic improvement and reduced vasopressor exposure with MB. Overall confidence in the pooled estimates was limited by small sample sizes, clinical heterogeneity, imprecision, and risk-of-bias concerns in some studies.

Conclusions

Current randomized evidence does not demonstrate a clear mortality or resource use benefit of MB in adult shock, despite signals of hemodynamic improvement. MB appears promising as an adjunctive therapy, but adequately powered, methodologically rigorous trials are required before its routine early use can be recommended.