Efficacy and Safety of Methylene Blue for Patients with Septic Shock A Systematic Review and Meta-analysis of Randomized Controlled Trials

Objective: To evaluate the efficacy and safety of intravenous Methylene Blue(MB) therapy in patients with septic shock. Background: Sepsis is a dysregulated host response to infection, with an abnormal nitric oxide metabolism among its characteristics. MB is a specific inhibitor of the inducible nitric oxide synthase and its downstream enzyme soluble guanylate cyclase. However, the efficacy and safety of MB in patients with septic shock are unclear. Methods: A comprehensive search of the Pubmed, EMBASE databases, Web of Science, Cochrane Library, and Chinese biomedical literature database was performed to identify randomized controlled trials that evaluated the effect of MB vs. placebo/blank in septic shock patients. The primary outcome was mortality within 28 days. The secondary outcomes were mean arterial blood pressure, lactate, mechanical ventilation time, the length of stay in the intensive care unit (ICU) and adverse effects. Results: Altogether, eight RCTs with a total of 387 participants were included in the meta-analysis, of whom 161 were randomized to receive the MB treatment, whereas 160 received a placebo or blank. The MB therapy significantly reduced mortality among patients with septic shock [relative risk (RR) = 0.72, 95% confidence interval (CI): 0.54 - 0.96]. However, in subgroup analysis, the reduction in mortality was only significant in the patients who received a low dose of intravenous MB administration(<5mg/kg) (RR= 0.60, 95% CI: 0.41 - 0.88) and not significant in the high dose group (≥5mg/kg) (RR= 1.06, 95% CI: 0.67 - 1.69). The MB group had an increased MAP, decreased Lactate, and reduced length of stay in ICU and a shorter mechanical ventilation time when compared with the control group. There were no significant differences in the adverse effects between the intervention and control groups. Conclusions: A low dose of intravenous MB administration (<5mg/kg) is a safe and efficacious therapy in reducing mortality in septic shock. For patients experiencing septic shock, Methylene Blue has been shown to significantly increase MAP, reduce serum Lactate levels, and shorten LOS in ICU and mechanical ventilation time. Registration: The information for this meta-analysis is available in PROSPERO (CRD42023417385).