Methylene Blue in Cancer Patients With Distributive Shock: A Target Trial Emulation

Introduction: Methylene blue (MB) has emerged as a potential adjunctive therapy in distributive shock due to its inhibition of nitric oxide–mediated vasodilation. However, data on its effectiveness and safety in patients with cancer remain limited.


Methods: We conducted a target trial emulation using real-world data from the TriNetX Global Collaborative Network, comprising 152 healthcare organizations. Adults aged 18–80 years with cancer and distributive shock who received norepinephrine and vasopressin were included. Patients were divided into two cohorts: those who received MB (n = 4,167) and those who did not (n = 55,238). After 1:1 propensity score matching, 4,427 patients remained in each group. Outcomes were assessed over a 30-day follow-up using risk difference, risk ratio, and Kaplan-Meier survival estimates.


Results: MB use was associated with significantly lower 30-day mortality (24.5% vs. 33.1%; risk difference −8.6%; p < 0.001; risk ratio 0.739; hazard ratio 0.697 [95% CI: 0.641–0.757]). Fewer patients required mechanical ventilation between 24–96 hours in the MB group (3.1% vs. 4.1%; p = 0.016). No cases of methemoglobinemia or hemolytic anemia were documented among MB recipients.


Conclusions: In this target trial emulation, MB was associated with improved survival and reduced need for mechanical ventilation in cancer patients with distributive shock. However, adverse events may have been underreported, limiting the safety assessment. Randomized controlled trials are needed to confirm efficacy and further evaluate safety.