Methylene blue versus hydroxocobalamin for septic shock: a real-world comparative effectiveness study using TriNetX.

BACKGROUND: Adjunctive therapies targeting pathologic vasodilation in septic shock are increasingly used when standard vasoactive strategies fail. Although methylene blue (MB) and high-dose hydroxocobalamin (HC) have shown potential hemodynamic benefits, comparative data in sepsis are lacking. We compared outcomes among septic patients treated with MB or HC using a large multicenter electronic health record network. METHODS: We conducted a retrospective cohort study using the TriNetX US network (65 health systems). Adults hospitalized with sepsis, severe sepsis, or septic shock from 2016 to 2025 who received MB or HC were included. Patients with nitroprusside exposure, methemoglobinemia, cardiogenic shock, or neither therapy were excluded. Propensity score matching (1:1) balanced 91 covariates. RESULTS: A total of 732 matched patients were analyzed (366 MB, 366 HC). Mortality and acute kidney injury rates were similar between groups. HC was associated with higher continuous renal replacement therapy initiation at 3-7 days and 7 days after treatment (both P < 0.001). Stroke and prolonged vasopressor use were more frequent with HC during days 3-7 but not by day 7. Other secondary outcomes were comparable. CONCLUSIONS: MB and HC demonstrated similar early mortality, but MB was associated with lower continuous renal replacement therapy use and fewer early strokes and prolonged vasopressor requirements. These findings suggest MB may be the more favorable adjunctive therapy, although prospective comparative studies are needed to confirm these observational results.