Adjunctive therapies that target pathologic vasodilation are increasingly used when standard vasoactive strategies fail in septic shock. Two such agents with reported hemodynamic effects are methylene blue (MB) and high-dose hydroxocobalamin (HC). Prior to this analysis, direct comparative data between MB and HC in sepsis were lacking.
This study used a large multicenter electronic health record network to evaluate real-world comparative outcomes among septic patients treated with MB or HC.
The investigators performed a retrospective cohort study using the TriNetX US network, which includes data from 65 health systems. The study population comprised adults hospitalized with sepsis, severe sepsis, or septic shock during the period 2016 to 2025 who received either MB or HC.
Exclusion criteria specified in the source included exposure to nitroprusside, presence of methemoglobinemia, cardiogenic shock, or receipt of neither MB nor HC. To address confounding, the analysis used propensity score matching in a 1:1 ratio, balancing 91 covariates between treatment groups.
After matching, the analytic sample included 732 patients: 366 who received methylene blue and 366 who received hydroxocobalamin.
In the matched cohort, early mortality rates were reported as similar between the MB and HC groups. Rates of acute kidney injury (AKI) were likewise similar across the two groups based on the abstracted outcomes.
However, initiation of continuous renal replacement therapy (CRRT) favored MB: HC was associated with higher CRRT initiation at 3–7 days and at 7 days after treatment, with both comparisons reaching statistical significance (both P < 0.001).
Neurologic and vasopressor-related differences were observed in the early post-treatment window. Stroke events and prolonged vasopressor use were more frequent in the HC group during days 3–7 after treatment; these differences were not present by day 7. The abstract states that other secondary outcomes were comparable between groups but does not list them specifically.
In this large, propensity-matched, real-world cohort drawn from a multicenter EHR network, methylene blue and hydroxocobalamin demonstrated similar early mortality in patients hospitalized with sepsis or septic shock. Differences emerged in renal replacement therapy use and selected early complications: MB was associated with lower CRRT initiation and fewer early strokes and prolonged vasopressor requirements compared with HC.
The authors interpret these findings to suggest that MB may be the more favorable adjunctive therapy in this observational dataset, while noting that prospective comparative studies are required to confirm these results.
For clinicians considering adjunctive treatments targeting vasodilation in refractory septic shock, these real-world data indicate no early mortality difference between MB and HC when patients are propensity-matched across many covariates.
Observed signals favoring methylene blue for lower subsequent need for CRRT and for fewer early strokes and prolonged vasopressor needs may inform local practice patterns where both agents are options, but these differences derive from observational data and should be interpreted cautiously.
Decisions about adjunctive therapy selection should continue to consider individual patient factors, contraindications (for example, known methemoglobinemia exclusion in this study), institutional experience, and drug availability.
The reported analysis is retrospective and observational using electronic health record data; residual confounding is possible despite propensity score matching across 91 covariates.
The abstract provides limited granularity on secondary endpoints and on timing, dosing, or administration protocols for MB and HC; those details were not reported in the abstract.
Important safety and long-term outcome measures beyond the early windows described may not be fully captured in the abstract.
The authors recommend prospective comparative trials to validate these observational findings and to better define the risk–benefit profile, optimal dosing, timing, and patient selection for methylene blue versus hydroxocobalamin in septic shock.