Methylene blue in septic shock!

Sepsis is a dysregulated host response to infection, leading to organ dysfunction and vasodilatory shock characterized by nitric oxide overproduction and reduced vascular tone. Standard treatment involves fluids, antibiotics, and vasopressors—primarily norepinephrine—but high-dose catecholamines are associated with myocardial stress, arrhythmias, immune suppression, and receptor desensitization.

To mitigate these risks, decatecholaminization strategies have gained interest. Among adjunct agents, methylene blue (MB) inhibits guanylate cyclase and restores vascular tone by counteracting nitric oxide–mediated vasoplegia. While MB is low-cost and widely available, robust clinical data have been limited until recently. An updated body of evidence, including new randomized trials, now allows for a more informed evaluation of MB’s role in septic shock [1].

Evidence for the Use of Methylene Blue in the ICU

The most robust evidence supporting methylene blue in septic shock comes from a 2023 randomized controlled trial by Ibarra-Estrada et al., which investigated the early use of methylene blue in adult patients with vasopressor-dependent septic shock. This double-blind, placebo-controlled trial enrolled 91 patients within 24 hours of initiating norepinephrine and randomized them to receive either intravenous methylene blue or placebo in addition to standard care. The primary endpoint—time to vasopressor discontinuation—was significantly shorter in the methylene blue group (median 69 hours) compared to the placebo group (94 hours), with a p-value of less than 0.001. This demonstrated a clinically meaningful acceleration in hemodynamic stabilization. Secondary outcomes were also favorable: patients receiving methylene blue had more vasopressor-free days, shorter ICU stays by 1.5 days, and reduced hospital length of stay by approximately 2.7 days. Mortality rates at 28 days were similar between groups, though the trial was not powered for this endpoint [2].

Importantly, methylene blue was well tolerated. Mild, transient elevations in methemoglobin levels were observed but did not require intervention or therapy discontinuation. No serious adverse events, including organ dysfunction or arrhythmias, were attributed to methylene blue. This trial stands out for its early intervention strategy, rigorous methodology, and relevance to modern ICU practice, providing strong support for the use of methylene blue as an adjunctive vasopressor-sparing agent in early septic shock [2],

To complement these findings, a 2025 systematic review and meta-analysis by Ng et al. evaluated the efficacy and safety of methylene blue in adult patients with septic shock across five randomized controlled trials involving a total of 205 patients. The pooled data showed a significant improvement in mean arterial pressure (MAP), with methylene blue increasing MAP by a mean difference of 9.5 mmHg compared to control (95% CI: 1.2 to 17.8; p = 0.02). This effect was consistent across different infusion protocols and timepoints, indicating a robust hemodynamic benefit. While mortality reduction did not reach statistical significance (OR 0.65; 95% CI: 0.39 to 1.09), the point estimate favored methylene blue, and no increase in harm was observed [3].

Other secondary outcomes, including serum lactate levels, oxygenation indices (PaO₂/FiO₂ ratio), hospital length of stay, and vasopressor duration, all trended in favor of methylene blue, although they did not achieve statistical significance. The heterogeneity across trials was low, and adverse events were minimal. Consistent with previous literature, the most common side effects included urine discoloration and transient methemoglobinemia, both of which were clinically benign. The authors concluded that methylene blue appears to be a safe and physiologically rational adjunct to conventional vasopressor therapy in septic shock, particularly when administered early in the course of illness [3].

Do you use methylene blue in patients with septic shock?

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Insights

Taken together, these two high-quality studies strengthen the case for methylene blue as a viable adjunctive agent in the management of septic shock. The randomized trial demonstrates clear hemodynamic benefits and reduced vasopressor dependence, while the meta-analysis reinforces these findings across multiple trials. Although survival benefits remain unproven, the consistency of MAP improvement, vasopressor-sparing effects, and favorable safety profile highlight methylene blue as a promising tool for targeted hemodynamic support in vasoplegic septic shock.

Optimal dosing strategies are still under investigation, but a common approach is a bolus injection (e.g., 1–2 mg/kg) followed by continuous infusion of 0.10–0.25 mg/kg/h, which may be more effective than bolus alone.

Conclusion

In summary, methylene blue is a non-adrenergic vasopressor option for catecholamine-resistant vasoplegia in the ICU, with evidence supporting its efficacy in improving hemodynamics and reducing vasopressor dependence. However, its use should be individualized, and further large-scale studies are warranted to clarify its impact on mortality and optimal administration protocols.

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References

1. The Story of Nitric Oxide, Sepsis and Methylene Blue: A Comprehensive Pathophysiologic Review. Saha BK, Burns SL. The American Journal of the Medical Sciences. 2020;360(4):329-337.

2. Early Adjunctive Methylene Blue in Patients With Septic Shock: A Randomized Controlled Trial. Ibarra-Estrada M, Kattan E, Aguilera-González P, et al. Critical Care (London, England). 2023;27(1):110.

3. Ng KT, Kwok PE, Lim WE, et al. The use of methylene blue in adult patients with septic shock: a systematic review and meta-analysis. Brazilian Journal of Anesthesiology. 2025;75(1):844580.