Methylene blue is produced as an additive in septic shock

Methylene blue is produced as an additive in septic shock

Could an old drug offer new hope for septic shock? Discover how methylene blue could change the critics, but why doctors still caution.

Methylene blue is an aromatic compound used to treat methemoglobinemia, a rare blood disorder that affects the oxygen tube capacity of red blood cells. The nitric oxide inhibitory activity of methylene blue makes it a potential adjunctive candidate for the treatment of septic shock, particularly in refractory cases. Published in a review article published in the journalCUREUSThe authors discuss the theoretical mechanisms, pharmacokinetics, clinical evidence, and practical considerations for the use of methylene blue in septic shock.

background

About septic shock: Methylene blue treats methemoglobinemia, a blood disorder in which hemoglobin cannot carry oxygen, by converting iron into functional iron in red blood cells.

Septic shock is a life-threatening condition characterized by profound circulatory and cellular/metabolic abnormalities that significantly increase mortality, with rates approaching 40%-60% in some cases. The disease is characterized by severe circulatory and cellular abnormalities that result in profound dilation of blood vessels (vasodilation), reduction in blood pressure, and inadequate tissue suction.

Norepinephrine, a neurotransmitter in the catecholamine family, is the first-line drug used to treat septic shock, which increases blood pressure by constricting blood vessels. However, long-term or high-dose catecholamine therapy is associated with several adverse health outcomes, shifting interest toward catecholamine parrying strategies.

Current guidelines recommend vasopressin as a second medication in septic shock. Methylene blue has recently attracted attention as a potential adjuvant candidate for the treatment of septic shock due to its inhibitory effect on the nitric oxide pathway, which plays a central role in the pathophysiology of septic vasodilation.

How methylene blue works

Medical Multitasker: It is used as a surgical dye for tracking lymph nodes, staining bone cements during joint replacements, and detecting leaks in gastrointestinal surgeries by turning urine blue.

Methylene blue is an aromatic compound used as both a surgical dye and a healing agent. It is available as a 1% (10 mg/ml) solution for intravenous administration in clinical settings. It has a half-life of approximately five hours in healthy individuals, and its concentration in the blood peaks within 30 minutes of intravenous administration.

In septic shock, proinflammatory cytokines and endotoxins profoundly upregulate the inducible nitric oxide synthase (INOS) enzyme, resulting in excessive production of nitric oxide. The potent vasodilatory effect of nitric oxide is the main mediator of the relaxation and vasodilation of vascular muscles observed in septic shock.

Methylene blue interrupts this chain of reactions through two mechanisms: direct inhibition of INOS and subsequent prevention of nitric oxide production or inhibition of soluble guanylate cyclase, an enzyme activated by nitric oxide and responsible for its vasodilatory effects. Methylene blue can also directly screen for nitric oxide, and its antioxidant properties may help improve the effects of septic shock.

Methylene blue in septic shock

Fish Pharmacy Staple: Aquarists use it to combat fungal infections in fish and protect eggs from fungus while also treating nitrite poisoning in aquatic environments.

The first pilot study of the therapeutic efficacy of methylene blue in patients with septic shock was conducted in 1995, which reported a transient increase in blood pressure with minimal effects on cardiac performance.

The first pilot randomized controlled trial was conducted in 2001, reporting that methylene blue used as adjunctive therapy reduced vasopressor therapy in septic shock patients without affecting oxygen delivery or other blood parameters.

A study conducted in 2002 reported that methylene blue increased blood pressure but had no significant effect on cytokine levels or mortality in septic shock patients.

In recent years there has been renewed interest in methylene blue for the treatment of septic shock. A single-center, randomized controlled trial conducted in 2023 reported that high-dose methylene blue significantly reduced norepinephrine-based treatment and shortened intensive care unit (ICU) and hospital length of stay. However, no effects on mortality or serious adverse events were observed in the study.

In addition to its vasopressor-sparing effect, a 2025 study using a 4 mg/kg bolus dose suggested a potential mortality benefit, although this effect was dose-dependent and not consistently observed in all studies. Preliminary evidence from a case series suggests that methylene blue may also have anti-inflammatory effects in septic shock patients treated with norepinephrine and vasopressin.

A 2025 study comparing methylene blue and vasopressin as adjunctive medications found vasopressin to be more effective than methylene blue beyond the initial 6-hour window in reducing the need for norepinephrine, improving lactate levels, and improving organ function.

Large meta-analyses conducted in 2024 reported low-certainty evidence suggesting that methylene blue may reduce mortality risk, although one analysis included non-septic populations. The analyzes also showed increased blood pressure and systemic vascular resistance, as well as reduced intensive care and hospital length of stay in patients with septic shock.

Regarding the optimal dosage of methylene blue, existing evidence suggests that higher bolus doses of methylene blue (e.g. 4 mg/kg) may specifically provide a mortality benefit in patients with septic shock, although both high and low doses reduced vasopressor requirements. Regarding the optimal timing of administration, evidence suggests that methylene blue is more suitable as a third-line agent than as a second-line replacement for vasopressin.

Security profile

SOCIAL MEDIA PRECUTS: Recent trends promote unapproved uses such as anti-aging or cognitive enhancement, but experts warn of toxicity risks and drug interactions without medical supervision.

Methylene blue is generally well tolerated when given in recommended doses, that is, 1 to 4 milligrams per kilogram of body weight. Critical security considerations include:

• Absolute Kontraindikationen bei Patienten mit G6PD -Mangel oder mit serotonergen Medikamenten
• Muss in 5% Dextrose (nicht normaler Kochsalzlösung) verdünnt werden, um Niederschläge zu vermeiden

However, in some cases it can cause mild to moderate adverse health effects, including blue-green discoloration of urine, skin and mucous membranes, hemolytic anemia, serotonin syndrome and cardiac rhythmias.

Future instructions

Overall, current evidence suggests that methylene blue has additional benefits in patients with septic shock, including reduced need for vasopressors such as norepinephrine and shorter duration of intensive care and hospital stays. However, it is not currently supported as a replacement for established second-line agents such as vasopressin. Further studies are needed to establish its role in clinical practice, particularly as a third-party intervention.

Future studies should focus on determining optimal dosing regimens, timing of administration, infusion rates, and duration of therapy. It is also important to identify specific patient populations that will benefit most from this intervention using predictive biomarkers or clinical characteristics.

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