Dosage / administration: The dose is 1 mg/kg intravenous (IV) given over 5-30 minutes. The dose can be repeated in 30 minutes to 1 hour if the patient has continued symptoms and a persistently high methemoglobin level. The injection should be diluted and administered in 50 ml of 5% dextrose (sodium chloride may decrease the solubility).

Doses for children are the same as for adults.

Intraosseous route (IO) can be used into the anterior tibia in infants. In neonates, the dose is reduced to 0.3-1 mg/kg (the presence of hemoglobin F and diminished nicotinamide adenine dinucleotide and hydrogen [NADH] reductase increases the risk of hemolysis, implying that the smallest effective dose of methylene should be used).

Pregnancy: Methylene blue is contraindicated in pregnancy (class X); however, IV methylene blue should be used to treat pregnant women with methemoglobinemia when the benefit outweighs the potential risk to the fetus.

Indications: Methylene blue is a water-soluble thiazine dye. It is the drug of choice and extremely effective antidote for acquired methemoglobinemia. This is the only US Food and Drug Administration (FDA)-approved indication (approved as ProvayBlue).

The onset of action is often within minutes, and maximum effect occurs within 30 minutes.

Methylene blue is mostly indicated in patients with symptomatic methemoglobinemia. Symptoms usually manifest when the levels are greater than 20%, but at lower levels, symptoms can occur in anemic patients and patients with pulmonary, cardiovascular, or central nervous system compromise.

Other off-label uses:

• Severe metformin toxicity with hypotension – Methylene blue can be used with other resuscitative modalities.
• Refractory vasoplegia post-cardiopulmonary bypass surgery.
• Refractory septic shock – After other resuscitative measures including vasopressors have failed to improve the hemodynamics.
• Ifosfamide-induced encephalopathy – Methylene blue can reverse the neurotoxic effects of ifosfamide metabolites.

Contraindications:

• Glucose-6-phosphate dehydrogenase deficiency – Treatment with methylene blue is ineffective for reversal of methemoglobin in these patients and may cause hemolysis.
• Severe renal failure
• Known hypersensitivity to methylene blue

The FDA reports a potential drug interaction with concomitant use of methylene blue with serotonergic drugs (eg, selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], and monoamine oxidase inhibitors). Methylene blue should generally not be given to patients taking serotonergic drugs unless the benefit is deemed to outweigh the risk.

Monitoring: Methemoglobin levels can help to monitor the treatment. Levels can be measured 30 minutes after the first dose.

Adverse effects:

• Pain in extremity, especially at the site of injection
• Chromaturia (discolored urine)
• Dysgeusia
• Dizziness
• Gastrointestinal upset
• Headache
• Hypotension

Toxicity: Methylene blue may precipitate potentially fatal serotonin toxicity at doses greater than 5 mg/kg. In rare cases, individuals can suffer severe anaphylactic shock.

In high doses (mostly from 2-4 mg/kg), methylene blue can cause Heinz body hemolytic anemia and skin desquamation, especially in infants.

Chest pain, abdominal pain, and fever can manifest at doses of 7 mg/kg and higher.

Mechanism of action: Methylene blue is a water-soluble thiazine dye that promotes a nonenzymatic redox conversion of methemoglobin to hemoglobin. In situ methylene blue is first converted to leucomethylene blue (LMB) via NADPH reductase (hemoprotein oxidoreductase). LMB then effectively reduces methemoglobin to hemoglobin. Approximately 40% of methylene blue is excreted into the urine unchanged.

Half life is approximately 24 hours.