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Introduction

  1. Pharmacology
    1. Methylene blue is a thiazine dye that increases the conversion of methemoglobin (ferric 3+) to hemoglobin (ferrous 2+). Methylene blue is reduced via methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue, which in turn reduces methemoglobin to hemoglobin. Glucose-6-phospate dehydrogenase (G6PD) is required to generate NADPH and is thus essential for methylene blue to function as an antidote. Therapeutic effect is seen within 30 minutes of administration. Methylene blue is excreted in bile and urine, which may turn blue or green.
    2. Methylene blue is a guanylate cyclase inhibitor, and reduces both cyclic guanosine monophosphate (cGMP) production and nitric oxide (NO) stimulation. Excessive NO activity may contribute to refractory vasodilatory shock associated with sepsis, cardiac surgery, anaphylaxis, and toxicity from metformin or amlodipine. Methylene blue has been used to improve hemodynamics in each of these scenarios.
    3. Methylene blue is also a MAO-A inhibitor and has been associated with precipitation of serotonin syndrome in patients on selective serotonin reuptake inhibitors (SSRIs).
  2. Indications
    1. Treatment of methemoglobinemia in patients with symptoms or signs of hypoxemia (eg, dyspnea, confusion, or chest pain) or a methemoglobin level higher than 20%. Note: Methylene blue is not effective for sulfhemoglobinemia.
    2. To reverse and prevent ifosfamide-related encephalopathy by reversing neurotoxic effects of the ifosfamide metabolites.
    3. Adjunctive therapy to improve hemodynamics in patients with refractory vasodilatory shock.
  3. Contraindications
    1. G6PD deficiency: Treatment with methylene blue may precipitate hemolysis.
    2. Severe renal failure.
    3. Known hypersensitivity to methylene blue.
    4. Methemoglobin reductase deficiency.
    5. Reversal of nitrite-induced methemoglobinemia in the treatment of cyanide poisoning.
    6. Adult respiratory distress syndrome in vasodilatory shock.
  4. Adverse effects
    1. Gastrointestinal upset, headache, and dizziness may occur.
    2. Excessive doses of methylene blue (>7 mg/kg) can paradoxically induce formation of methemoglobinemia by directly oxidizing hemoglobin. Doses higher than 15 mg/kg are associated with hemolysis, particularly in neonates.
    3. May dye secretions and mucous membranes blue.
    4. Long-term administration may result in marked anemia.
    5. Extravasation may result in local tissue necrosis.
    6. Use in pregnancy. FDA Category X (fetal abnormalities demonstrated when used in amniocentesis). This does not preclude its acute, short-term use for a seriously symptomatic patient (Introduction).
  5. Drug or laboratory interactions
    1. Serotonin syndrome is a potential risk when methylene blue is administered in the presence of other serotoninergic drugs due to its inhibition of MAO-A.
    2. The intravenous preparation should not be mixed with other drugs.
    3. Transiently false-positive methemoglobin levels of about 15% may be measured following doses of methylene blue of 2 mg/kg or higher.
    4. Methylene blue may transiently lower pulse oximeter readings.
  6. Dosage and method of administration (adults and children)
    1. Methemoglobinemia
      1. Administer 1-2 mg/kg (0.1-0.2 mL/kg of 1% solution) IV slowly over 5 minutes. May be repeated in 30-60 minutes.
      2. Simultaneous administration of dextrose may be warranted to provide adequate NAD and NADPH cofactors.
      3. If no response after two doses, do not continue dosing; consider G6PD deficiency or methemoglobin reductase deficiency.
      4. Patients with ongoing production of methemoglobin from a long-acting oxidant stress (eg, dapsone) may require repeated dosing every 6-8 hours for 2-3 days. Alternatively, give as a continuous IV infusion of 0.10-0.25 mg/kg/h (compatible with normal saline and dilute to a concentration of 0.05%).
      5. Flush IV line with 15-30 mL of normal saline to reduce incidence of local pain.
    2. Ifosfamide encephalopathy
      1. Prophylaxis. Administer 50 mg PO or IV (slowly over 5 minutes) every 6-8 hours while the patient is receiving ifosfamide.
      2. Treatment. Administer 50 mg IV (slowly over 5 minutes) every 4-6 hours until symptoms resolve.
    3. Vasodilatory shock. Reported dosing is 1-2 mg/kg IV (slowly over 5 minutes) for persistent hypotension despite vasopressor administration. This was followed with a continuous IV infusion of 1 mg/kg/h in a case of amlodipine toxicity.