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  1. Pharmacology.

    1. Methylene blue is a thiazine dye that increases the conversion of methemoglobin to hemoglobin. Methylene blue is reduced via methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue, which in turn reduces methemoglobin. Glucose-6-phospate dehydrogenase (G6PD) is essential for the generation of NADPH and is thus essential for the function of methylene blue as an antidote. Therapeutic effect is seen within 30 minutes. Methemoglobin is excreted in bile and urine, which may turn blue or green.

    2. Methylene blue has been used to treat ifosfamide-induced encephalopathy, but the exact pathophysiologic mechanisms responsible are not known. Methylene blue may reverse the neurotoxic effects of the ifosfamide metabolites.

    3. Methylene blue, as a guanylate cyclase inhibitor, reduces cyclic guanosine monophosphate (cGMP) production and nitric oxide (NO) stimulation. Excessive NO activity may contribute to refractory vasodilatory shock associated with sepsis, vasoplegia following cardiac surgery, anaphylactic shock, and metformin and amlodipine toxicity. Methylene blue has been used to improve hemodynamics in each of these circumstances.

    4. Methylene blue is an MAO-A inhibitor and has been responsible for the precipitation of a serotonin syndrome in patients treated with selective serotonin reuptake inhibitors (SSRIs) when used for cardiac and parathyroid surgery.

  2. Indications

    1. Methylene blue is used to treat methemoglobinemia (See Methemoglobinemia) if the patient has symptoms or signs of hypoxemia (eg, dyspnea, confusion, or chest pain) or a methemoglobin level higher than 30%. Note: Methylene blue is not effective for sulfhemoglobinemia.

    2. Methylene blue has been used to reverse and prevent ifosfamide-related encephalopathy.

    3. Methylene blue has been used as adjunctive therapy to improve hemodynamics in patients with refractory vasodilator shock.

  3. Contraindications

    1. G6PD deficiency. Treatment with methylene blue is ineffective and may cause hemolysis.

    2. Severe renal failure.

    3. Known hypersensitivity to methylene blue.

    4. Methemoglobin reductase deficiency.

    5. Reversal of nitrite-induced methemoglobinemia for treatment of cyanide poisoning.

  4. Adverse effects

    1. Gastrointestinal upset, headache, and dizziness may occur.

    2. Excessive doses of methylene blue (≥7 mg/kg) can actually cause methemoglobinemia by directly oxidizing hemoglobin. Doses higher than 15 mg/kg are associated with hemolysis, particularly in neonates. May also dye secretions and mucous membranes and interfere with clinical findings of cyanosis.

    3. Long-term administration may result in marked anemia.

    4. Extravasation may result in local tissue necrosis.

    5. Use in pregnancy. FDA Category C (indeterminate). This does not preclude its acute, short-term use for a seriously symptomatic patient (See Introduction in Section III).

  5. Drug or laboratory interactions

    1. Serotonin syndrome is a potential risk when methylene blue is administered with other serotoninergic drugs owing 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% are produced by doses of methylene blue of 2 mg/kg. Methylene blue may also alter 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 repeat ...

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