DESCRIPTION

Methylene blue is a thiazine dye used to reverse drug-induced methemoglobinemia.

FORMS AND USES

• Methylene blue is produced as a dark green crystalline powder that stains blue.
• It is typically provided in an ampule of 1% (1 mg/ml) solution or as tablets containing up to 65 mg.
• It is used in the treatment of methemoglobinemia.
• It is also used to inject into joints, ducts, or tubes in the body to assess integrity.
• Methylene blue is occasionally used as a weak urinary antibiotic.

MECHANISM OF ACTION

• Normally, the methemoglobin level is less than 1%; a small amount of methemoglobin is produced by the body each day and converted to normal hemoglobin by the enzymes NADH and NADPH methemoglobin reductase.
• The NADH methemoglobin reductase cannot accommodate large increases in methemo-globin; if large increases occur, methemoglobin accumulates, producing cyanosis and hypoxia.
• The NADH methemoglobin reductase cannot be rapidly induced; however, action of NADPH methemoglobin reductase can be accelerated when an exogenous electron carrier such as methylene blue is provided.
• Following injection, methylene blue is rapidly reduced to leukomethylene blue by NADPH methemoglobin reductase; leukomethylene blue then reduces methemoglobin (Fe³⁺) to hemoglobin (Fe²⁺).

DRUG AND DISEASE INTERACTIONS

There is no known drug interaction with methylene blue.

PREGNANCY AND LACTATION

• US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• Mild methemoglobinemia does not appear to adversely affect pregnancy. In more severe cases, the physiologic (tissue hypoxia) condition of the mother should guide its use.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• MECHANISM OF ACTION
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

• Asymptomatic patient with methemoglobin level greater than 30% and rising
• Symptomatic patient with elevated methemoglobin level (some patients will develop symptoms at lower methemoglobin levels due to underlying disease or other factors)
• Symptomatic patient with cyanosis that does not correct with administration of 100% oxygen (administration of a single empiric dose is warranted before methemoglobin level is known, if the methemoglobin level is not immediately available)

CONTRAINDICATIONS

A previous anaphylactic reaction to methylene blue is an absolute contraindication. Relative contraindications include:

• Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Although methylene blue may paradoxically increase methemoglobinemia in G-6-PD-deficient patients, most patients will have some activity of the enzyme, and methylene blue may be used cautiously in symptomatic patients.
• Known NADPH methemoglobin reductase deficiency.

ADVERSE EFFECTS

• A cumulative dose of more than 7 mg/kg can result in a paradoxical increase in methemoglobin.
• Rapid infusion can cause flushing, shortness of breath, apprehension, and vomiting.
• Tissue necrosis can occur with extravasation.
• Large doses may cause nausea and vomiting, headaches, dizziness, confusion, sweating, chest pain, hyper- or hypotension, and dysrhythmias.
• Blue-green discoloration of urine and stools may occur.
• Delayed hemolysis may be noted in patients with G-6-PD deficiency.

Section Outline:

• CONTRAINDICATIONS
• ADVERSE EFFECTS

ASYMPTOMATIC PATIENT WITH METHEMOGLOBIN LEVEL GREATER THAN 30% AND RISING

• The initial dose is 1 to 2 mg/kg of a 1% solution (1 to 2 ml/kg) administered via intravenous push over 5 minutes for both adult and pediatric patients.
• The bolus infusion should be followed by administration of 15 to 30 ml of crystalloidal fluid flush.
• A second dose of 1 to 2 mg/kg can be given intravenously 30 to 60 minutes later if no clinical effect is noted.
• The maximum effect is expected within 30 minutes, after which the methemoglobin level should be checked again.
• If symptoms persist or methemoglobinemia recurs, repeated doses of methylene blue can be administered (the effectiveness of decontamination should also be reexamined).
• The cumulative dose of methylene blue should not exceed 7 mg/kg.

SYMPTOMATIC PATIENT WITH ELEVATION OF METHEMOGLOBIN LEVEL

• The dose and administration of methylene blue are the same as for a methemoglobin level greater than 30%.
• The reason that the patient has symptoms at a low level of methemoglobin should be carefully examined.
  • If the patient is anemic or another underlying disease makes the patient susceptible, other therapy may be needed to achieve full response.
  • These patients are also at increased risk of adverse effects (i.e., the paradoxical methemoglobin induced by large doses of methylene blue will compromise a larger portion of hemoglobin in an anemic patient).
  • Repeat doses should be carefully considered. Consultation with a poison control center or medical toxicologist is recommended.

SYMPTOMATIC PATIENT WITH CYANOSIS THAT DOES NOT CORRECT WITH ADMINISTRATION OF 100% OXYGEN

• Dose and administration of methylene blue are the same as for a methemoglobin level greater than 30%.
• However, an accurate methemoglobin level should be determined as quickly as possible by cooximeter to guide further therapy.
• Failure to achieve response indicates possibility of enzyme deficiency or underlying disease causing cyanosis (G-6-PD deficiency, NADPH methemoglobin deficiency, cardiac shunting, other causes of hypoxia).

Section Outline:

• SYMPTOMATIC PATIENT WITH ELEVATION OF METHEMOGLOBIN LEVEL
  • SYMPTOMATIC PATIENT WITH CYANOSIS THAT DOES NOT CORRECT WITH ADMINISTRATION OF 1000XYGEN

DIAGNOSIS

• Patients with anemia or other underlying disease may have symptoms at methemoglobin levels much lower than 30%.
• Serial methemoglobin levels should be performed to assess response to therapy and possible recurrence of methemoglobin.

TREATMENT

• Patients with G-6-PD deficiency may have partial or no response due to lack of NADPH.
• Patients with hereditary G-6-PD deficiency are at an increased risk of developing methemoglobinemia and of having methemoglobinemia complicate methylene blue therapy.
• Patients with NADPH methemoglobin reductase deficiency may have no response to therapy.
• Doses over 7 mg/kg can result in paradoxical increase in methemoglobin.
• Inadvertent administration of adult doses of methylene blue to children may result in serious methemoglobinemia.
• Patients with no symptoms and methemoglobin levels lower than 30% do not require treatment unless they become symptomatic.
• Some hospital pharmacies fail to stock antidotes adequately, and it may be necessary to obtain methylene blue from another hospital.
• Sulfhemoglobinemia appears as methemoglobinemia, but does not respond to methylene blue therapy.

Section Outline:

• DIAGNOSIS
• TREATMENT

Poisoning by agents primarily affecting blood constituents.

See Also: SECTION II, Methemoglobinemia chapter.

RECOMMENDED READING

Avner JR, Henretig FM, McAneney CM. Acquired methemoglobinemia: the relationship of cause to course of illness. Am J Dis Child 1990;144:1229-1230.

Curry S. Methemoglobinemia. Ann Emerg Med 1982;11:214-221.

Author: Richard Chen

Reviewer: Luke Yip