What causes and treats methemoglobinemia?

From the Guidelines

Methemoglobinemia is caused by oxidation of iron in hemoglobin from the ferrous (Fe2+) to ferric (Fe3+) state, rendering it unable to transport oxygen, and can be acquired through exposure to oxidizing medications or chemicals, or inherited as congenital forms due to enzyme deficiencies or hemoglobin M disease. This condition can be treated with intravenous methylene blue, which is the first-line treatment for symptomatic patients or those with methemoglobin levels above 20% 1.

Causes of Methemoglobinemia

• Acquired methemoglobinemia occurs after exposure to an oxidant stressor, such as nitrates, nitrites, and many pharmaceuticals (e.g., dapsone, benzocaine, phenazopyridine) 1
• Inherited methemoglobinemia can be caused by enzyme deficiencies (cytochrome b5 reductase) or hemoglobin M disease 1

Treatment of Methemoglobinemia

• Intravenous methylene blue is the primary treatment for decreasing methemoglobin levels, acting as a cofactor to reduce methemoglobin to hemoglobin 1
• The usual starting dose of methylene blue is 1–2 mg/kg infused intravenously over 3 to 5 minutes, which can be repeated if symptoms do not resolve within 30–60 minutes 1
• Ascorbic acid (vitamin C) can be used as an alternative treatment, especially in patients with G6PD deficiency, at a dose of 300-1000 mg/day orally in divided doses 1
• Severe cases may require exchange transfusion or hyperbaric oxygen therapy 1

Prevention

• Prevention involves avoiding triggering agents in susceptible individuals and proper monitoring when using high-risk medications 1
• Patients with known hereditary or acquired methemoglobinemia should avoid substances that can precipitate methemoglobinemia, such as nitrates, sulfonamides, and nitroglycerine 1

From the FDA Drug Label

Information for Patients Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics: PRECAUTIONS General: Hemolysis and Heinz body formation may be exaggerated in individuals with a glucose-6-phosphate dehydrogenase (G6PD) deficiency, or methemoglobin reductase deficiency, or hemoglobin M.

Methemoglobinemia can be caused by:

• The use of local anesthetics 2
• Concurrent exposure to certain drugs, including other local anesthetics 2
• A glucose-6-phosphate dehydrogenase (G6PD) deficiency, or methemoglobin reductase deficiency, or hemoglobin M 3
• The use of dapsone, especially in individuals with a G6PD deficiency 3 Key points to consider when evaluating the cause of methemoglobinemia include:
• The patient's medical history, including any known deficiencies or conditions that may increase the risk of methemoglobinemia
• The patient's current medications, including any local anesthetics or other drugs that may contribute to the development of methemoglobinemia
• The presence of any signs or symptoms of methemoglobinemia, such as pale, gray, or blue colored skin, headache, rapid heart rate, shortness of breath, lightheadedness, or fatigue 2

From the Research

Causes of Methemoglobinemia

• Methemoglobinemia can be caused by oxidizing reactions to certain substances, including:
  • Cocaine-derived anesthetics, such as benzocaine and lidocaine 4
  • Antibiotics, such as dapsone and other sulfonamides 4, 5, 6, 7
  • Gases, such as nitric oxide 4, 6
  • Nitrites, such as amyl or isobutyl nitrite 6
  • Sodium nitrite 6
  • Food contaminated with nitrates 6
  • Sepsis 6
• Methemoglobinemia can also be caused by congenital enzymatic defects or alterations in the hemoglobin molecule 8

Treatment of Methemoglobinemia

• Effective treatments for methemoglobinemia include:
  • Intravenous administration of methylene blue 4, 5, 8, 6
  • Ascorbic acid 4
  • Riboflavin 4
• Removal of the offending agent, if medication-induced, is also an important part of treatment 8, 6, 7
• Aggressive oxygen therapy may also be used to treat methemoglobinemia 8

Diagnosis of Methemoglobinemia

• Co-oximetry is the gold standard for diagnosis of methemoglobinemia 8
• Arterial blood gas paired with pulse oximetry and serum methemoglobin levels can also confirm the diagnosis clinically 8
• CO-oximetry is superior to standard pulse oximetry in detecting methemoglobinemia 4