Methemoglobinemia Treatment & Management

Updated: Dec 09, 2018
  • Author: Mary Denshaw-Burke, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Approach Considerations

Prompt recognition of the condition and initiation of treatment, as indicated (especially in acquired methemoglobinemia), are critical in the management of methemoglobinemia. However, at the same time, it may be imperative to initiate extensive and sometimes invasive investigations to rule out cardiac and pulmonary abnormalities that often result in a similar clinical picture with cyanosis. Once the diagnosis is confirmed, management should be instituted as indicated. Initial care includes administration of supplemental oxygen and removal of the offending oxidizing substance.

Patients with methemoglobinemia who have asymptomatic cyanosis resulting from ingestion of a known substance are the only patients who should be considered for early discharge. They may be discharged after a 6-hour observation period only if the implicated cause has been eliminated and is not known to cause rebound methemoglobinemia.

Symptomatic patients with methemoglobinemia or those with a significantly elevated methemoglobin level should be admitted to the hospital. A lower threshold for hospital admission should occur for patients with complicating factors, such as underlying anemia, chronic cardiopulmonary disease, or peripheral vascular disease. The specific symptoms determine the level of care that is needed.

Intravenous (IV) methylene blue is the first-line antidotal agent. Exchange transfusion and hyperbaric oxygen treatment are second-line options for patients with severe methemoglobinemia whose condition does not respond to methylene blue or who cannot be treated with methylene blue (eg, those with glucose-6-phosphate dehydrogenase [G6PD] deficiency).

Patient transfer should occur when life-threatening methemoglobinemia that is refractory to treatment occurs in a facility that cannot provide the appropriate critical care.

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Initial Management

Early clinical recognition of methemoglobinemia is paramount, as patients often have only vague, nonspecific complaints, especially in the initial phase. High levels of methemoglobinemia can be life-threatening and necessitate emergency therapy. Patients with chronic mild increases in methemoglobin level may be completely asymptomatic and require no specific therapy (provided that they have no evidence of end-organ damage).

Once the diagnosis of methemoglobinemia has been confirmed and appropriate management has been initiated, the underlying etiology should be sought. In acquired methemoglobinemia, if the toxin or drug is not known from the history, it may be identified by obtaining blood levels, performing gastric lavage, or both. In asymptomatic patients with low levels of methemoglobin, monitoring serial serum levels may be all that is necessary. The levels normalize over time unless recurrent or chronic exposure to the offending agent occurs.

Treatment is advisable for patients with acute exposure to an oxidizing agent who have methemoglobin levels of 20% or higher. Patients with significant comorbidities (eg, coronary artery disease [CAD] or anemia) may require therapeutic intervention at lower methemoglobin levels (eg, 10%), especially if end-organ dysfunction (eg, cardiac ischemia) is present.

If methemoglobinemia is the result of toxin exposure, then removal of this toxin is imperative. Further ingestion or administration of the drug or chemical should be avoided. If the substance is still present on the skin or clothing, the clothing should be removed and the skin washed thoroughly. These patients may be unstable and should be cared for in a closely monitored situation, with oxygen supplementation provided as needed.

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Pharmacologic Therapy, Exchange Transfusion, and Hyperbaric Oxygen

Methylene blue is the primary emergency treatment for documented symptomatic methemoglobinemia. It is given in a dose of 1-2 mg/kg (up to a total of 50 mg in adults, adolescents, and older children) as a 1% solution in IV saline over 3-5 minutes. Administration may be repeated at 1 mg/kg every 30 minutes as necessary to control symptoms. Methylene blue is itself an oxidant at doses greater than 7 mg/kg and thus may cause methemoglobinemia in susceptible patients; hence, careful administration is essential.

Methylene blue is contraindicated in patients with G6PD deficiency. Because it requires G6PD to work, it is ineffective in G6PD-deficient patients with methemoglobinemia. Additionally, methylene blue administration may cause hemolysis in these patients.

Methylene blue is also not effective in patients with hemoglobin M (Hb M). Other conditions in which methylene blue may be ineffective or even deleterious include nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase (ie, diaphorase II) deficiency and sulfhemoglobinemia.

Methylene blue is listed as a category X teratogen. Intravenous ascorbic acid appears to be a potential alternative to methylene blue in in pregnant patients with acute methemoglobinemia. However, given that the data on the teratogenicity of methylene blue are mostly related to intra-amniotic or intra-uterine administration, it is possible that in life-threatening cases of methemoglobinemia during pregnancy, the benefits of methylene blue may outweigh the risk. [61]

Methylene blue is listed as a category X teratogen. Intravenous ascorbic acid appears to be a potential alternative to methylene blue in in pregnant patients with acute methemoglobinemia. However, given that the data on the teratogenicity of methylene blue are mostly related to intra-amniotic or intra-uterine administration, it is possible that in life-threatening cases of methemoglobinemia during pregnancy, the benefits of methylene blue may outweigh the risk.62The US Food and Drug Administration (FDA) warns against using methylene blue concurrently with serotonergic psychiatric drugs, unless such usage is indicated for life-threatening or urgent conditions. Methylene blue may increase central nervous system (CNS) serotonin levels as a result of monoamine oxidase (MAO)-A inhibition, thus increasing the risk of serotonin syndrome. [62]

Exchange transfusion (which replaces abnormal hemoglobin with normal hemoglobin) may be considered for G6PD-deficient patients who are severely symptomatic or unresponsive to methylene blue. Patients who are on long-acting medication (eg, dapsone) may have initial treatment success with subsequent relapse of symptoms. Gastric lavage followed by charcoal administration may decrease this prolonged drug effect. These patients should be monitored closely and retreated with methylene blue as necessary.

Hyperbaric oxygen treatment is another option for situations where methylene blue therapy is ineffective or contraindicated. This approach permits tissue oxygenation to occur through oxygen dissolved in plasma, rather than through hemoglobin-bound oxygen.

Infants with methemoglobinemia due to metabolic acidosis should be treated with IV hydration and bicarbonate to reverse the acidosis. The NADPH-dependent methemoglobin reductase enzyme system requires glucose for the clearance of methemoglobin. Therefore, IV hydration with dextrose 5% in water (D5W) is often effective.

Patients with mild chronic methemoglobinemia due to enzyme deficiencies may be treated with oral medications in an attempt to decrease cyanosis. These medications include methylene blue, ascorbic acid, and riboflavin. The methylene blue dosage in this setting is 100-300 mg/day, which may turn the urine blue in color. The ascorbic acid dosage is 200-500 mg/day; unfortunately, long-term oral ascorbic acid therapy can cause the formation of sodium oxalate stones. The riboflavin dosage is 20 mg/day.

Methylene blue is listed as a category X teratogen. Intravenous ascorbic acid appears to be a potential alternative to methylene blue in in pregnant patients with acute methemoglobinemia. However, given that the data on the teratogenicity of methylene blue are mostly related to intra-amniotic or intra-uterine administration, it is possible that in life-threatening cases of methemoglobinemia during pregnancy, the benefits of methylene blue may outweigh the risk. [61]

Cimetidine can be used in dapsone-induced methemoglobinemia to prevent further formation of its metabolite. N-acetylcysteine has been shown to reduce methemoglobin in some studies but is not currently an approved treatment for methemoglobinemia.

No pharmacologic treatment exists for hereditary forms of methemoglobinemia.

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Diet and Activity

Rarely, the patient’s diet may include a substance that is the source of the methemoglobinemia. Well water contamination with inorganic nitrates can be a particular problem with infants whose formula is prepared with this water. Methemoglobinemia due to the ingestion of homemade fennel puree has been reported in infants. Some vegetables (eg, beets, spinach, carrots, borage, and chard) are high in nitrite or nitrate content and may have to be avoided by susceptible patients. [63]

Curcumin, the main curcuminoid in turmeric, has been shown experimentally to reduce methemoglobinemia in rats treated with dapsone. [64]

No change in activity is indicated.

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Prevention

Recognition and avoidance of precipitating factors are important for prevention of methemoglobinemia, especially in susceptible populations. Monitoring of well water levels may be needed. Individuals with known G6PD deficiency or methemoglobin reductase enzyme deficiencies should use great care with the ingestion of oxidizing medications and endeavor to minimize or prevent toxin exposure.

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Consultations

Consultation with a toxicologist should be obtained for those who are not familiar with or who are not comfortable with the treatment of methemoglobinemia. Consultation with other specialists (eg, a hematologist, cardiologist, or pulmonologist) may be required to assist in the search for the cause of the methemoglobinemia.

In patients with severe symptoms, consultation with a critical care specialist should be obtained. If the methemoglobinemia is severe, it may be life-threatening; hence, an American Association of Poison Control Centers (AAPCC)-certified regional poison control center or a medical toxicologist should be consulted.

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Long-Term Monitoring

Close outpatient follow-up care is required in patients treated for methemoglobinemia. Discharged patients should be reevaluated by a physician within 24 hours for any signs or symptoms of recurring disease. Patients should also be provided with strict discharge instructions detailing symptoms that should prompt immediate medical reevaluation, such as shortness of breath, increasing fatigue, or chest pain.

Once appropriate treatment has been instituted for acquired methemoglobinemia, identification and removal of the precipitating cause is all that is often necessary. Clear instructions to avoid future exposure to the precipitating agent (and related agents) should be given to the patient. If treatment is indicated on an ongoing basis, patients should be observed for therapeutic and toxic effects of treatment.

Outpatient medications for the treatment of cyanosis that is associated with chronic mild methemoglobinemia include oral methylene blue, ascorbic acid, and riboflavin.

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