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Methemoglobinemia Treatment & Management

  • Author: Mary Denshaw-Burke, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Jan 04, 2016
 

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 with 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 there is 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, the toxin or drug 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.

After acute exposure to an oxidizing agent, it is advisable to treat patients with 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, and it is also not effective in patients with hemoglobin M (Hb M). Other conditions in which methylene blue may be ineffective or even deleterious include the following:

  • Nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase (ie, diaphorase II) deficiency
  • Sulfhemoglobinemia

The 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.[58]

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.

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.[59]

Curcumin, the main curcuminoid in turmeric, has been shown experimentally to reduce methemoglobinemia in rats treated with dapsone.[60]

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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Contributor Information and Disclosures
Author

Mary Denshaw-Burke, MD, FACP Clinical Assistant Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Clinical Assistant Professor, Affiliated Clinical Faculty of the Lankenau Institute for Medical Research; Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Medical Center

Mary Denshaw-Burke, MD, FACP is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Mudra Kumar, MD, MRCP, FAAP Professor of Pediatrics, Course Director, Course 6 MSII, Preclerkship Director, Clinical Integration, Department of Pediatrics, University of South Florida Morsani College of Medicine

Mudra Kumar, MD, MRCP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Deric C Savior, MD Fellow, Department of Hematology/Oncology, Lankenau Hospital

Disclosure: Nothing to disclose.

Amy Lawser Curran, MD Fellow, Department of Hematology/Oncology, Lankenau Hospital

Amy Lawser Curran, MD is a member of the following medical societies: Alpha Omega Alpha, Sigma Xi

Disclosure: Nothing to disclose.

Elizabeth DelGiacco, DO Chief Fellow, Department of Hematology/Oncology, Main Line Health, Lankenau Medical Center

Elizabeth DelGiacco, DO is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Steven K Bergstrom, MD Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology

Disclosure: Nothing to disclose.

Matthew Bouchard, MD Consulting Staff, Department of Emergency Medicine, Altoona Regional Health System

Disclosure: Nothing to disclose.

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: Nothing to disclose.

Max J Coppes, MD, PhD, MBA Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Kathy L Ferguson, DO Attending Physician, Department of Emergency Medicine, New York Hospital of Queens

Kathy L Ferguson, DO is a member of the following medical societies: American College of Emergency Physicians and American College of Medical Toxicology

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Sharada A Sarnaik, MBBS Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children's Hospital of Michigan

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians and American Society of Hematology

Disclosure: Nothing to disclose.

John Schoffstall, MD Associate Professor, Department of Emergency Medicine, Medical College of Pennsylvania

John Schoffstall, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Pennsylvania Medical Society, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Michael J Verive, MD Medical Director, Pediatric Intensive Care, Department of Pediatrics, St Mary's Hospital for Women and Children

Michael J Verive, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, Pediatric Sedation, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Note chocolate brown color of methemoglobinemia. In tubes 1 and 2, methemoglobin fraction is 70%; in tube 3, 20%; and in tube 4, normal.
 
 
 
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