eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Methemoglobinemia

Mary Denshaw-Burke, MD, FACP, Assistant Clinical Professor, Institute for Medical Research, Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Hospital; Consulting Staff, Roxborough Memorial Hospital
Deric C Savior, MD, Fellow in Hematology/Oncology, Lankenau Hospital; John Schoffstall, MD, Associate Professor, Department of Emergency Medicine, Medical College of Pennsylvania

Updated: Oct 4, 2009

Introduction

Background

Methemoglobinemia is diagnosed when the percentage of methemoglobin (metHb) exceeds 1% in the blood. Methemoglobin differs from normal hemoglobin in that the oxygen-carrying ferrous (+2) iron in the heme groups has been oxidized to ferric (+3) iron. Methemoglobin is characterized by the inability to bind oxygen, resulting in a functional anemia and failure to deliver oxygen to the body's tissues.^1,2,3,4

The classic presentation of methemoglobinemia is cyanosis in the presence of a normal alveolar partial pressure of oxygen (PaO₂), with brown- or chocolate-colored blood that does not become red on exposure to oxygen. Additional symptoms such as shortness of breath, anxiety, palpitations, and confusion occur as the level of metHb increases.^3,5,6

Methemoglobinemia is a misnomer, because metHb is only increased within the red blood cells and is not dissolved in the plasma. Methemoglobinemia can be hereditary or acquired. Acquired methemoglobinemia is usually secondary to medications or various exogenous exposures.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.

Pathophysiology

Methemoglobin occurs naturally in the body due to oxidative stresses, but it is usually only in small amounts (<1% of total hemoglobin). levels exceeding 1% are termed methemoglobinemia. This low level of methemoglobin is maintained through a system of enzymatic functions that reduces methemoglobin to hemoglobin through successive electron transfers.

The major enzymatic system involved is adenine dinucleotide (NADH)–dependent methemoglobin reduction.⁷ This has also been called the diaphorase pathway. Cytochrome b5 reductase plays a major role in this process by transferring electrons from NADH to methemoglobin, which results in the reduction of methemoglobin to hemoglobin. This enzyme system is responsible for the removal of 95-99% of the methemoglobin that is produced under normal circumstances.

Another enzyme system, nicotinamide adenine dinucleotide phosphate (NADPH)–dependent methemoglobin reduction, usually plays only a minor role in the removal of methemoglobin. This enzyme system utilizes glutathione production and glucose-6-phosphate dehydrogenase (G6PD) to reduce methemoglobin to hemoglobin. This secondary enzymatic system assumes larger and more important role in methemoglobin regulation in patients with cytochrome b5 reductase deficiencies.

Methylene blue accelerates the NADPH-dependent methemoglobin reduction pathway.^3,5,7,8 In the absence of further accumulation of methemoglobin, these methemoglobin reduction pathways can clear methemoglobin at a rate of approximately 15% per hour.

At least 2 forms of congenital cytochrome b5 reductase deficiency states exist. Both are inherited in an autosomal recessive pattern. Type Ib5R deficiency is the more common form. In this clinical entity, cytochrome b5 reductase is absent only in red blood cells. Homozygotes appear cyanotic, but they are usually otherwise asymptomatic. Methemoglobin levels are typically in the range of 10-35%. Life expectancy is not adversely influenced, and pregnancies are not complicated. Heterozygotes may develop acute, symptomatic methemoglobinemia after exposure to certain drugs or toxins.

Type IIb5R cytochrome reductase deficiency is more uncommon and accounts for only 10-15% of cases of congenital cytochrome b5 reductase deficiency. In this condition, cytochrome b5 reductase is deficient in all cells (not just red blood cells). It is associated with multiple other medical problems, including mental retardation, microcephaly, and other neurologic complications. Life expectancy is severely compromised, and patients usually die at a very young age. The exact mechanism for the neurologic complications is not known.

Abnormal hemoglobins can also cause methemoglobinemia. These abnormal hemoglobins are called hemoglobin M (Hb M) because they are associated with methemoglobinemia. In most of them, a tyrosine replaces the histidine residue, which binds heme to globin. This replacement displaces the heme moiety and permits oxidation of the iron to the ferric state. Then, hemoglobin M is more resistant to reduction by the methemoglobin reduction enzymes previously described. The end result is a functionally impaired hemoglobin with a decreased affinity for oxygen.

The inheritance pattern for this hemoglobin M disorder is autosomal dominant. Patients appear cyanotic but are otherwise generally asymptomatic. The cyanosis in patients with hemoglobin M may appear somewhat brownish gray in color. Two varieties of hemoglobin M exist. The alpha chain variant causes cyanosis from birth, whereas the beta chain variant does not cause cyanosis until several months after birth, when the level of fetal hemoglobin decreases.^7,9

Most cases of methemoglobinemia are due to excessive production of methemoglobin following exposure to oxidant drugs, chemicals, or toxins. This increased production of methemoglobin overwhelms the physiologic regulatory mechanisms previously discussed. These agents can cause an increase in methemoglobin levels either by ingestion or by absorption through the skin. Such agents fall into 2 general categories: nitrites or aromatic amines. Dapsone¹⁰ and benzocaine¹¹ are common causes for methemoglobinemia.¹²

Clinical evidence of cyanosis is dependent on the level of methemoglobin. Skin discoloration can occur in patients who are not anemic when as little as 1.5 g/dL, or approximately 10%, of hemoglobin is in the methemoglobin form. This compares with a level of as much as 5 g/dL of deoxyhemoglobin required to produce cyanosis. In methemoglobinemia, cyanosis is usually the first presenting symptom, in contrast to other causes of hypoxemia in which it is a later finding. In patients with severe anemia, a higher percentage of methemoglobin is required for cyanosis to occur. These patients may exhibit signs of hypoxemia with less cyanosis than in patients who do not have anemia.

Substances that can cause methemoglobinemia

• Inorganic agents
  • Nitrates – Fertilizers, contaminated well water, preservatives, industrial products
  • Chlorates
  • Copper sulfate – Fungicides
• Organic nitrites/nitrates
  • Amyl nitrite
  • Isobutyl nitrite
  • Sodium nitrite
  • Nitroglycerin
  • Nitroprusside
  • Nitric oxide
  • Nitrogen dioxide
  • Trinitrotoluene (TNT), combustion products
• Others
• Local anesthetics – Benzocaine, lidocaine, prilocaine, phenazopyridine (Pyridium)^13,14
• Antimalarials – Primaquine, chloroquine¹⁵
• Rasburicase¹⁶
• Antineoplastic agents – Cyclophosphamide, ifosfamide, flutamide
• Analgesics/antipyretics – Acetaminophen, acetanilid, phenacetin, celecoxib
• Zopiclone¹⁷
• Herbicides – Paraquat (dipyridylium)
• Methylene blue (high dose or in G6PD deficient patients¹⁸ )
• Indigo Carmine (Indigotindisulfonate)
• Resorcinol
• Antibiotics – Sulfonamides, nitrofurans, P-amino-salicylic acid, Dapsone
• Industrial/household agents – Aniline dyes, nitrobenzene, naphthalene (moth balls), aminophenol, nitroethane (nail polish remover)

Frequency

United States

Hereditary methemoglobinemia is a rare condition. The most common cause of congenital methemoglobinemia is cytochrome b5 reductase deficiency (type Ib5R). This enzymatic deficiency is endemic in certain Native American tribes (Navajo and Athabascan Alaskans).
 
Most cases of congenital methemoglobinemia are acquired and result from exposure to certain drugs or toxins. One of the more common causes of acquired methemoglobinemia is exposure to topical benzocaine during medical procedures. An estimated 0.115% of patients undergoing transesophageal echocardiography (TEE) develop methemoglobinemia.^11,19,20 The incidence with other agents is not known.

Infants are more susceptible to the development of methemoglobinemia after toxin exposure, because they have a decreased ability to clear methemoglobin once it is formed. Premature infants are particularly susceptible.

A retrospective study from 2 large teaching hospitals in the United States identified 138 cases of acquired methemoglobinemia over a period of 28 months.¹²

International

Methemoglobinemia occurs rarely throughout the world. Cytochrome b5 reductase deficiency (type Ib5R) is also endemic in the Yakutsk people of Siberia.

Mortality/Morbidity

Acquired toxic methemoglobinemia can be life threatening, but it is usually not fatal with proper treatment. This is particularly true when the exposure is intentional or the condition is not recognized. One fatality and 3 near-fatalities were reported in a study of 138 patients.¹² Acquired toxic methemoglobinemia usually responds to treatment when it is recognized and properly treated.

The clinical course of hereditary forms of methemoglobinemia is generally benign. However, individuals with type IIb5 cytochrome reductase deficiency are an exception to this rule. These persons have a markedly shortened life expectancy primarily due to multiple neurologic complications.

Race

The congenital form of methemoglobinemia due to cytochrome b5 reductase deficiency (type Ib5R) is endemic in certain ethnic groups. These groups include the Navajo, Athabascan Alaskans, and the Yakutsk people in Siberia.

Sex

No difference exists in disease occurrence of acquired methemoglobinemia between males and females. The inheritance pattern of the congenital enzyme deficiency form of the disease is autosomal recessive. Hemoglobin M is inherited in an autosomal dominant pattern.

Age

Infants (especially premature infants) are more susceptible to the development of methemoglobinemia after drug or toxin exposure. This is because infants have significantly lower levels of cytochrome b5 reductase.

Clinical

History

The history is important for distinguishing methemoglobinemia between cyanosis that is due to cardiopulmonary abnormalities and that from other causes of discoloration of the skin and mucous membranes. Acute methemoglobinemia can be life threatening and usually is due to toxic exposure or drugs. Therefore, obtaining a history of exposure to substances that can induce methemoglobinemia is important. In contrast, patients with hereditary methemoglobinemia are often asymptomatic despite the presence of cyanosis. The failure of 100% oxygen to correct cyanosis is suggestive of methemoglobinemia.

• Symptoms are proportional to the level of methemoglobin.
  • Less than 10% methemoglobin – No symptoms
  • 10-20% methemoglobin – Skin discoloration only (most notably
    on mucus membranes)
  • 20-30% methemoglobin – Anxiety, headache, dyspnea on
    exertion
  • 30-50% methemoglobin – Fatigue, confusion, dizziness,
    tachypnea, palpitations
  • 50-70% methemoglobin – Coma, seizures, arrhythmias, acidosis
  • Greater than 70% methemoglobin – Death
• Infants and children can develop methemoglobinemia in association with metabolic acidosis that is caused by prolonged dehydration and diarrhea. Sources of accidental toxin exposure that need to be considered in infants and children include the ingestion of water from wells contaminated with excess nitrates and exposure to local anesthetics in teething gels.²¹ These factors can sometimes be elicited in a thorough history.
• Any known family history of methemoglobinemia or G6PD deficiency is important to clarify. Even patients who are heterozygous for methemoglobin reductase enzyme deficiencies are susceptible to low doses of oxidant drugs with resultant methemoglobinemia.
• The presence of gastrointestinal (GI) symptoms (nausea, vomiting, diarrhea) may suggest the possibility of ingestion of a toxic substance.
• The clinical effects of methemoglobinemia are exacerbated in the presence of anemia.

Physical

The physical examination of patients suspected of methemoglobinemia should include careful examination of the skin and mucous membranes for discoloration or cyanosis.

• Vital signs should be documented, along with an assessment of the patient's mental status.
• Careful attention should be paid to the cardiac, respiratory, and circulatory examinations to assess for evidence of an underlying disease (either congenital or acquired).
• Pallor of the skin or conjunctiva may suggest anemia (and possible hemolysis).
• Significant anemia may mask the cyanosis of methemoglobinemia.
• Skeletal abnormalities and mental retardation are associated with certain types of methemoglobin reductase enzyme deficiencies.

Causes

The pathophysiology of methemoglobinemia has been previously discussed (see Pathophysiology). In general, methemoglobinemia can be acquired or congenital. Acquired methemoglobinemia is usually due to the ingestion of drugs or toxic substances. Congenital causes of methemoglobinemia include methemoglobin reductase enzyme deficiencies or abnormal hemoglobins (Hb M) that are more prone to form methemoglobin.

• Organic and inorganic nitrites/nitrates are common causes of methemoglobinemia. Many of these substances can also be absorbed through the skin, and many prescription cardiac medications contain these compounds. Dietary intake may occur in infants or adults who ingest well water that has been contaminated with nitrites caused by water runoff from fertilized fields.²¹
• Chlorates are another group of oxidizing agents that can cause methemoglobinemia. These substances are found in matches, explosives, and fungicides.
• Topical and injected local anesthetics have also caused methemoglobinemia. Predisposing factors for the development of this toxicity include the presence of a mucosal injury with resultant increased absorption or a previously undiagnosed methemoglobin reductase enzyme deficiency. This toxicity can also be idiosyncratic.
• Dapsone is another medication that can cause methemoglobinemia. It is used to prevent and treat Pneumocystis carinii pneumonia (PCP) and to treat leprosy and other skin diseases. This drug should be used with great caution in patients with known G6PD deficiency, methemoglobin reductase deficiency, or hemoglobin M.
• Patients with low catalase activity (inherited or acquired) may be at risk for the development of methemoglobinemia secondary to the formation of hydrogen peroxide after being treated with rasburicase for tumor lysis syndrome.²² Some authors have suggested that catalase activity be measured before initiating therapy with rasburicase in this setting.
• Red blood cells in patients with liver cirrhosis undergo severe oxidative stress, especially in the setting of bleeding complications.²³ The level of methemoglobin is significantly higher in the red blood cells of these patients as compared with nonbleeding patients.
• Idiopathic methemoglobinemia can occur in association with systemic acidosis. This typically occurs in infants younger than 6 months and is usually caused by dehydration and diarrhea. Idiopathic methemoglobinemia is exacerbated by the lower levels of methemoglobin reductase enzyme found in infants (50% of adult levels).

Differential Diagnoses

Other Problems to Be Considered

The initial differential diagnosis of a patient presenting with methemoglobinemia is large. Any disease process that causes symptoms consistent with decreased oxygen delivery to the tissues can mimic methemoglobinemia. Such diseases include heart disease, lung disease, anemia, or any severe infection; however, the hallmark of methemoglobinemia is cyanosis that is unresponsive to high-flow oxygen in the absence of cardiac or pulmonary disorders.

Once these findings are elicited, the differential diagnosis narrows significantly. Aside from methemoglobinemia, only sulfhemoglobinemia, skin contamination with dye, or methylene blue should cause cyanosis that is completely unresponsive to oxygen.

• Sulfhemoglobinemia is a disease entity that causes cyanosis at extremely low levels, is extremely rare, and only can be cured by removal of the offending agent.
• Skin contamination can occur with any blue dye and can mimic the asymptomatic cyanotic state of mild methemoglobinemia.^24,25
• Methylene blue can impart a cyanotic discoloration to the skin after the treatment of patients with methemoglobinemia; therefore, bluish discoloration following treatment does not necessarily imply treatment failure.
• Argyria due to excessive exposure to silver compounds can mimic methemoglobinemia.

Workup

Laboratory Studies

• Bedside test: To distinguish between deoxyhemoglobin and methemoglobin, place 1 or 2 drops of the patient's blood on a white filter paper. Deoxyhemoglobin brightens after exposure to atmospheric oxygen, but methemoglobin does not change color. Blowing oxygen on the filter paper speeds the reaction.
• The limitation of arterial blood gas (ABG) is that methemoglobin can falsely elevate the calculated oxygen saturation. One possible clue to the diagnosis of methemoglobinemia is the presence of a "saturation gap." This occurs when there is a difference between the oxygen saturation measured on pulse oximetry and the oxygen saturation calculated on ABG results.
• Pulse oximetry: Findings on bedside pulse oximetry are misleading. This device only measures the relative absorbance of 2 wavelengths of light to differentiate oxyhemoglobin from deoxyhemoglobin; however, methemoglobin absorbs both of these wavelengths equally. Therefore, at high levels of methemoglobin, the pulse oximeter reads a saturation of 85%, which corresponds to equal absorbance of both wavelengths. This is an inaccurate depiction of the hemoglobin oxygen-carrying capacity. Also important to note is that the partial pressure of oxygen (pO₂) value on the ABG finding reflects plasma oxygen content, does not correspond to the oxygen-carrying capacity of hemoglobin, and should be within the reference range in patients with methemoglobinemia.
• Co-oximetry: The co-oximeter is an accurate device for measuring methemoglobin and is the key to diagnosing methemoglobinemia. It is a simplified spectrophotometer that can measure the relative absorbance of 4 different wavelengths of light and, therefore, can differentiate methemoglobin from carboxyhemoglobin, oxyhemoglobin, and deoxyhemoglobin. Newer machines also can measure sulfhemoglobin, which can be confused with methemoglobin by co-oximetry. Unfortunately, not all clinical laboratories have these machines. Lipemic specimens may result in a falsely elevated methemoglobin level. The presence of methylene blue interferes with the accurate measurement of methemoglobin by co-oximetry. Therefore, this method cannot be used to monitor methemoglobin levels following treatment with methylene blue. Blood substitutes can also cause unreliable results.
• Potassium cyanide test: This test can distinguish between methemoglobin and sulfhemoglobin. Methemoglobin reacts with cyanide to form cyanomethemoglobin, which has a bright red color. Sulfhemoglobin does not react with cyanide and therefore does not change to a bright red color.
• Tests to rule out hemolysis (eg, complete blood cell [CBC] count, reticulocyte counts, lactate dehydrogenase [LDH], indirect bilirubin, haptoglobin) and to test for organ failure and general end-organ dysfunction (eg, liver function tests, electrolytes, blood urea nitrogen [BUN], creatinine) should be performed. In selected cases, a Heinz body preparation may be helpful to further evaluate hemolysis. On routine analysis, an acidic urine may appear reddish brown in color. A review of the peripheral blood smear may show evidence of bite cells (abnormal red blood cells). These bite cells are the result of removal of oxidized hemoglobin by the spleen.
• Tests to evaluate a hereditary cause for methemoglobinemia should be ordered when appropriate. Hemoglobin M can often be diagnosed by hemoglobin electrophoresis. However, some difficult cases require more sophisticated techniques such as DNA sequencing of the globin chain gene or mass spectrometry for diagnosis. NADH-dependent methemoglobin reductase deficiencies are diagnosed by specific enzyme assays. If possible, these levels should be measured in multiple cell lines (ie, platelets, granulocytes, and fibroblasts). Type I cytochrome b5 reductase deficiency is found only in red blood cells. Type II cytochrome b5 reductase deficiency is found in multiple cell lines. These enzyme assays may have to be performed in a specialized research laboratory.

Treatment

Medical Care

• If methemoglobinemia is the result of toxin exposure, then removal of this toxin is imperative. Further ingestion or administration of the drug or chemical is to 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 in a closely monitored situation with oxygen supplementation as needed.
• Methylene blue is the primary emergency treatment for documented, symptomatic methemoglobinemia.
  • The methylene blue dose is 1-2 mg/kg administered as a 1% solution in intravenous saline over 3-5 minutes. This dose may be repeated at 1 mg/kg every 30 minutes as necessary to control symptoms. Doses of methylene blue should not exceed 7 mg/kg, because this agent in itself can be toxic and cause dyspnea, chest pain, and hemolysis. Methylene blue requires G6PD to work. Therefore, it is not effective in patients who have G6PD deficiency with methemoglobinemia. Additionally, methylene blue administration may cause hemolysis in these patients, and it is also not effective in patients with hemoglobin M.
  • Exchange transfusion can be considered for patients who are G6PD deficient and severely symptomatic or for those patients whose condition fails to respond to methylene blue. Patients who are on long-acting medication (eg, dapsone) can 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.
• Infants with methemoglobinemia due to metabolic acidosis should be treated with intravenous hydration and bicarbonate to reverse the acidosis. The NADPH-dependent methemoglobin reductase enzyme system requires glucose for the clearance of methemoglobin. Therefore, intravenous hydration with dextrose 5% in water (D5W) is often appropriate.
• 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 dose of methylene blue in this setting is 100-300 mg/d, which may turn the urine blue in color. The dose of ascorbic acid is 500 mg/d. Unfortunately, chronic oral ascorbic acid can cause the formation of sodium oxalate stones. The dose of riboflavin is 20 mg/d.

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 a critical care specialist should be obtained in patients with severe symptoms.

Diet

Rarely, the patient's diet may include a substance that is the source of the methemoglobinemia. Well water contamination with inorganic nitrates has been previously mentioned. This 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.

Medication

The goals of pharmacotherapy are to reduce toxicity, prevent complications, and reduce morbidity.

Antidotes

Antidote agents act as cofactors in the NADPH-dependent methemoglobin reductase system.

Methylene blue (Urolene Blue)

Used to convert the ferrous iron of reduced hemoglobin (methemoglobin) to ferric form (hemoglobin).

Dosing

Adult

1-2 mg/kg IV (0.1-0.2 mL/kg of 1% saline solution) over 5 min initially; may repeat at 1 mg/kg in 30 min if there's an inadequate response; not to exceed 7 mg/kg

The mild chronic form is due to enzyme deficiencies: 100-300 mg/d PO to treat cyanosis

Pediatric

1 mg/kg IV (0.1 mL/kg of 1% saline solution) over 5 min

Interactions

None reported

Contraindications

Documented hypersensitivity; renal insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not for use in G6PD deficiency (may cause hemolytic anemia and will not be effective); may cause discoloration of the skin and urine; can cause dizziness, dyspnea, and chest pain (particularly with doses >7 mg/kg)

Vitamins

Vitamins can be used to treat collagen synthesis and tissue repair. They may also act as cofactors in erythrocyte glutathione reductase and NADH dehydrogenase.

Ascorbic acid (vitamin C)

Can occasionally reduce the cyanosis associated with chronic methemoglobinemia but has no role in the treatment of acute acquired methemoglobinemia.

Dosing

Adult

500 mg/d PO

Pediatric

Not established

Interactions

Decreases the effects of warfarin and fluphenazine; increases aspirin levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Prolonged high doses may cause renal calculi (sodium oxalate)

Riboflavin (vitamin B-2)

Can reduce the cyanosis associated with chronic methemoglobinemia but has no role in the treatment of acute severe acquired methemoglobinemia

Dosing

Adult

20 mg/d PO

Pediatric

Not established

Interactions

Probenecid may decrease absorption

Contraindications

Documented hypersensitivity to riboflavin

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Can cause urine discoloration

Follow-up

Further Inpatient Care

• Patients with methemoglobinemia with asymptomatic cyanosis from a known substance ingestion are the only patients who should be considered for discharge. Discharge these patients after a 6-hour observation period only if the implicated cause has been eliminated and is not known to cause rebound methemoglobinemia.
• Patients with methemoglobinemia who are symptomatic or who have 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. These patients should be admitted. Symptomatology determines the level of care that is needed.
• Exchange transfusion and hyperbaric oxygen treatment are second-line treatment options for patients with severe methemoglobinemia whose condition does not respond to intravenous methylene blue or who cannot be treated with methylene blue (eg, G6PD deficient patients). Exchange transfusion basically replaces the abnormal hemoglobin in the red blood cells with normal hemoglobin. Hyperbaric oxygen treatments permit tissue oxygenation to occur through oxygen dissolved in plasma, rather than through hemoglobin-bound oxygen.

Further Outpatient Care

• Good 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.

Inpatient & Outpatient Medications

• Inpatient medication for methemoglobinemia is primarily intravenous methylene blue (see Medical Care and Medication).
• Outpatient medications for the treatment of cyanosis that is associated with chronic mild methemoglobinemia include oral methylene blue, ascorbic acid, and riboflavin.

Transfer

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

Deterrence/Prevention

• Individuals who ingest well water in heavily agricultural areas should have their well water checked periodically for the presence of inorganic nitrates and other chemicals.
• Individuals with known G6PD deficiency or methemoglobin reductase enzyme deficiencies should use great care with the ingestion of medication and minimize or prevent toxin exposure.

Complications

• Patients can die from acute acquired methemoglobinemia, especially if the clinical entity is not recognized.

Prognosis

• Congenital methemoglobinemia patients are usually asymptomatic except for the presence of chronic cyanosis.
• Patients with acquired methemoglobinemia due to toxin exposure can be severely ill when diagnosed. However, with prompt diagnosis and appropriate treatment, a full recovery is possible.

Patient Education

• Patients with inherited methemoglobinemia should be counseled regarding the avoidance of toxins, chemicals, and certain drugs (eg, dapsone).

Miscellaneous

Medicolegal Pitfalls

• Failure to consider methemoglobinemia in the patient with cyanosis that is unresponsive to oxygen therapy
• Failure to evaluate for hemolysis in patients with methemoglobinemia
• Treating patients who are G6PD deficient with methylene blue
• Treating patients with asymptomatic cyanosis with IV methylene blue
• Administering additional IV methylene blue to patients with successful initial treatment but who have methylene blue – induced skin discoloration
• Failure to consider the possibility of rebound methemoglobinemia
• Failure to admit to the appropriate level of care

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Keywords

methemoglobinemia, cyanosis, methemoglobin, metHb, hemoglobin M, Hb M, NADH-metHb reductase deficiencies, acquired methemoglobinemia, enterogenous methemoglobinemia, secondary methemoglobinemia, congenital methemoglobinemia, hereditary methemoglobinemia, hereditary methemoglobinemic cyanosis, primary methemoglobinemia, cytochrome b5 reductase deficiency, cyt b5R

Contributor Information and Disclosures

Author

Mary Denshaw-Burke, MD, FACP, Assistant Clinical Professor, Institute for Medical Research, Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology, Lankenau Hospital; Consulting Staff, Roxborough Memorial Hospital
Mary Denshaw-Burke, MD, FACP is a member of the following medical societies: American College of Physicians and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Coauthor(s)

Deric C Savior, MD, Fellow in Hematology/Oncology, Lankenau Hospital
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.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
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: No financial interests None None

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor Matthew Bouchard, MD, to the development and writing of this article.

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