AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Methemoglobinemia is diagnosed when the percent of methemoglobin (metHb) is greater than 1.5%. Methemoglobin differs from normal hemoglobin in that the oxygen-carrying ferrous iron in the heme groups has been oxidized to the ferric iron. Methemoglobin cannot bind oxygen, and this results in a functional anemia and failure of delivery of oxygen to tissues.

The classic presentation is cyanosis in the presence of a normal 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. Levels above 1% are termed methemoglobinemia.

Methemoglobinemia is a misnomer since metHb is only increased within the red blood cells and not dissolved in the plasma. Methemoglobinemia can be hereditary and acquired. Acquired methemoglobinemia is usually due to medications.

Pathophysiology

Methemoglobinemia occurs naturally in the body due to oxidative stresses but usually only in small amounts ( <1% of total hemoglobin). 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 NADH-dependent methemoglobin reduction. 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. This 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, 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 this NADPH-dependent methemoglobin reduction pathway. 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 two 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 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. 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 (Hgb M) because they are associated with methemoglobinemia. In most of them, a tyrosine replaces the histidine residue, which binds heme to globin. This displaces the heme moiety and permits oxidation of the iron to the ferric state. Hemoglobin M is more resistant to reduction by the methemoglobin reduction enzymes previously described. The end result is a functionally impaired hemoglobin with decreased affinity for oxygen. The inheritance pattern for this disorder is autosomal dominant. Patients appear cyanotic but are otherwise generally asymptomatic. The cyanosis in patients with hemoglobin M may appear somewhat brownish grey in color. Two varieties of hemoglobin M exist. The alpha chain variant causes cyanosis from birth, while the beta chain variant does not cause cyanosis until several months after birth when the level of fetal hemoglobin decreases.

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 via skin exposure. These agents generally fall into 2 general categories: nitrites or aromatic amines. See the list below for substances that can cause methemoglobinemia. Dapsone and benzocaine are common causes for methemoglobinemia.

Clinical evidence of cyanosis is dependent on the level of metHb. Skin discoloration can occur in patients who are not anemic when as little as 1.5 g/dL, or approximately 10% of Hb, is in the metHb form. This compares with a level of as much as 5 g/dL of deoxyhemoglobin required to produce cyanosis; therefore, cyanosis usually is the first presenting symptom in patients with methemoglobinemia, in contrast to other causes of hypoxemia in which cyanosis is a later finding. In patients with severe anemia, a higher percentage of metHb is required for cyanosis to occur. These patients may exhibit signs of hypoxemia with less cyanosis than 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
  • TNT
• Others
• • Local anesthetics - Benzocaine, lidocaine, prilocaine, phenazopyridine (Pyridium)
  • Antimalarials - Primaquine, chloroquine
  • Antineoplastic agents - Cyclophosphamide, ifosfamide, flutamide
  • Analgesics/antipyretics - Acetaminophen, acetanilid,
  • phenacetin, celecoxib
  • Herbicide - Paraquat
  • 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. These tribes include the Navajo and Athabascan Alaskans.

Most cases, when they do occur, are acquired and are the result of exposure to certain drugs or toxins. One of the more common causes of acquired methemoglobinemia is exposure to topical benzocaine during procedures. An estimated 0.115% of patients undergoing transesophageal echo (TEE) develop methemoglobinemia. 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.

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

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 is usually not fatal with proper treatment. One fatality and 3 near-fatalities were reported in a recent study of 138 patients. This is particularly true when the exposure is intentional or the condition is not recognized. However, it 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. They 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 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The history is important for distinguishing metHb from cyanosis due to cardiopulmonary abnormalities and other causes of discoloration of the skin and mucous membranes. Acute metHb can be life threatening and usually is due to toxic exposure or drugs. Therefore, obtaining a history of exposure to substances that can induce metHb is important. In contrast, patients with hereditary metHb 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 metHb.
• • Less than 10% metHb - No symptoms
  • 10-20% metHb - Skin discoloration only (most notably
    on mucus membranes)
  • 20-30% metHb - Anxiety, headache, dyspnea on
    exertion
  • 30-50% metHb - Fatigue, confusion, dizziness,
    tachypnea, palpitations
  • 50-70% metHb - Coma, seizures, arrhythmias, acidosis
    Greater than 70% metHb - Death
• Infants and children can develop methemoglobinemia in association with metabolic acidosis 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. 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 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

Physical examination should include careful examination of the skin and mucus 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 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 ingestion of drugs or toxic substances. Congenital causes of methemoglobinemia include methemoglobin reductase enzyme deficiencies or abnormal hemoglobins (HbM) that are more prone to form methemoglobin.

• Organic and inorganic nitrites/nitrates are common causes of methemoglobinemia. Many can also be absorbed through the skin. Many prescription cardiac medications contain these compounds. Dietary intake may occur in infants or adults who ingest well water contaminated with nitrites caused by water runoff from fertilized fields.
• 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.
• 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. This condition is exacerbated by the lower levels of methemoglobin reductase enzyme found in infants (50% of adult levels).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. Methylene blue can impart a cyanotic discoloration to the skin after 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

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Bedside test: To distinguish between deoxyhemoglobin and metHb, place 1 or 2 drops of the patient's blood on a white filter paper. Deoxyhemoglobin brightens after exposure to atmospheric oxygen, but metHb does not change color. Blowing oxygen on the filter paper speeds the reaction.
• The limitation of arterial blood gas (ABG) is that metHb 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 O₂ saturation measured on pulse oximetry and the O₂ saturation calculated on arterial blood gases.
• 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, metHb absorbs both of these wavelengths equally. Therefore, at high levels of metHb, the pulse oximeter reads a saturation of 85%, which corresponds to equal absorbance of both wavelengths. This is an inaccurate depiction of the Hb oxygen-carrying capacity. Also important to note is that the partial pressure of oxygen (pO₂) value on the ABG reflects plasma oxygen content, does not correspond to the oxygen-carrying capacity of Hb, and should be within the reference range in patients with methemoglobinemia.
• Co-oximetry: The co-oximeter is an accurate method for measuring metHb and is the key to diagnosing metHb. It is a simplified spectrophotometer that can measure the relative absorbance of 4 different wavelengths of light and, therefore, can differentiate metHb 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 can not 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 metHb 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, CBC, reticulocyte counts, lactate dehydrogenase [LDH], indirect bilirubin, haptoglobin) and to test for organ failure and general end-organ dysfunction (eg, liver function tests, electrolytes, BUN, creatinine) should be performed. In selected cases, a Heinz body prep 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 metHb should be ordered when appropriate. Hemoglobin M often can 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 b5R deficiency is found only in red blood cells. Type II cytochrome b5R deficiency is found in multiple cell lines. These enzyme assays may have to be performed in a specialized research laboratory.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

High levels of methemoglobinemia can be life threatening and require emergency therapy. After acute exposure to an oxidizing agent, it is advisable to treat patients with levels of methemoglobin of 20% or greater. Patients with significant comorbidities may require treatment at lower levels of methemoglobinemia because of significant symptoms. Patients with chronically mild increases in methemoglobin level may be completely asymptomatic and require no specific therapy.

• 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 dose is 1-2 mg/kg administered as a 1% solution in saline IV 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 by 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 and methemoglobinemia. Additionally, methylene blue administration may cause hemolysis in these patients. Methylene blue 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 who fail 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 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 is 100-300 mg/d. This 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 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Antidotes

These agents act as cofactors in the NADPH-dependent metHb reductase system.

Drug Category: Vitamins

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with asymptomatic cyanosis from a known 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 who are symptomatic or who have a significantly elevated methemoglobin level should be admitted. A lower threshold for 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 needed.
• Exchange transfusion and hyperbaric oxygen treatment are second-line treatment options for patients with severe methemoglobinemia who do not respond to IV methylene blue or who can not 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. Discharged patients should be reevaluated by a physician within 24 hours for any signs or symptoms of recurring disease. Patients should be provided strict discharge instructions detailing symptoms that should prompt immediate medical reevaluation, such as shortness of breath, increasing fatigue, or chest pain.

In/Out Patient Meds

• Inpatient medication for methemoglobinemia is primarily IV methylene blue. This has been previously discussed in detail in Medical Care and Medication.
• Outpatient medications for treatment of cyanosis 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 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 avoidance of toxins, chemicals, and certain drugs (eg, dapsone).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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 G-6-PD 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

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). Sep 2004;83(5):265-73. [Medline].
• Bloom J. Comprehensive Toxicology. 1997;4:62-66.
• Curry S. Methemoglobinemia. Ann Emerg Med. Apr 1982;11(4):214-21. [Medline].
• Curry S. Methemoglobinemia. In: The Clinical Practice of Emergency Medicine [book on CD-ROM]. 1997.
• Fan AM, Steinberg VE. Health implications of nitrate and nitrite in drinking water: an update on methemoglobinemia occurrence and reproductive and developmental toxicity. Regul Toxicol Pharmacol. Feb 1996;23(1 Pt 1):35-43. [Medline].
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• Grauer SE, Giraud GD. Toxic methemoglobinemia after topical anesthesia for transesophageal echocardiography. J Am Soc Echocardiogr. Nov-Dec 1996;9(6):874-6. [Medline].
• Henretig FM, Gribetz B, Kearney T. Interpretation of color change in blood with varying degree of methemoglobinemia. J Toxicol Clin Toxicol. 1988;26(5-6):293-301. [Medline].
• Hoffman R, Benz E, Shattil S. Hematology: Basic Principles and Practice. 4th ed. 2005:650-657.
• Mansouri A, Lurie AA. Concise review: methemoglobinemia. Am J Hematol. Jan 1993;42(1):7-12. [Medline].
• Percy MJ, McFerran NV, Lappin TR. Disorders of oxidised haemoglobin. Blood Rev. Mar 2005;19(2):61-8.
• Rausch-Madison S, Mohsenifar Z. Methodologic problems encountered with cooximetry in methemoglobinemia. Am J Med Sci. Sep 1997;314(3):203-6. [Medline].
• Rosen PJ, Johnson C, McGehee WG. Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med. Jul 1971;75(1):83-6. [Medline].
• Schweitzer SA. Spurious pulse oximeter desaturation due to methaemoglobinaemia. Anaesth Intensive Care. May 1991;19(2):269-71. [Medline].
• Tomaszewski CA, Thom SR. The use of hyperbaric oxygen in toxicology. Emergency Medicine Clinics of North America. 1994;12(2):437-454. [Medline].
• Ward KE, McCarthy MW. Dapsone-induced methemoglobinemia. Ann Pharmacother. May 1998;32(5):549-53. [Medline].
• Wright RO, Magnani B, Shannon MW. N-acetylcysteine reduces methemoglobin in vitro. Ann Emerg Med. Nov 1996;28(5):499-503. [Medline].
• Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med. Nov 1999;34(5):646-56. [Medline].

Article Last Updated: Nov 7, 2006