eMedicine Specialties > Pediatrics: General Medicine > Hematology

Methemoglobinemia

Michael J Verive, MD, Medical Director, Pediatric Intensive Care, Department of Pediatrics, St Mary's Hospital for Women and Children
Mudra Kumar, MD, MBBS, MRCP, Associate Professor, Department of Pediatrics, University of South Florida College of Medicine

Updated: Oct 6, 2009

Introduction

Background

Methemoglobinemia is a condition in which the iron within hemoglobin is oxidized from the ferrous (Fe²⁺) state to the ferric (Fe³⁺) state. Because iron needs to be in the ferrous state to allow hemoglobin-to-oxygen binding, methemoglobinemia results in variable degrees of deficiencies of oxygen transport. Clinically, this condition causes cyanosis, often posing a diagnostic dilemma.

Methemoglobinemia in children usually results from exposure to oxidizing substances (such as nitrates or nitrites; aniline dyes; or medications, including lidocaine, prilocaine, phenazopyridine hydrochloride [Pyridium], and others) or is the result of inborn errors of metabolism (especially glucose-6-phosphate dehydrogenase [G6PD] deficiency and cytochrome b5 oxidase deficiency) or severe acidosis, which impairs the function of cytochrome b5 oxidase. This is particularly evident in young infants with diarrhea,¹ in whom excessive stool bicarbonate loss leads to metabolic acidosis, which exacerbates the relatively immature cytochrome b5 oxidase system.

Note the chocolate brown color of methemoglobinemia. Tube 1 and tube 2 have a methemoglobin concentration of 70%; tube 3, a concentration of 20%; and tube 4, a normal concentration.

Pathophysiology

Hemoglobin molecules are tetrameric and contain iron within a porphyrin heme structure. The iron moiety in hemoglobin is normally in the ferrous state (Fe²⁺) in both oxyhemoglobin and deoxyhemoglobin and is capable of reversibly binding with oxygen only in this (ferrous) state. The oxidation of iron to the ferric state (Fe³⁺) results in the formation of methemoglobin, which alters absorption and causes a brownish discoloration of the blood.

In healthy children, the ferric iron in methemoglobin is readily reduced to the ferrous state, primarily through the function of cytochrome b5 oxidase (also referred to as methemoglobin reductase), which is present in erythrocytes and other cells. Patients who are deficient in cytochrome b5 reductase are particularly prone to methemoglobinemia, especially when exposed to oxidizing medications and other chemicals, including nitrates, nitrites, prilocaine and lidocaine, nitric oxide, and aniline dyes. Because methemoglobin is incapable of reversibly binding and transporting oxygen or carrying carbon dioxide, if it is present in significant amounts, methemoglobinemia can result in impaired oxygen delivery to (and carbon dioxide removal from) all tissue beds.

Cyanosis is commonly caused by either an excess of deoxygenated hemoglobin (usually in amounts >5 g/dL) or significant amounts of abnormal hemoglobins such as methemoglobin (>1.5 g/dL) or sulfhemoglobin (>0.5 g/dL), resulting in a grayish-bluish coloration of the skin and mucous membranes. Because the absolute amount of deoxygenated or abnormal hemoglobin (rather than its percentage) is required for cyanosis to be clinically evident, patients with moderate-to-severe anemia may not appear cyanotic, even with elevated percentages of deoxygenated or abnormal hemoglobins.

In healthy individuals, ongoing RBC exposure to various oxidizing agents produces small amounts of methemoglobin; however, the concentration of methemoglobin (as a fraction of total hemoglobin) is maintained below 1% by a reduction enzyme system (mainly cytochrome b5 along with nicotinamide adenine dinucleotide [NADH] reductase), with additional protection provided by other systems, including glutathione reductase and G6PD. Methemoglobinemia occurs if the rate of oxidation is significantly increased and overwhelms the protective and reductive capacities of the cells, if the structure of hemoglobin is altered and is resistant to reduction, or if the rate of reduction of methemoglobin is decreased. Methemoglobinemia may be acquired or congenital.

Acquired methemoglobinemia

Acquired methemoglobinemia is more common than congenital forms. Exposure to oxidant drugs and toxins in amounts that exceed the enzymatic reduction capacity of RBCs precipitates symptoms of methemoglobinemia.²

Acquired methemoglobinemia is more frequent in premature infants and infants younger than 4 months. The following factors may have a role in the higher incidence in this age group:

• Fetal hemoglobin may more easily (auto) oxidize than adult hemoglobin.
• The level of NADH reductase is low at birth and increases with age; it reaches reference range limits by age 4 months.
• Higher gastric pH in infants may facilitate bacterial proliferation, resulting in increased conversion of dietary nitrates to nitrites.
• An association between methemoglobinemia and acute gastroenteritis in infants has been noted in several studies and may be due to acidosis from stool bicarbonate loss impairing the already immature function of the methemoglobin reductase system in these young patients.

Congenital (ie, hereditary) methemoglobinemia

Hereditary methemoglobinemias may be divided into 2 categories: methemoglobinemia due to an altered form of hemoglobin (hemoglobin M) and enzyme deficiency (NADH reductase deficiency) that decreases the rate of reduction of iron in the hemoglobin molecule.³ Four types of hereditary methemoglobinemias are secondary to deficiency of NADH cytochrome b5 reductase. All types are autosomal recessive disorders. Heterozygotes have 50% enzyme activity and no cyanosis. Homozygotes that have elevated methemoglobin levels above 1.5% have clinical cyanosis.

• Type I: This is the most common variant, and the enzyme deficiency is limited to the erythrocytes causing cyanosis.
• Type II: Widespread deficiency of the enzyme occurs in various tissues, including erythrocytes, liver, fibroblasts, and brain. It is associated with severe CNS symptoms, including encephalopathy, microcephaly, hypertonia, athetosis, opisthotonus, strabismus, mental retardation, and growth retardation. Cyanosis is evident at an early age.
• Type III: Although the hemopoietic system (platelets, RBCs, white cells including lymphocytes and granulocytes) is involved, the only clinical consequence is cyanosis.
• Type IV: Similar to type I, this type has isolated involvement of the erythrocytes but results in chronic cyanosis.

Deficiency of nicotinamide adenine dinucleotide phosphate (NADPH)–flavin reductase can also cause methemoglobinemia.

An amino acid substitution in or near the heme pocket affects the heme-globin bond, and the hemoglobin molecule becomes more stable in the oxidized form, resisting reduction. Several variants of hemoglobin M have been described, including hemoglobin Ms, hemoglobin M_Iwate, hemoglobin M_Boston, hemoglobin M_{Hyde Park}, and hemoglobin M_Saskatoon. These are usually autosomal dominant in nature. Alpha chain substitutions cause cyanosis at birth, whereas those in the beta chain become clinically apparent in infants aged 4-6 months.

Frequency

United States

Theexact incidence is unknown.

International

The exact incidence is unknown.

Mortality/Morbidity

Patients with congenital methemoglobinemia are generally asymptomatic other than cyanosis. Life expectancy is normal, unless the methemoglobin level is above 25-40%. Acquired methemoglobinemia is usually mild but may be severe and rarely fatal, depending on the cause. Mild-to-moderate transient methemoglobinemia may be present but may escape clinical detection; a high index of suspicion must be maintained.⁴

Age

Hereditary forms appear early in life. Young infants, especially infants aged 3-4 months, are more susceptible to acquired methemoglobinemia.

Clinical

History

• Congenital methemoglobinemia: The characteristic history is diffuse persistent slate-gray cyanosis, often present from birth, without evidence of cardiopulmonary disease.
• Acquired methemoglobinemia
  • Presentation may be dramatic, with cyanosis, dyspnea, lethargy, headache, dizziness, deterioration of mental functioning, or stupor.
  • History of exposure to a known toxin or drug may not always be available but should be sought because long-term or repeated exposure may occur. 
  • Discussion with a toxicologist may be necessary, especially when methemoglobinemia occurs shortly after exposure to a new medication, because the list of medications known to cause methemoglobinemia constantly changes. A comprehensive review of all medications, herbs, and other nutritional supplements may disclose exposure to a toxin not previously known to cause hemoglobinemia.

Physical

• Congenital methemoglobinemia
  • These patients are described as being more blue than sick.
  • Patients appear cyanotic with a diffuse slate-gray appearance.
  • Cyanosis is easily observed on the nose, cheeks, fingers, toes, and in the mucous membranes, including the fundi, and may go unrecognized for a long time in patients with more heavily pigmented skin or in patients with moderate-to-severe anemia. Clubbing is absent.
  • Methemoglobin levels of 10-20% are tolerated with no clinical symptoms, whereas levels of 30-40% may be associated with headaches and dyspnea, especially upon exertion.
• Patients with hemoglobin M disease with the alpha chain variant can present at birth with cyanosis, whereas patients with the beta chain variants present in the later half of infancy.

Causes

• Acquired methemoglobinemia: Exposure to various drugs or toxins may result in acquired methemoglobinemia. These include the following:
  • Nitrites, particularly in well water (Prepackaged foods [including baby food] may contain significant levels of nitrites.)^5,6
  • Aniline dyes
  • Silver nitrate
  • Nitroprusside
  • Antimalarials
  • Zopiclone⁷
  • Local anesthetics (eg, Benzocaine, prilocaine, and lidocaine), particularly when applied to mucosa, such as during bronchoscopy, or after repeated cutaneous exposure to eutectic mixture of lidocaine-prilocaine (EMLA(R) cream) over a short period of time
  • Nitric and nitrous oxides
  • Dapsone, rasburicase, and phenazopyridine
  • Inadequately cooked vegetables (eg, spinach, beets, carrots) contaminated with bacteria (Infants and patients on gastric acid-reduction therapy are particularly prone to developing methemoglobinemia because gastric acid production may not be sufficient to maintain low levels of nitrate-reducing bacteria in the intestine.)
• Hereditary methemoglobinemia: This may be due to the deficiency of nicotinamide adenine dinucleotide (NADH) cytochrome b5 reductase or NADPH-flavin reductase or the presence of hemoglobin M.

Differential Diagnoses

Acrodermatitis Enteropathica

Other Problems to Be Considered

Pulmonary disease
Cyanotic heart disease (right-to-left shunts)
Hemoglobin variants with altered oxygen affinity
Sulfhemoglobinemia
Chronic/massive blue dye ingestion

Workup

Laboratory Studies

• An arterial blood sample from a patient with methemoglobinemia is characteristically chocolate brown.
  
  

  

  Note the chocolate brown color of methemoglobinemia. Tube 1 and tube 2 have a methemoglobin concentration of 70%; tube 3, a concentration of 20%; and tube 4, a normal concentration.

  
  
  • Blood that is cyanotic or dark in color due to cardiopulmonary disease turns red upon exposure to oxygen, whereas blood with methemoglobin does not.
  • A quick and easy bedside test is to bubble 100% oxygen in a tube that contains the dark blood. Blood that remains dark likely does so because of the presence of methemoglobin.
  • Another simple test (and one that is less likely to splash potentially infectious blood) is to place 1-2 drops of blood on white filter paper, then evaluate for color change upon exposure to oxygen (this test can be accelerated by gently blowing supplemental oxygen onto the filter paper). Deoxygenated hemoglobin changes from dark red or violet to bright red, whereas methemoglobin remains brown.
• Serum methemoglobin levels of more than 1% are considered abnormal, although higher levels are commonly encountered in smokers (and patients with long-term exposure to second-hand smoke). Symptomatic individuals usually have levels of more than 40-50%.
• Serum levels of nitrites or other offending drugs may be determined; however, most of these results are not immediately available, and treatment must not be withheld or delayed pending test results.
• Nicotinamide adenine dinucleotide (NADH) reductase levels should be checked.
• Hemoglobin electrophoresis may be needed to confirm hemoglobin M disease.
• Pulse oximetry may be a useful tool in patient with cyanosis, although its results must be interpreted with caution.
  • The blood is exposed to light using a small probe placed across a capillary bed, usually on a finger or toe. Light wavelengths of 660 nm and 940 nm are used, and the ratio of absorption of light at each of these wavelengths is converted into oxygen saturation using calibration curves.
  • A pulse oximetry reading in a child with respiratory or cardiac disease reflects the degree of hypoxia and is proportionate to the amount of reduced hemoglobin.
  • Methemoglobin increases absorption of light at both wavelengths (more at 940 nm) and, therefore, offers optical interference to the pulse oximetry by falsely absorbing light. This leads to the plateau in the oxygen saturation at 85%.
  • In a patient with methemoglobinemia, the severity of the cyanosis does not correspond to the pulse oximetry reading. The patient may appear extremely cyanotic but have a pulse oximetry reading in the high 80s.
  • In methemoglobinemia, the oxygen saturations (as determined by pulse oximetry) plateau at around 85%; therefore, a patient with a methemoglobin level of 5% and a patient with a methemoglobin level of 40% both have pulse oximetry readings of around 85%.
• Co-oximetry should be performed to evaluate for methemoglobinemia (although some equipment does not differentiate between sulfhemoglobin and methemoglobin).

Imaging Studies

• Chest radiography may be helpful to exclude pulmonary or cardiac disease.
• If needed, use echocardiography to determine the presence of congenital heart disease with right-left (pulmonary-systemic) shunt.

Treatment

Medical Care

Once the diagnosis of methemoglobinemia has been confirmed and appropriate treatment 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 is all that may be necessary. The levels normalize over time unless recurrent or chronic exposure to the offending agent occurs.
• If the methemoglobin levels are more than 30%, methylene blue should be intravenously administered at 1-2 mg/kg (up to 50 mg/dose in adults, adolescents, and older children) as a 1% solution over 5 minutes; repeat in 1 hour, if necessary. Methylene blue is an oxidant at levels of more than 7 mg/kg and, therefore, may cause methemoglobinemia in susceptible patients; thus, care must be taken in administration of this drug. Methylene blue is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because it can lead to severe hemolysis.
• Ascorbic acid is an antioxidant that may also be administered in patients with methemoglobin levels of more than 30%.
• N -acetylcysteine has been shown to reduce methemoglobin in recent studies but is not yet an approved treatment for methemoglobinemia.
• No pharmaceutical treatment for hereditary forms of methemoglobinemia exists. 
  • Oral ascorbic acid (200-500 mg) has been found to be partially effective, if continued on an ongoing basis; however, this therapy has the potential risk of renal stones and hyperoxaluria. Methylene blue has also been used in these patients.
  • In severe cases, exchange transfusion may be necessary.

Consultations

• Consultation with other specialists, such as hematologists, cardiologists, and pulmonologists, may be required to assist in the search for the cause of the methemoglobinemia.

Diet

• Some vegetables (eg, beets, spinach, and carrots) are high in nitrite content and may need to be avoided in susceptible patients.
• Well water can be contaminated with nitrites, nitrates, and oxidants and could lead to methemoglobinemia, especially in small infants (<4 mo) when well water is used to prepare formula or is given alone.

Activity

• No change in activity is indicated.

Medication

Unless the methemoglobinemia is severe or symptomatic, the treatment is purely for cosmetic and/or psychological reasons. Various agents can reduce the methemoglobin levels to within the reference range or to acceptable levels (5-10%). Methylene blue, ascorbic acid, and, rarely, exchange transfusion may be used. N -acetylcysteine has been shown to reduce levels of methemoglobin in studies but is not yet approved for the treatment of methemoglobinemia.

Antidotes

These agents are used in the management of poisoning or overdose to prevent toxic effects or in metabolic disorders in which toxic substances accrue. Mechanisms of action are variable (eg, antagonists, toxin transformation, altered metabolism, chelation, directed antibodies).

Methylene blue (Urolene blue)

Increases the activity of NADH-methemoglobin reductase in RBCs, assisting in the conversion of ferric (Fe³⁺) to ferrous (Fe²⁺) iron.

Dosing

Adult

1-2 mg/kg (up to 25-50 mg/dose) IV as a single dose over 5 min can rapidly reduce the methemoglobin level by approximately 50%
As noted above, methylene blue is an oxidant at doses >7 mg/kg and must be administered with care

Pediatric

Acute cases: 1-2 mg/kg/dose IV over 5 minutes; not to exceed 25-50 mg/dose; may be repeated hourly, not to exceed a cumulative dose of 7 mg/kg
Chronic cases: 100-300 mg PO qd

Interactions

None reported

Contraindications

Documented hypersensitivity; renal insufficiency; G6PD deficiency

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Can cause profound anemia in G6PD deficiency; do not inject into the CNS; secretions, such as urine and feces, may be stained blue to greenish blue; contact with clothing should be avoided; may cause urinary irritation; safety for long-term use has not been established; cumulative doses may lead to dyspnea, chest pain, tremor, cyanosis, and hemolytic anemia; because methylene blue absorbs light in the deoxyhemoglobin range, concurrent pulse oximetry may be unreliable

Ascorbic acid (Vita-C, Cecon, Cevalin)

Antioxidant and coenzyme for reduction. It may be helpful in the treatment of congenital methemoglobinemia if used daily and on a continual basis.

Dosing

Adult

200-500 mg/d PO; some authors recommend using higher doses of up to 1000 mg/d

Pediatric

Administer as in adults

Interactions

High doses (ie, >1 g/d) increase plasma levels of ethinyl estradiol, thus, women who use PO contraceptives may have breakthrough bleeding when the ascorbic acid is discontinued; decreases effects of warfarin and fluphenazine; increases aspirin levels

Contraindications

None known

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Has been shown to lead to nephrolithiasis; very large doses can lead to renal failure; may cause hyperoxaluria; may cause significant hemolysis with G6PD deficiency

Follow-up

Further Inpatient Care

• Acquired methemoglobinemia: The underlying cause should be identified, and measures should be instituted to avoid further exposure of the patient to precipitating causes.
• Hereditary methemoglobinemia: Methemoglobin levels and adverse effects of medication should be monitored on an ongoing basis.
  

Further Outpatient Care

• Once the treatment has been instituted for acquired methemoglobinemia, identification and removal of the precipitating cause is all that is necessary, with instruction to avoid future exposure to the precipitating agent (and related agents).
• If treatment is indicated on an ongoing basis, as in some cases of congenital methemoglobinemia, patients should be observed for effect and toxicity. Both methylene blue and ascorbic acid have been used for this purpose.

Inpatient & Outpatient Medications

• See Medication and Further Outpatient Care.

Transfer

• The most important step in management is recognition of this entity without subjecting the patient to extensive and invasive studies for cardiopulmonary conditions.
• Once the diagnosis is established, management should be instituted as indicated.

Deterrence/Prevention

• Recognition and avoidance of precipitating factors (such as ingestion of nitrate-contaminated water and exposure to oxidizing medications) are important, especially in susceptible populations.

Patient Education

• Patients with both congenital and acquired methemoglobinemia should receive instruction regarding avoidance of precipitating factors.
• Patients receiving therapy for chronic methemoglobinemia should receive balanced information regarding the risks and benefits expected with treatment.

Miscellaneous

Medicolegal Pitfalls

• The most important issue is recognition and prompt treatment, if indicated, especially in acquired methemoglobinemia and before institution of extensive and invasive investigations to rule out cardiac and pulmonary abnormalities that result in a similar clinical picture of cyanosis.
• Reliance on pulse oximetry rather than co-oximetry can lead to falsely elevated estimation of oxyhemoglobin concentrations in the setting of methemoglobinemia and related dyshemoglobinemias.
• Failure to identify patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to treatment with methylene blue predisposes them to risk of hemolytic anemia.
• Overtreatment with methylene blue (>7 mg/kg cumulative dose) can produce methemoglobinemia.

Special Concerns

• In congenital cases, genetic counseling is important. Treatment in type II cases does not prevent or reverse CNS progression.

Multimedia

Media file 1: Note the chocolate brown color of methemoglobinemia. Tube 1 and tube 2 have a methemoglobin concentration of 70%; tube 3, a concentration of 20%; and tube 4, a normal concentration.

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Keywords

methemoglobinemia, methemoglobin, cyanosis, glucose-6-phosphate dehydrogenase deficiency, cytochrome b5 oxidase deficiency, acquired methemoglobinemia, congenital methemoglobinemia, encephalopathy, microcephaly, hypertonia, athetosis, opisthotonus, strabismus, mental retardation, growth retardation, diagnosis, treatment

Contributor Information and Disclosures

Author

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, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Mudra Kumar, MD, MBBS, MRCP, Associate Professor, Department of Pediatrics, University of South Florida College of Medicine
Mudra Kumar, MD, MBBS, MRCP is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, 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.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida; Clinical Professor, Department of Pediatrics, University of North Carolina; Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
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.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Mudra Kumar, MD, MBBS, MRCP, to the original writing and development of this article.

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