Risk Factors for Acquired Methemoglobinemia


Hereditary/Congenital Methemoglobinemia

Hemoglobin M Disease

  • General Comments
    • Usually Autosomal Dominant
  • Hb Ms
  • Hb MIwate
  • Hb MBoston
  • Hb MHyde Park
  • Hb MSaskatoon

Hemoglobin E Disease

  • Hb E β-Thalassemia Patients Have Been Demonstrated to Have Increased Methemoglobin Levels

NADH Cytochrome b5 Reductase (cyb5R) Deficiency

  • General Comments
    • Epidemiology
      • Autosomal Recessive
    • Physiology
      • Decreased Enzymatic Reduction of Methemoglobin Back to Normal Hemoglobin
  • Type I Cytochrome b5 Reductase (cyb5R) Deficiency
    • *Most Common Type (Represents 85-90% of Cases)
    • Endemic in Specific Native American tribes (Navajo, Athabaskan Alaskans) and Yakutsk People of Siberia
    • Physiology
      • Cytochrome b5 Reductase (cyb5R) Deficiency is Limited to Red Blood Cells
  • Type II Cytochrome b5 Reductase (cyb5R) Deficiency: represents 10-15% of cases
    • Physiology
      • Cytochrome b5 Reductase (cyb5R) Deficiency in Multiple Tissues (Including Red Blood Cells, Liver, Fibroblasts, and Brain)
    • Clinical
      • Cyanosis (see Cyanosis): evident at an early age
      • Severe Central Nervous Symptoms
        • Athetosis
        • Encephalopathy
        • Growth Retardation
        • Hypertonia
        • Microcephaly
        • Opisthotonos (see Opisthotonos)
        • Strabismus (see Strabismus)
        • Mental Retardation
  • Type III Cytochrome b5 Reductase (cyb5R) Deficiency
    • Physiology
      • Cytochrome b5 Reductase (cyb5R) Deficiency in Red Blood Cells, White Blood Cells, and Platelets
    • Clinical
      • Cyanosis (see Cyanosis): only clinical symptom
  • Type IV Cytochrome b5 Reductase (cyb5R) Deficiency
    • Phsyiology
      • Cytochrome b5 Reductase (cyb5R) Deficiency is Limited to Red Blood Cells
    • Clinical
      • Cyanosis (see Cyanosis): only clinical symptom

NADPH-Flavin Reductase Deficiency

  • Epidemiology
    • May Also Cause Methemoglobinemia

Cytochrome b5 Deficiency

  • Epidemiology
    • Rare


  • General Comments
    • While Skin/Mucosal Breaches May Increase the Absorption of Anesthetic Agents, MethemoglobinemiaMay Occur Due to Either a Previously-Undiagnosed Methemoglobin Reductase Enzyme Deficiency or Idiosyncratic Toxicity
  • Benzocaine (see Benzocaine)
    • Epidemiology
      • Common Etiology
      • Benzocaine Has Been Widely Used in Over-the-Counter Products Sold for Relief of Pain Asssociated with Infant Teething
      • Incidence of Methemoglobinemia When Using Benzocaine During Transesophageal Echocardiogram (TEE) Has Been Reported to Be 1:1000 Cases
        • In TEE-Associated Cases, Active Infection and Anemia Appear to Increase the Risk of Methemoglobinemia
    • Physiology
      • Unclear Mechanism, as prior/subsequent benzocaine exposure may not elicit methemoglobinemia in affected patients
    • Clinical
      • Severe Methemoglobinemia May Occur
  • Bupivicaine (see Bupivicaine)
    • Epidemiology
      • Common Etiology
  • Cetacaine (see Cetacaine)
    • Epidemiology
      • Common Etiology
  • Lidocaine (see Lidocaine)
    • Epidemiology
      • Common Etiology
  • Prilocaine
    • Epidemiology
      • Common Etiology

Nitrites and Nitrates (see Nitrites and Nitrates)

  • Amyl Nitrite (see Amyl Nitrite)
  • Cerium Nitrate
  • Farryl Nitrite
  • Ingestion of High Nitrite/Nitrate Foods
    • Associated Foods
      • Beets
      • Borage
      • Carrots
      • Chard
      • Spinach
  • Ingestion of Nitrite-Contaminated Well Water
    • Epidemiology
      • Cases Have Been Reported Where Well Water Has Been Contaminated by Nitrite Runoff from Fertilized Farm Fields
  • Ingestion of Nitrites in Packaged Foods
  • Inhaled Nitric Oxide (iNO) (see Nitric Oxide)
    • Epidemiology
      • However, in Clinical Trials of iNO in ARDS, Clinically SignificantMethemoglobinemia was Not Observed
  • Isobutyl Nitrite (Inhaled “Rush”, “Poppers”) (see Isobutyl Nitrite)
  • Isosorbide Dinitrate (see Isosorbide)
  • Methyl Nitrite
  • Nitroglycerin (see Nitroglycerin)
  • Nitroprusside (Nipride) (see Nitroprusside)
  • Silver Nitrate (see Silver Nitrate)
  • Sodium Nitrite (see Sodium Nitrite)


Antineoplastic Agents

  • 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (Triapine)
    • Physiology
      • Ribonucleotide Reductase Inhibitor
  • Cyclophosphamide (Cytoxan) (see Cyclophosphamide)
    • Physiology
      • XXXXXX
  • Flutamide (Eulexin) (see Flutamide)
    • Physiology
      • XXXXXXX
  • Ifosfamide (Ifex) (see Ifosfamide)
    • Physiology
      • Due to Interaction Between 4-Thiofosfamide Metabolite and Glutathione, Resulting in Oxidative Stress

Other Drugs/Toxins

  • 2,4-Dinitrophenol
    • Epidemiology
      • Used as a Weight Loss Agent
  • Acetaminophen (Tylenol) (see Acetaminophen)
    • Physiology
      • XXXX
  • Acetanilide (Acetanilid, Antifebrin) (see Acetanilide)
    • Epidemiology
      • Used in the Manufacture of Sulfa Drugs, Rubbers, Dyes, and Camphor, etc
      • Previously Used Medicinally (Acetaminophen is a Metabolite of Acetanilide)
  • Ammonium Carbonate
    • Epidemiology
      • Used in Smelling Salts
  • Benzene Derivatives
    • Aniline/Aniline Dyes/Aniline Derivatives (Aminophenol, Phenylhydroxylamine)
    • Naphthalene (see Naphthalene
      • Epidemiology
        • Used in Moth Balls
    • Nitrobenzene
      • Physiology
        • Precursor to Aniline
    • Resorcinol
  • Bromates (see Bromates)
    • Epidemiology
      • Bromates (Sodium Bromate, Potassium Bromate) Can Be Present as Municipal Water Contaminants
        • Bromate in Drinking Water is a Suspected Human Carcinogen
        • Presence or Bromates in Coca-Cola’s Dasani Bottled Water Forced a Recall of that Product in the United Kingdom in 2004
  • Chlorates
    • Epidemiology
      • Chlorates are Oxidizers Which are Found in Matches, Explosives, and Fungicides
        • However, Most Pyrotechnic Applications that Formerly Used Chlorates Now Use the More Stable Perchlorates Instead
  • Clofazimine (see Clofazimine)
  • Cocaine (see Cocaine)
  • Copper Sulfate
  • Curcumin (see Turmeric)
    • Epidemiology
      • The Main Curcuminoid in Turmeric Has Been Demonstrated to Cause Methemoglobinemia in Rats Treated with Dapsone (see Dapsone)
  • Dapsone (see Dapsone)
    • Epidemiology
      • Dapsone is a Well-Documented Etiology of Methemoglobinemia (Liver Transpl Surg, 1997) [MEDLINE] (Pharmacother, 1998) [MEDLINE] (Pharmacother, 2011) [MEDLINE] (Intern Med, 2015) [MEDLINE] (Cureus, 2021) [MEDLINE]
      • Methemoglobinemia is Known to Occur More Frequently with Dapsone Doses >200 mg/day (and Dapsone-Induced Development of Methemoglobinemia is Dose-Dependent)
    • Induction of Dapsone Tolerance
      • Cimetidine May Be Used to Chronically Enhance Dapsone Tolerance, as it is a Selective Inhibitor of N-Hydroxylation and Chronically Lowers Methemoglobin Levels by >25% (see Cimetidine)
  • Ingestion of Fava Beans in a Patient with G6PD Deficiency (see Favism)
  • Herbicides/Pesticides
    • Aluminum Phosphide
    • Indoxacarb
    • Paraquat (Dipyridylium) (see Paraquat)
  • Indigo Carmine (see Indigo Carmine)
    • Epidemiology
      • Indigo Carmine is an Intravenous Dye Used During Urologic Surgery
        • It is Rapidly Filtered by the Kidneys and Turns the Urine Blue
  • Menadione (“Vitamin K3”) (see Menadione)
    • Physiology
      • Nutritional Supplement (Which is an Analog of 1,4-Naphthoquinone)
  • Methylene Blue (see Methylene Blue)
    • Physiology
      • At High Doses, Methylene Blue Functions as an Oxidant: it can cause acute hemolysis in patients with G6PD deficiency -> further decreasing oxygen delivery
      • At High Doses, Methylene Blue Can also Paradoxically Cause Methemoglobinemia
  • Metoclopramide (Reglan) (see Metoclopramide)
    • Epidemiology
      • XXXXXX
  • Naphthoquinone
    • Epidemiology
      • Plants with Compounds Derived from Naphthoquinone are Used in China and South America for their Medicinal Properties
  • Nitroethane (see Nitroethane)
    • Epidemiology
      • Used in Nail Polish Remover
  • Nitrofurans
    • General Comments
      • Nitrofurans are Used as Antimicrobials
    • Furazolidone
    • Furylfuramide
    • Nifuratel
    • Nifuroxazide
    • Nifurquinazol
    • Nifurtimox
    • Nifurtoinol
    • Nifurzide
    • Nitrofurantoin (Macrodantin) (see Nitrofurantoin)
    • Nitrofurazone
    • Ranbezolid
  • P-Aminosalicylic Acid
  • Phenacetin (see Phenacetin)
  • Phenazopyridine (Pyridium) (see Phenazopyridine)
  • Phenylamine
    • Epidemiology
      • Psychoactive Stimulant Used as a Recreational Drug
  • Rasburicase (Elitek) (see Rasburicase)
    • Epidemiology
      • Cases of Combined Oxidative Hemolysis and Methemoglobinemia Have Been Reported with the Use of Rasburicase in the Setting of G6PD Deficiency (Acta Haematol, 2013) [MEDLINE] (see Glucose-6-Phosphate Dehydrogenase Deficiency)
      • Cases of Methemoglobinemia Have Been Reported with the Use of Rasburicase in the Setting of G6PD Deficiency (Eur J Haematol, 2015) [MEDLINE] (see Glucose-6-Phosphate Dehydrogenase Deficiency)
      • Patients with Low Inherited or Acquired Catalase Activity May Be at Risk for Methemoglobinemia After Rasburicase Administration (Due to the Formation of Hydrogen Peroxide)
        • Some Experts Recommend the Measurement of Catalase Activity Before Administering Rasburicase
  • Smoke Inhalation (see Smoke Inhalation)
    • Physiology
      • Due to Inhalational Exposure to Oxidants
  • Sodium Chlorite (see Sodium Chlorite)
  • Sulfonamides (see Sulfonamides)
  • Toxic Mushrooms (see Toxic Mushrooms)
    • Epidemiology
      • Associated with Gyromitrin-Containing Mushrooms
        • Cyathipodia Macropus
        • Gyromitra Esculenta
        • Gyromitra Infula
        • Sarcosphaera Coronaria
    • Clinical
  • Zopiclone (Imovane, Zimovane) (see Zopiclone)

Miscellaneous Other Conditions

  • Cirrhosis (see Cirrhosis)
    • Physiology
      • Red Blood Cells in Cirrhotic Patients Undergo Severe Oxidative Stress, Especially in the Setting of Bleeding Complications
      • Levels of Methemoglobin are Significantly Higher in the Red Blood Cells of Bleeding Cirrhotics than in Non-Bleeding Cirrhotics (Indian J Med Res, 2007) [MEDLINE]
  • Post-Splenectomy (see Splenectomy)
    • Epidemiology
      • Increased Methemoglobin Levels Have Been Observed in Patients Following Splenectomy
  • Sepsis (see Sepsis)
    • Epidemiology
      • Methemoglobin Levels May Increase in Sepsis (Acta Anaesthesiol Scand, 1998) [MEDLINE]
    • Physiology
      • May Be Related to the Synthesis of Nitric Oxide Which Occurs in Sepsis: nitric oxide is converted to methemoglobin and nitrate


Normal Physiologic Conversion of Hemoglobin to Methemoglobin

  • As Part of Normal Physiology, Iron within Hemoglobin is Normally Auto-Oxidized at a Low Rate of 0.5-3.0% Per Day from its Ferrous (Fe2+) State (i.e. within Hemoglobin) to a Ferric (Fe3+) State (i.e. within Methemoglobin)
    • Consequently, Methemoglobin Levels of <1-3% are Considered Normal
  • Two Potential Chemical Mechanisms Exist to Reduce Methemoglobin Back to Hemoglobin
    • NADH-Dependent Reaction Catalyzed by Cytochrome b5 Reductase (b5R)
      • This is the Only Physiologically Important Mechanism Under Normal Conditions (Accounting for Clearance of 95-99% of the Methemoglobin That is Produced Under Normal Circumstances)
    • Generation of NADPH by Glucose-6-Phosphate Dehydrogenase (G6PD) in the Hexose Monophosphate Shunt within the Red Blood Cell
      • This Mechanism is Not Natively Physiologically Active, as it Requires an Extrinsically-Administered Electron Acceptor (Such as Methylene Blue and Riboflavin)
      • This Mechanism Becomes Important in the Treatment of Methemoglobinemia as Methylene Blue Accelerates the NADPH-Dependent Methemoglobin Reduction Pathway
      • Note: G6PD Deficiency is a Risk Factor for Acquired Methemoglobinemia

Pathophysiology in the Setting of Methemoglobinemia

  • Oxidation of Iron in Hemoglobin from the Ferrous (Fe2+) to the Ferric (Fe3+) State
    • Ferric Hemes of Methemoglobin are Unable to Bind Oxygen and Therefore, Result in a “Functional Anemia” with Decreased Oxygen Delivery to Tissues
    • Left-Shifting of the Hemoglobin Dissociation Curve (see Hypoxemia)
      • While the Ferric Heme is Unable to Bind Oxygen, the Remaining Three Ferrous Hemes in the Hemoglobin Tetramer Have Increased Avidity for Oxygen, Resulting in Impaired Oxygen Unloading at the Tissues (Exacerbating Tissue Hypoxia)

Predisposition of Premature Neonates and Infants to Methemoglobinemia

  • Factors Increasing the Risk of Methemoglobinemia in Premature Neonates/Infants <4 mo of Age
    • Propensity of Fetal Hemoglobin to More Easily Oxidize than Adult Hemoglobin
    • Low Levels of NADH Reductase at Birth
      • NADH Reducase Levels Increase to Adult Levels by 4 mo of Age
    • Higher Gastric pH with Increased Bacterial Conversion of Dietary Nitrates to Nitrites
    • Association of Methemoglobinemia with Gastroenteritis Illnesses in Ifants
      • This May Be Related to Increased Stool Loss of Bicarbonate


Pulse Oximetry (see Pulse Oximetry)

Principles of Pulse Oximetry

  • Pulse Oximeter Only Measures the Relative Absorbance of 2 Light Wavelengths (660 nm and 940 nm) to Differentiate Oxyhemoglobin from Deoxyhemoglobin
    • Methemoglobin Increases the Absorption of Both Light Wavelengths (Although More So at 940 nm), Optically Interfering with the Pulse Oximetry Measurement
  • Newer Generation Multi-Wavelength Pulse Oximeters are in Development

Methemoglobinemia Results in Interference with the Pulse Oximetry Measurement, Causing Inaccurate Readings

  • Decreased SpO2 on the Pulse Oximeter
    • When Methemoglobin is <30%
      • Pulse Oximetry Will Overestimate the Percentage of Oxyhemoglobin in Presence of Methemoglobin by an Amount Roughly Equal to 50% of the Amount of Methemoglobin Present
      • In the Presence of 20% Methemoglobin and a SpO2 90%, Percentage of Oxyhemoglobin Will Be About 80%
    • When Methemoglobin is >30%
      • Pulse Oximetry Will Plateau at About 85%
    • Note that Severity of the Cyanosis Does Not Correspond to the Pulse Oximetry Reading

Arterial Blood Gas (ABG) (see Arterial Blood Gas)

  • Appearance of Blood in ABG Syringe
    • Chocolate or Brown-Blue Color
  • Arterial pO2 (from the Arterial Blood Gas)
    • Normal
    • Note that the Arterial pO2 Reflects the Plasma Oxygen Content and Does Not Reflect the Oxygen-Carrying Capacity of Hemoglobin

Methods to Determine the SaO2 from an Arterial Blood Gas Sample

  • General Comments
    • It is Critical to Know Which Device is Being Used by Your Specific Laboratory to Report the SaO2, Since the Presence of Dyshemoglobinemias Can Lead to Misinterpretation of the Data
Blood Gas Analyzer without Co-Oximetry
  • Principle: pO2 is measured by the analyzer and the SaO2 is calculated using a standard equation
    • Technical Issues
      • Blood Gas Analyzer Uses a Calculated or Default Hemoglobin Value
      • Blood Gas Analyzer Assumes a Normal Hemoglobin Value and the Absence of Dyshemoglobinemias (Such as Methemoglobin, Carboxyhemoglobin, Sulfhemoglobin)
  • Clinical Scenarios
    • Methemoglobinemia (see Methemoglobinemia): pO2 and (calculated) SaO2 will both be reported as normal
Functional Hemoglobin Saturation from Simple Co-Oximetry
  • Principle: determination of SaO2 utilizing measurement of oxyhemoglobin (O2Hb) and deoxyHb (DeO2Hb) only
    • Equation: Total Hemoglobin = O2Hb + DeO2Hb + MetHb + COHb + SulfHb
    • Equation: SaO2 = O2Hb/O2Hb + DeO2Hb
Fractional Oxygen Saturation Method from Co-Oximetry (Fractional Oxyhemoglobin, FO2Hb)
  • Principle
    • Determination Utilizing Oxyhemoglobin (O2Hb) and Total Hemoglobin
    • Equation: Total Hemoglobin = O2Hb + DeO2Hb + MetHb + COHb + SulfHb
    • Equation: FO2Hb = O2Hb/Total Hb
    • FO2Hb is Usually Expressed as a Percentage
      • Typically Ranges from 90-95% in Healthy Normals
  • Clinical Scenarios
    • Methemoglobinemia (see Methemoglobinemia): the reported FO2Hb will be considerably lower than the SaO2 reported by the blood gas analyzer

Co-Oximetry on Arterial Blood Gas (ABG) Sample

  • Principle
    • Co-Oximeter is a Simplified Spectrophotometer Which Measures Light Absorbance at Various Different Wavelengths of Light
    • Early Co-Oximeters Were Capable of Measuring Light Absorbance at Four Wavelengths of Light
    • Modern Co-Oximeters (Continuous Wave Spectrophotometers) are Capable of Measuring Absorbance at >100 Different Wavelengths of Light
      • Additional Wavelengths Improve Accuracy, Minimize Artifacts from Interfering Substances, and Enable Reporting of Additional Components
    • More Complex Modern Co-Oximetry Devices Can Measure Absorbance at 128 Wavelengths, Allowing Determination of Total Hemoglobin Concentration, SaO2, Fractional Oxyhemoglobin, and Fractional Carboxyhemoglobin, Fractional Methemoglobin, and Fractional Sulfhemoglobin
  • Hemoglobin Species Detected by Co-Oximetry Devices
    • Oxyhemoglobin
    • Deoxyhemoglobin
    • Carboxyhemoglobin
    • Methemoglobin: peak absorbance at 630 nm
    • Sulfhemoglobin: peak absorbance at 614 nm (overlaps to 630 nm and may be reported as methemoglobin on older machines)
  • Normal Range of Methemoglobin: <1-3%
    • Clinical Symptoms are Correlated with the Percentage of Methemoglobin Present (See Below)
  • Etiology of False-Positive Results by Co-Oximetry
  • Etiology of Inaccurate Results with Co-Oximetry
    • Use of Blood Substitute

Evelyn-Malloy Assay of Methemoglobin

  • Technique
    • Addition of Cyanide, Which Binds to Positively Charged Methemoglobin: eliminates the peak at 630-635 nm
    • Subsequent Addition of Ferricyanide: converts entire specimen to cyanomethemoglobin, which then allows measurement of total hemoglobin concentration
  • Specificity: Evelyn-Malloy assay is more specific than co-oximetry for detection of methemoglobin
  • Clinical Utility: Evelyn-Malloy assay is a good confirmatory test and is especially useful after methylene blue administration

Potassium Cyanide Test

  • Distinguishes Between Methemoglobin and Sulfhemoglobin
    • Methemoglobin reacts with cyanide to form cyanomethemoglobin: bright red color change
    • Sulfhemoglobin does not react with cyanide: lack of bright red color change

Drop Test

  • Technique: place 1-2 drops of blood onto white filter paper -> in the presence of significant methemoglobinemia, blood will remain dark (ie: will not oxygenate as normal blood would)
    • May accelerate process by gently blowing 100% onto the blood drop on the filter paper

Aeration of Tube of Blood with 100% Oxygen

  • Technique: bubble 100% oxygen through blood -> in the presence of significant methemoglobinemia, blood will remain dark (ie: will not oxygenate as normal blood would)

Hemoglobin Electrophoresis (see Hemoglobin Electrophoresis)

  • May Be Used to Identify Hemoglobin M

Clinical Manifestations of Congenital Methemoglobinemia

Type I Cytochrome b5 Reductase Deficiency-Related Methemoglobinemia

  • General Comments
    • Functional Deficiency of Cytochrome b5 Reductase is Limited to Red Blood Cells
    • Methemoglobin Level: usually 10-35%
  • Asymptomatic Cyanosis (see Cyanosis)
    • Usually the Only Clinical Manifestation and is Often Present from Birth
    • Cyanosis is Clinically Apparent when Methemoglobin Levels Exceed 8-12% (at a Normal Hemoglobin Concentration)
      • Equivalent to >1.5 g/dL
  • Polycythemia (see Polycythemia)
    • Rarely Observed

Type II Cytochrome b5 Reductase Deficiency-Related Methemoglobinemia

  • General Comments: cytochrome b5 reductase is deficient in all cells
  • Cyanosis (see Cyanosis)
    • Often Present from Birth
  • Developmental Abnormalities
  • Mental Retardation
  • Death Within First Year of Life

Clinical Manifestations of Acquired Methemoglobinemia

General Comments

Relationship of Clinical Symptoms to Methemoglobin Level

Influence of Heterozygous State for Cytochrome b5R Deficiency

  • Although Patients Heterozygous for Cytochrome b5R Deficiency May Develop Methemoglobinemia More Readily than Normals, Most Acquired Methemoglobinemia Cases Occur in Patients Who are Not Heterozygous for Cytochrome b5R Deficiency

Influence of Anemia (see Anemia)

  • The Clinical Symptoms of Methemoglobinemia are Exacerbated in the Presence of Anemia

Cardiovascular Manifestations


Shock (see Hypotension)

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX

Syncope (see Syncope)

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX

Neurologic Manifestations

Altered Mental Status

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX
  • Clinical

Dizziness (see Dizziness)

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX

Fatigue (see Fatigue)

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX

Generalized Weakness (see Weakness)

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX

Headache (see Headache)

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX

Seizures (see Seizures)

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX

Pulmonary Manifestations

Appearance of Chocolate-Brown Blood in the Bronchoscopic Field of View (see Bronchoscopy)

  • Epidemiology
    • May Be Observed in Cases that Occur During Bronchoscopy (or During Other Videoscopic Procedures)

Cyanosis Accompanied by Decreased Pulse Oximetry SpO2 and a Normal Arterial Blood Gas SaO2 and pO2 (see Cyanosis)

  • Physiology
    • This Constellation of Findings Reflects the Dysfunction of the Pulse Oximeter Caused the Presence of the Methemoglobin
      • XXXXXX
  • Clinical
    • Bluish-Brown Coloration of Skin and Mucous Membranes
    • Cyanosis is Clinically Apparent at Methemoglobin Level >8-12% (at a Normal Hemoglobin Concentration): equivalent to >1.5 g/dL
      • Note: in Contrast, a Deoxyhemoglobin Level of 5 g/dL is Required to Produce Clinical Cyanosis
      • In Patients with Severe Anemia, a Higher Percentage of Methemoglobin is Required for Cyanosis to Be Clinically Apparent
        • These Patients are More Likely to Exhibit Signs of Hypoxemia and Have Lesser Degrees of Cyanosis, as Compared to Non-Anemic Patients
        • The Clinical Symptoms of Methemoglobinemia are Exacerbated in the Presence of Anemia
  • Management
    • Lack of Response of Cyanosis to Supplemental Oxygen (in the Absence of Cardiopulmonary Disease) is a Hallmark of Methemoglobinemia
      • While Cyanosis in Most Pulmonary Diseases Will Respond to Supplemental Oxygen, Cyanosis in Cardiac Disease with a Right-to-Left Intracardiac Shunt Usually Does Not Respond to Supplemental Oxygen Administration

Dyspnea/Respiratory Distress (see Dyspnea)

  • Epidemiology
    • XXXX
  • Physiology
    • XXXX

Renal Manifestations

Lactic Acidosis (see Lactic Acidosis)

  • Epidemiology
    • Lactic Acidosis May Occur (J Pediatr, 1982) [MEDLINE]
  • Physiology
    • Due to Tissue Hypoxia


Treatment of Congenital Methemoglobinemia

  • Ascorbic Acid (Vitamin C) (see Vitamin C)
    • May Cosmetically Decrease Cyanosis
  • Riboflavin (Vitamin B2) (see Vitamin B2)
    • May Cosmetically Decrease Cyanosis
  • Methylene Blue (see Methylene Blue)
    • May Cosmetically Decrease Cyanosis

Treatment of Hemoglobin M Disease-Associated Methemoglobinemia

  • No Effective Treatment

Treatment of Acquired Methemoglobinemia

Withdraw or Avoid the Drug/Offending Agent

  • Recommended Measures
    • Withdrawal/Avoidance Alone May Be Adequate in an Asymptomatic Patient with Methemoglobin <20%
    • Dietary Avoidance of Orally Ingested Precipitant Agents
    • Removal of Clothing Which May Contain the Offending Agent

Supplemental Oxygen (see Oxygen)

  • Rationale
    • Oxygen is Critical to Treat Tissue Hypoxia in the Ssetting of Methemoglobinemia

Dextrose-Containing Intravenous (IV) Fluid

  • Rationale
    • The NADPH-Dependent Methemoglobin Reductase Enzyme System Requires Glucose for the Clearance of Methemoglobin

Correction of Metabolic Acidosis

  • Sodium Bicarbonate (see Sodium Bicarbonate)
    • Sodium Bicarbonate May Be Necessary in Some Cases (Especially in Those Involving Infants)

Methylene Blue (see Methylene Blue)

  • Pharmacology
    • Methylene Blue Reduces Methemoglobin (By Serving as an Artificial Electron Transporter) Via an NADPH-Dependent Pathway
  • Indications
    • General Comments
      • Methylene Blue is Considered the Preferred Treatment for Patients with the Appropriate Indications
    • Hypoxic Symptoms (see Hypoxemia and Respiratory Failure)
    • Methemoglobin >20-30%
      • These Levels are Considered Life-Threatening
    • Methemoglobin 10% In Setting of Significant Co-Morbid Disease or End-Organ Dysfunction (Cardiac Ischemia, etc)
      • Treatment of This Group Should Be Considered
  • Contraindications
    • Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency (see Glucose-6-Phosphate Dehydrogenase Deficiency)
      • G6PD Deficiency is Found in African-Americans, Mediterranean Descent, and Southeast Asians
      • Methylene Blue is Ineffective in Patients with G6PD Deficiency (Since it Requires NADPH Generated by G6PD)
      • Patients with G6PD Deficiency are at High Risk for Hemolysis After Methylene Blue Administration
    • Use of Other Serotonergic Agents (see Serotonin Syndrome)
      • Methylene Blue Functions as a Reversible Monoamine Oxidase (MAO) Inhibitor (see Monoamine Oxidase Inhibitors): in the setting of other serotonergic agents, methylene blue may preceipitate the serotonin syndrome
      • FDA Alert (7/26/11): avoid use of methylene blue in conjunction with selective serotonin reuptake inhibitors (SSRI’s) (see Selective Serotonin Reuptake Inhibitors)
    • Hemoglobin M Disease
    • NADPH Methemoglobin Reductase (Diaphorase II) Deficiency
    • Sulfhemoglobinemia (see Sulfhemoglobinemia)
  • Administration
    • Dose: 1-2 mL/kg (of 1% solution) IV over 5 min
    • Latency
      • Resolution Typically Occurs within 1 hr (Often within 20 min)
    • Re-Treatment
      • Treatment Can Be Repeated in 1 hr if the Methemoglobin Level Remains Elevated
    • Serial Monitoring of Methemoglobin Level (by Evans-Malloy Method) is Recommended Due to Prolonged Absorption of the Offending Drug from Topical Sites/Gastrointestinal Tract
      • Co-Oximetry Cannot Be Used to Follow Serial Methemoglobin Levels After Methylene Blue Dosing Since Methylene Blue is Erroneously “Read” as Methemoglobin
      • Some Cases May Manifest Significant Rebound Methemoglobinemia Up to 18 hrs Later
      • Dapsone Undergoes Enterohepatic Recirculation (see Dapsone): re-treatment may be necessary in some cases
  • Adverse Effects/Cautions
    • Blue Discoloration of Skin After Administration (see Cyanosis)
      • Methylene Blue Can Impart a Blue Discoloration to the Skin After Administration, This Does Not Imply Treatment Failure
    • Excessive Dosing
      • Cumulative Methylene Blue Doses >7 mg/kg Can Result in Hemolysis, Dyspnea, and Chest Pain
    • Interference with Pulse Oximetry (see Pulse Oximetry)
      • Since Methylene Blue Interferes with Subsequent Pulse Oximetry, Must Not Rely on an Improving SpO2 (by Pulse Oximetry) as a Marker for Successful Treatment
    • Serotonin Syndrome (see Serotonin Syndrome)

Ascorbic Acid (Vitamin C) (see Vitamin C)

  • Indication
  • Administration
    • Dose: moderate dose 300-1000 mg/day in divided doses
    • Avoid High Doses, as Ascorbic Acid May Cause Oxidant Hemolysis in G6PD Deficient Patients

Hyperbaric Oxygen (see Hyperbaric Oxygen)

  • Technique
    • Permits Tissue Oxygenation to Occur Through Oxygen Dissolved in Plasma, Rather Than Through Hemoglobin-Bound Oxygen
  • Indications
    • Methemoglobinemia with Either Resistance to Methylene Blue or Contraindications to Its Use

Packed Red Blood Cell (PRBC) Transfusion/Exchange Transfusion (see Packed Red Blood Cells)

  • Indications
    • Methemoglobinemia with Either Resistance to Methylene Blue or Contraindications to Its Use

Other Agents

  • Cimetidine (Tagamet) (see Cimetidine)
    • May Be Used in the Setting of Dapsone to Increase Tolerance to this Agent
  • N-Acetylcysteine (Mucomyst, Acetadote, Fluimucil, Parvolex) (see N-Acetylcysteine)
    • Although N-Acetylcysteine Has Been Effective in Some Studies, it is Not Currently Approved for the Treatment of Methemoglobinemia
  • Riboflavin (Vitamin B2) (see Vitamin B2)