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DESCRIPTION
- Methemoglobin is hemoglobin in which the iron molecule has been oxidized from the normal ferrous state (Fe2+) to the ferric state (Fe3+).
- Methemoglobinemia is the clinical condition in which more than the normal amount of hemoglobin (2%) has been oxidized.
PATHOPHYSIOLOGY
- Under normal conditions, the methemoglobin level is less than 2%.
- A methemoglobin molecule cannot carry oxygen.
- Methemoglobin also increases the affinity of normal hemoglobin for oxygen, shifting the oxygen hemoglobin dissociation curve to the left, which results in reduced ability of normal hemoglobin to release oxygen; this reduces oxygen delivery to the tissues.
- Normally, the enzyme NADH methemoglobin reductase reduces methemoglobin back to hemoglobin; however, when large amounts of methemoglobin are produced, this pathway is overwhelmed.
- Another enzyme, NADPH methemoglobin reductase, also reduces a small amount of methemoglobin under normal conditions; unlike NADH methemoglobin reductase, this enzyme system can be accelerated when supplied with an exogenous electron carrier, such as methylene blue.
- Elevated methemoglobin levels can be produced by oxidizing agents, hemoglobin M (heterozygous), deficiency of NADH or NADPH methemoglobin reductase, and by oxidative stress in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
EPIDEMIOLOGY
- Poisoning is uncommon.
- Toxic effects are typically mild to moderate.
- There is a higher incidence of comorbid diseases in the elderly population that may increase methemoglobin toxicity.
- Death is unusual, occurring in untreated cases with methemoglobin levels greater than 70%.
CAUSES
Most cases are secondary to adverse medication reaction, therapeutic misadventure, or recreational abuse of amyl nitrites ("poppers").
RISK FACTORS
- The heterozygous form of hemoglobin M, deficiencies in NADPH or NADH methemoglobin reductase, and G6PD deficiency may lead to methemoglobinemia.
- Fetal hemoglobin is oxidized to methemoglobin more easily than normal hemoglobin is; NADH methemoglobin reductase is not fully active until 4 months of age.
- Infants also have increased skin permeability to aniline compounds, which can cause methemoglobinemia.
- Patients with underlying heart disease, pulmonary disease, or anemia may develop symptoms at lower methemoglobin levels.
PREGNANCY AND LACTATION
- Because fetal hemoglobin is more susceptible to oxidation, the threshold for treatment of methemoglobinemia in pregnant patients should be lower.
- Anilines and some other drugs and chemicals can cross the placental barrier.
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DIFFERENTIAL DIAGNOSIS
Further information on each poison is available in SECTION IV, CHEMICAL AND BIOLOGICAL AGENTS.
Common Toxicologic Causes
Acetanilid, amyl nitrite, aniline dyes, antipyrine, benzocaine, chloroquine, dapsone, methylene blue, mothballs (more common with naphthalene), nitrates (including contaminated well water), nitrites (most commonly abused inhaled amyl nitrites), nitroglycerin, phenacetin, phenols, prilocaine, primaquine, pyridium, sulfonamides, toluidine, trinitrotoluene.
Uncommon Toxicologic Causes
Chlorates, dimethylamine, dimethyl aniline, dinitrobenzene, dinitrophenol, dinitrotoluene, hydroxylamine, marking inks, lidocaine, methanol, nitrobenzene, nitrofurans, nitrophenol, phenytoin, silver nitrite.
SIGNS AND SYMPTOMS
- Symptoms are related to decreased oxygen delivery to tissues and often correlate with methemoglobin concentration.
- Cyanosis of noncardiac and nonpulmonary etiologies that is unresponsive to oxygen therapy is suggestive of methemoglobinemia.
- Neonates are at risk for acute diarrheal syndrome caused by nitrite-producing bacteria; occult methemoglobinemia develops, causing acidemia, hyperchloremia, and low pO2.
Vital Signs
- Tachycardia and tachypnea are common.
- Hypotension may develop in severe methemoglobinemia secondary to tissue hypoxia and acidosis.
Dermatologic
- Cyanosis occurs when methemoglobin concentrations exceed 1.5%.
- The cyanosis is typically more brown ("chocolate cyanosis") than blue in color, and is unresponsive to oxygen therapy.
Cardiovascular
- Dysrhythmias may occur in severe cases.
- Cardiac arrest and myocardial infarction have been reported.
- Hypotension may occur in severe cases from acidosis and hypoxia.
- Hypotension also may be due to nitrates and related compounds that are vasodilators, in addition to causes of methemoglobinemia.
Pulmonary
- Shortness of breath is common.
- Acute respiratory arrest has been reported.
Gastrointestinal
Nausea and vomiting may be present.
Hematologic
- Blood will have a chocolate brown color that does not change to red when oxygen is bubbled through it.
- Methemoglobin has been associated with hemolysis.
Neurologic
Lethargy, confusion, syncope, seizures, and coma may develop at high methemoglobin concentrations.
PROCEDURES AND LABORATORY TESTS
Essential Tests
- Methemoglobin level should be determined.
- Normal methemoglobin level is less than 2%.
- With 15% to 20% methemoglobin, cyanosis is present and the patient is generally asymptomatic.
- With 20% to 45% methemoglobin, anxiety, headache, dizziness, fatigue, syncope, and dyspnea occur.
- With 45% to 55% methemoglobin, CNS depression occurs.
- With 55% to 75% methemoglobin, coma, seizures, dysrhythmias, and shock occur.
- With more than 70% methemoglobin, death may occur if the condition is untreated.
- Blood color comparison. A drop of the patient's blood should be placed on a white sheet and compared with that from a normal control; blood with methemoglobinemia has a characteristic chocolate brown color.
Recommended Tests
- Arterial blood gases should be determined in symptomatic patients.
- This should be performed using a cooximeter to measure methemoglobin, carboxyhemoglobin, and pO2 because calculated oxygen saturations may be inaccurate.
- Pulse oximetry readings may not be accurate.
- Serum G6PD determination is used to determine etiology (not helpful in acute management).
- Serum electrolytes, BUN, and creatinine assess for elevated anion gap acidosis.
- Complete blood count with smear and haptoglobin level are used to look for evidence of hemolysis.
- ECG, serum acetaminophen, and aspirin levels in an overdose setting can detect occult ingestion.
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- Supportive care with appropriate airway management is vital.
- Dose and time of exposure should be determined for all substances involved.
- Specific treatment should be initiated while supportive care continues.
- Methylene blue should be administered in severe cases.
- Many patients with mild methemoglobinemia require no specific therapy other than humidified oxygen and removal of the inciting drug or chemical.
DIRECTING PATIENT COURSE
The health-care provider should call the poison control center when:
- cause of cyanosis or methemoglobinemia is unclear.
- coingestant, drug interaction, or underlying disease presents unusual problems.
Admission Considerations
Patients with severe methemoglobinemia and those unresponsive to therapy should be admitted.
DECONTAMINATION
Out of Hospital
- Following acute ingestion, emesis should be induced with ipecac for alert pediatric or adult patient, if health-care evaluation will be delayed, especially if the patient is known to be G6PD deficient.
- Exposed skin areas should be washed to limit further toxin absorption.
In Hospital
- Ipecac-induced emesis is not recommended.
- Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion or if serious effects are present.
- One dose of activated charcoal (1-2 g/kg) should be administered if a substantial ingestion has occurred within the previous few hours.
- Exposed skin area should be washed to limit further toxin absorption.
ANTIDOTES
Methylene blue is a specific antidote for methemoglobinemia.
Methylene Blue
Indications
- Methemoglobin level above 20% to 25% and increasing in an asymptomatic patient
- Symptomatic patient with any elevation of methemoglobin level
- Symptomatic patient with cyanosis that does not correct with administration of 100% oxygen (before methemoglobin level is available)
- Any evidence of CNS or cardiac hypoxia (anxiety, confusion, hypotension, chest pain, etc.)
Contraindications
- Known allergy to methylene blue
- Known NADPH methemoglobin reductase deficiency or G6PD deficiency
Method of Administration
- Dose is 1 to 2 mg/kg of 1% solution intravenously over 5 minutes; clinical improvement should be apparent shortly after.
- Methemoglobin level is assessed 30 to 60 minutes later; if it is still elevated and patient is still symptomatic, dose is appropriate.
Potential Adverse Effects
- Hemolysis in patients with G6PD deficiency
- Paradoxical worsening of methemoglobinemia with extremely large doses of methylene blue (unlikely with cumulative dose less than 7 mg/kg)
Ascorbic Acid
Ascorbic acid works very slowly and is not recommended; it is used in cases of heterozygous hemoglobin M and NADH deficiency.
ADJUNCTIVE TREATMENT
Exchange transfusion and hyperbaric oxygen are used rarely for life-threatening methemoglobinemia refractory to methylene blue therapy or in patient with severe G6PD deficiency.
Hypotension
- Use atropine to correct hypotension related to bradycardia.
- Patient should receive 10 to 20 ml/kg 0.9% saline and be placed in Trendelenburg position.
- Further fluid therapy should be guided by central pressure monitoring to avoid volume overload.
- Vasopressor may be added if needed.
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PATIENT MONITORING
Monitor respiratory and cardiac function continuously.
EXPECTED COURSE AND PROGNOSIS
The reconversion rate of methemoglobin in normal patients is about 15% per hour, assuming no further methemoglobin production.
DISCHARGE CRITERIA/INSTRUCTIONS
Patients who have known cause and become asymptomatic following therapy may be discharged following a psychiatric evaluation, if needed.
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DIAGNOSIS
- Other causes of cyanosis may be mistaken for methemoglobinemia.
- Some of the chemicals require transformation to toxic metabolites to produce methemoglobinemia; thus, signs and symptoms may be delayed for several hours or days.
- Sulfhemoglobinemia produces effects indistinguishable from methemoglobinemia and should be suspected when methemoglobinemia fails to respond to methylene blue treatment.
TREATMENT
Overdosing methylene blue, especially in patients with G6PD deficiency, can lead to worsening methemoglobinemia, cyanosis, and hemolysis.
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ICD-9-CM 964Poisoning by agents primarily affecting blood constituents.
See Also: SECTION II, Hypotension chapter; SECTION III, Methylene Blue chapter; and SECTION IV, chapters on specific agents.
RECOMMENDED READING
Curry S. Methemoglobinemia. Ann Emerg Med 1982;11:214-221.
Price D. Methemoglobinemia. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al, eds. Goldfrank's toxicologic emergencies, 6th ed. Norwalk, CT: Appleton & Lange, 1998.
Authors: Christopher R. DeWitt and Kennon Heard
Reviewers: Luke Yip and G. O'Malley