Methemoglobinemia

Methemoglobinemia is a condition in which more than 1% of hemoglobin contains iron in its oxidized form and cannot participate in oxygen delivery. Methemoglobinemia can be inherited but is more commonly an acquired condition that follows exposure to local anesthetics, dapsone, nitrates, or other chemicals. Symptoms typically do not begin until methemoglobin makes up over 10% of the total hemoglobin and include cyanosis, fatigue, and tachycardia. Diagnostic findings include decreased conventional pulse oximeter saturation readings that remain fixed around 85%, direct methemoglobin elevation on CO-oximetry, and blood that appears dark brown. All patients receive supportive treatment, e.g., oxygen and IV hydration. Patients who are symptomatic and/or have methemoglobin levels > 30% are typically treated with methylene blue.

• Methemoglobin
  • A form of hemoglobin in which an iron molecule has been oxidized from a ferrous (Fe²⁺) to a ferric (Fe³⁺) state
  • Cannot bind oxygen
  • Normally < 1% of total hemoglobin
• Methemoglobinemia: a blood concentration of methemoglobin greater than 1%

Acquired methemoglobinemia ^[2][3][4]

Acquired methemoglobinemia is the most common form of methemoglobinemia and occurs as a result of exposure to substances that increase methemoglobin levels.

Medications

• Local anesthetics: benzocaine, lidocaine
• Vasodilators: inhaled nitric oxide, nitroglycerin, isosorbide mono- and dinitrate (See also “Cardiovascular drug toxicity.”)
• Antiinfectious agents: dapsone, sulfonamides, primaquine ^[5]
• Other: phenazopyridine, metoclopramide, aniline derivatives

Have a high index of suspicion for methemoglobinemia in patients with symptoms of hypoxia who have recently received topical benzocaine, e.g., during TEE or endoscopy. ^[6]

Patients who are taking dapsone on a sustained basis, e.g., as PCP prophylaxis or as treatment of leprosy, should be monitored for methemoglobinemia. ^[7][8]

Food and water ^[9]

In the gastrointestinal tract, nitrates are partially converted to nitrites, which catalyze the conversion of oxyhemoglobin to methemoglobin.

• Sodium nitrites: used to cure meat and some cheeses
• Nitrates: found in high concentration in some vegetables, e.g., spinach, beets, carrots
• Drinking water contamination: increased nitrate concentration, usually related to nearby agricultural activity

Infants and children have an increased risk of methemoglobinemia after nitrate ingestion because they have lower methemoglobin reductase levels. ^[10][11]

Hereditary methemoglobinemia ^[2][3]

• NADH-cytochrome b5 reductase deficiency (autosomal recessive)
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency ^[12]
• Congenital methemoglobinemia (M hemoglobins)

• Methemoglobin is created when reduced ferrous iron (Fe²⁺) bound to oxyhemoglobin is oxidized to ferric iron (Fe³⁺).
• Ferric iron in methemoglobin cannot bind oxygen→ ↓ total blood oxygen content and ↓ blood oxygen saturation → tissue hypoxia
• Oxygen-hemoglobin dissociation curve also shifts to the left in methemoglobinemia → further decrease in oxygen delivery

The ferric iron in methemoglobin has a high affinity for cyanide, thus, amyl nitrite-induced methemoglobin is used as a competitive inhibitor in the treatment of cyanide poisoning. ^[4]

The clinical presentation depends on the concentration of methemoglobin, how fast the concentration has increased, and patient comorbidities, e.g., anemia. ^[2]

Always suspect methemoglobinemia in a patient with unexplained cyanosis and hypoxemia. ^[2]

The symptoms of methemoglobinemia are similar to those of anemia because the concentration of functioning oxyhemoglobin is decreased in both conditions. ^[2]

Cyanosis typically occurs when methemoglobin levels are ≥ 1.5 gm/dL (∼10% of total hemoglobin). ^[1]

The clinical history of a patient with cyanosis and/or hypoxia may lead to a preliminary diagnosis of methemoglobinemia, which can be rapidly confirmed with CO-oximetry.

Basic diagnostics ^[3][4]

• Pulse oximetry
  • Conventional pulse oximeter: The displayed oxygen saturation is decreased and often fixed ∼ 85%. ^[3]
  • CO-oximeter: direct measurement of methemoglobin; displayed as the percentage of total hemoglobin
• ABG
  • Normal PaO2 but decreased total oxygen content, i.e., a saturation gap ^[13][14]
  • Metabolic acidosis
• Bedside testing: Blood appears dark brown (“chocolate-colored”) and does not turn red with exposure to oxygen.

Additional diagnostics ^[4]

• CBC: to evaluate for anemia
• CXR: to evaluate for respiratory causes of cyanosis
• ECG, echocardiogram: to evaluate for cardiac causes of hypoxia

Consider other causes of central cyanosis, e.g.:

• Respiratory failure and arrest
• Heart failure
• Cyanotic congenital heart defects
• Polycythemia vera
• Other hemoglobinopathies, e.g., sulfhemoglobinemia
• Other causes of hypoxemia

The differential diagnoses listed here are not exhaustive.

Approach ^[1][2]

• Initial management
  • Stop exposure to any known precipitant (see “Etiology”).
  • Wear PPE and initiate body surface decontamination for patients exposed to anilines or pesticides.
  • Provide supportive care: oxygen therapy, cardiac support, fluid resuscitation, treatment of hypoglycemia
  • Call poison control for acquired methemoglobinemia; the US National Poison Help line is 1-800-222-1222.
• Definitive treatment
  • Begin definitive treatment with methylene blue and/or reducing agents if methemoglobin level is > 30% or the patient is symptomatic.
  • Monitor asymptomatic patients with methemoglobin levels < 30% for resolution. ^[1]

In patients with acquired methemoglobinemia, assess for potential triggers and stop exposure immediately.

Methylene blue ^[1][2][3]

Methylene blue is the first-line treatment for acquired methemoglobinemia. ^[2]

• Indications: acquired methemoglobinemia with
  • Methemoglobin level > 30%
  • Or symptoms of oxygen deprivation
• Initial dosing: methylene blue
• Subsequent dosing
  • Repeat initial dose once after 60 minutes if symptoms persist or the methemoglobin level remains > 30%.
  • Additional dosing may be required if there is continued GI absorption or slow metabolism of the precipitating agent, e.g., dapsone.
  • If there is no improvement after 2 doses, consider the possibility of severe G6PD deficiency or an alternate diagnosis.
• Relative contraindications
  • G6PD deficiency: may precipitate acute hemolysis ^[2]
  • MAO inhibitor or selective serotonin uptake inhibitor use: may precipitate serotonin syndrome ^[3][15]
  • Pregnancy: Methylene blue is a known teratogen.

Avoid over-administration of methylene blue; doses ≥ 7 mg/kg can directly oxidize hemoglobin to methemoglobin and worsen methemoglobinemia. ^[1]

Methylene blue will cause a transient decrease in the pulse oximeter saturation readings because it absorbs light with a frequency of 660 nm. ^[1]

Alternative treatments ^[2][3]

Alternative treatments may be considered if methylene blue is unavailable, ineffective, or contraindicated.

• Reducing agents: ascorbic acid (vitamin C) or riboflavin
  • Reduce methemoglobin to hemoglobin, but less efficiently than methylene blue
  • Used primarily for inherited methemoglobinemia or as an adjunct to methylene blue
• Hyperbaric oxygen therapy
• Whole blood exchange transfusion

Disposition ^[4]

Admit the patient if any of the following conditions apply:

• Symptoms are present
• Methemoglobin level is > 15%
• Methylene blue was administered