Methemoglobinemia inducing Agents

Pathophysiology  A large number of chemical agents are capable of oxidizing ferrous (Fe2+)
hemoglobin to its ferric state (Fe3+) (methemoglobin), a form that cannot carry
oxygen and thus inducing a functional anemia.
 Usually, 5 g/dL (>30% of total hemoglobin) of reduced hemoglobin (deoxyHb)
produces clinical cyanosis; but only 1.5 g/dL (>10%) of methemoglobin produces
noticeable cyanosis due to the combined:
- Decrease in O2 carrying capacity
- Shift in oxyhemoglobin dissociation curve to the left
Types  Inherited:
1. Cytochrome b5 reductase deficiency:
- Type I: limited to RBC - Type II: All cells (most die in infancy)
2. Hemoglobin M disease: mutation in either alpha or beta globin molecule
 Acquired: Chemically induced.
MetHb inducing Aniline dyes * Benzocaine, Lidocaine** High dose Methylene blue
Chemical Agents Antimalarial agents Chlorates, copper salts Nitrites, Nitrates ***
p-Aminosalicylic Acid Dapsone Sulfonamides
* Aniline dyes: printing ink on diaper, leather dyes in new shoes, marking crayons.
** Benzocaine: local anesthetic, teething ointments Orajel® & hemorrhoidal creams
*** Nitrites, Nitrates:
- Fertilizers & Animal waste product: soil and water contamination
- Meat preservatives
- Vegetables (spinach & carrot in infants)
- Recreational drugs: Volatile nitrites (amyl nitrite, butyl nitrite)
- Nitrosation of nitrite with amines  nitrosamine: a potent carcinogen.
The conversion of nitrates to nitrites by bacteria in the upper gastrointestinal tract,
fatal methemoglobinemia may be produced in infants who ingest well water or
vegetables (spinach & carrot) high in nitrate concentrations due to:
- Less acidic gastric pH in infants
- Less active MetHb reductase in infants
Clinical MetHb Conc (%) Clinical effects
Manifestations 3-15 % Slight skin discoloration, asymptomatic
15 – 20 % Asymptomatic Gray cyanosis, persistent even with oxygen
therapy, Chocolate brown blood
20 – 50 % Headache, dyspnea, Chest pain, metabolic acidosis
50 – 70 % Arrthymias, seizures, homodynamic instability and shock
> 70 % Usually, death
Treatment MetHb level <30% Removing of the offender agents
High-flow oxygen
MetHb level >30% Methylene blue, 1–2 mg/kg (of 1% solution) IV
IV hydration and bicarbonate (for metabolic acidosis)
Hyperbaric O2 and exchange transfusion may be used in:
- Patients with G6PD deficiency (Methylene blue is contraindicated)
- Severe cases (Methemoglobin level > 70%)
Good Luck

Mokhtar Alhrani, MD