Methemoglobinemia

What happens in methemoglobinemia

Hemoglobin carries oxygen using iron in its reduced (ferrous, Fe2+) form. Some medicines and chemicals oxidize this iron to the ferric (Fe3+) form, creating methemoglobin. Methemoglobin cannot bind oxygen, and it also makes the remaining normal hemoglobin hold onto oxygen more tightly, so even less reaches the tissues.

The body normally keeps methemoglobin below about 1% to 2% using an enzyme called cytochrome b5 reductase. Problems arise when oxidizing exposures overwhelm this system, or when the enzyme is deficient.

Causes

Acquired (most common)

• Topical anesthetics: benzocaine sprays, gels and lozenges (including teething products), and less often lidocaine and prilocaine. The FDA warns against benzocaine teething products for children under 2.
• Dapsone: used for skin conditions and to prevent pneumonia in people with HIV.
• Nitrites and nitrates: contaminated well water used in infant formula ("blue baby syndrome"), cured meats in excess, vegetable-based purees in young infants, and inhaled amyl or butyl nitrite ("poppers").
• Antimalarials: primaquine, chloroquine.
• Rasburicase (used in cancer treatment), especially in people with G6PD deficiency.
• Inhaled nitric oxide in intensive care.
• Medicine overdoses and poisonings more generally; see drug poisoning.
• Industrial chemicals: aniline dyes, nitrobenzene, some herbicides.
• Infants with diarrhea and dehydration can develop methemoglobinemia without a drug cause.

Babies under 6 months are especially vulnerable because their enzyme systems are immature.

Congenital (rare)

• Cytochrome b5 reductase deficiency: lifelong mild bluish color; usually otherwise well (type 1) or with neurological problems (type 2).
• Hemoglobin M disease: an inherited abnormal hemoglobin.

Symptoms by methemoglobin level

People with anemia, heart or lung disease feel symptoms at lower levels.

Clues to the diagnosis

• Cyanosis that does not improve with oxygen, often a slate-gray color (unlike carbon monoxide poisoning, which typically does not cause blue skin)
• Chocolate-brown blood that does not turn red when exposed to air
• Pulse oximeter reading stuck around 85% regardless of the true level
• Saturation gap: a normal oxygen level (PaO2) on an arterial blood gas despite low oximeter readings

Diagnosis

• Co-oximetry: a blood gas analyzer that measures methemoglobin percentage directly confirms the diagnosis.
• Blood count and markers of hemolysis, because some causes also break down red cells (hemolytic anemia).
• G6PD testing before methylene blue if possible, especially in at-risk groups, though treatment should not be delayed in severe cases.
• Enzyme or hemoglobin studies for suspected inherited forms.

Treatment

Remove the cause

Stop the drug or chemical. Remove contaminated clothing and wash skin after chemical exposure.

Supportive care

• high-flow oxygen
• monitoring in hospital
• treating dehydration and acidosis

Methylene blue

Intravenous methylene blue rapidly converts methemoglobin back to normal hemoglobin. It is typically given for methemoglobin above about 20% to 30%, or lower levels with symptoms. Urine turns blue-green afterward.

Methylene blue is not effective and can trigger hemolysis in people with G6PD deficiency. It also interacts with serotonergic antidepressants, risking serotonin syndrome.

Other treatments

• ascorbic acid (vitamin C): an alternative when methylene blue cannot be used, though slower
• exchange transfusion or hyperbaric oxygen for severe, refractory cases

Congenital methemoglobinemia

Usually needs no treatment, or oral methylene blue or vitamin C for cosmetic reasons. Avoid oxidizing drugs.

Prevention

• do not use benzocaine teething gels in children under 2
• use topical anesthetic sprays only as directed
• test private well water for nitrates before using it for infant formula; use bottled water if levels are high
• check G6PD status before medicines such as dapsone, primaquine and rasburicase where recommended
• tell doctors if you have had methemoglobinemia before

Frequently asked questions

What causes methemoglobinemia?

Most cases are caused by exposure to oxidizing medicines or chemicals, such as benzocaine numbing sprays and gels, dapsone, nitrites and nitrates, some antimalarials and rasburicase. Rarely, it is inherited due to an enzyme deficiency or abnormal hemoglobin.

What are the symptoms of methemoglobinemia?

Early signs are blue or gray skin and lips, followed by headache, tiredness, dizziness and breathlessness. At high levels it causes a fast heartbeat, confusion, seizures and can be fatal. The blood may look chocolate brown.

How is methemoglobinemia treated?

The cause is stopped, oxygen is given, and intravenous methylene blue is used for significant levels or symptoms. Methylene blue works quickly but must be avoided in people with G6PD deficiency, in whom vitamin C or other treatments are used.

Why does a pulse oximeter read about 85% in methemoglobinemia?

Methemoglobin absorbs light at both wavelengths used by pulse oximeters, which pushes readings toward about 85% regardless of the true oxygen level. A co-oximeter, which measures several types of hemoglobin, is needed for an accurate reading.

Is benzocaine safe for teething babies?

No. The FDA advises against using benzocaine teething products in children under 2 because they can cause methemoglobinemia. Safer options include a chilled (not frozen) teething ring or gently rubbing the gums with a clean finger.