Methemoglobinemia is a blood disease where hemoglobin in the blood is converted to another form called methemoglobin that cannot deliver oxygen to body tissues. Methemoglobinemia can either be congenital or acquired.
The molecule hemoglobin in the blood is responsible for binding oxygen to provide to the body. When hemoglobin is oxidized to methemoglobin its structure changes and it is no longer able to bind oxygen. Hemoglobin is constantly under oxidizing stresses. However, normally less than 1% of a person's hemoglobin is in the methemoglobin state. This is due to the body's systems that reduce methemoglobin back to hemoglobin. Infants have a higher risk of acquiring methemoglobinemia because infant hemoglobin is more prone to be oxidized to methemoglobin.
Methemoglobinemia occurs rarely throughout the world. Most cases of methemoglobinemia are acquired and result from exposure to certain drugs or other chemicals. However, the true incidence of acquired methemoglobinemia is unknown. Estimated incidence based on methylene blue use (the treatment of methemoglobinemia) reported to the American Association of Poison Control Centers is approximately 100 cases per year. This number is considered to be a underestimation due to underreporting of methemoglobinemia cases to U.S. poison control centers. One of the more common causes of acquired methemoglobinemia is exposure to topical benzocaine during medical procedures. An estimated 0.115% of patients undergoing transesophageal echocardiography (TEE) develop methemoglobinemia.
Hereditary methemoglobinemia has been classified as a rare disease, which is defined as one person or less affected per two thousand people.
There are two causes of the congenital form of the disease. One cause is a defect in the body's systems to reduce methemoglobin to hemoglobin. The other cause is an inherited mutant form of hemoglobin called hemoglobin M that cannot bind to oxygen. Both of these forms are typically benign.
Acquired methemoglobinemia, which is more common than inherited forms, is caused by an external exposure to certain oxidizing chemicals or drugs, including anesthetics such as benzocaine, benzene, certain antibiotics (e.g., dapsone), and nitrites. These compounds can increase the formation of methemoglobin up to one thousand times.
Infants under six months of age are particularly susceptible to developing methemoglobinemia. They may acquire methemoglobinemia by drinking water containing nitrates (which are converted to nitrites in the digestive system of an infant), thereby developing a condition called blue baby syndrome. The nitrites react with hemoglobin in the blood, forming high amounts of methemoglobin. Nitrates may contaminate well waters from agricultural use of fertilizers or from septic systems. The U.S. Environmental Protection Agency drinking water standard of 10 milligrams per liter of nitrate-nitrogen is based on protecting infants from developing methemoglobinemia. Other causes of methemoglobinemia in infants are dehydration due to excessive diarrhea or from topical anesthetics containing benzocaine or prilocaine applied to their tissues (as may be done to gums to soothe the pain of teething).
With a methemoglobin level of 3-15% skin can turn to a pale gray or blue (cyanosis). With levels above 25% the following symptoms may be present:
When methemoglobin levels are above 70% death may result if not treated immediately.
Diagnosis is based on the symptoms and history. If these are indicative of methemoglobinemia, blood tests are performed to confirm the presence and level of methemoglobin.
For acquired methemoglobinemia, the typical treatment is with supplemental oxygen and with methylene blue. Methylene blue is administered with an IV over a five-minute period, followed by an IV flush with normal saline. Results are typically seen within 20 minutes. Methylene blue reduces methemoglobin to hemoglobin.
Though congenital methemoglobinemia is usually benign, the form due to a defective reducing system can be treated with ascorbic acid (vitamin C) taken daily. There is no treatment for the other congenital form due to hemoglobin M.
Alternative treatments include hyperbaric oxygen therapy and exchange transfusions. Hyperbaric oxygen therapy uses a special chamber, sometimes called a pressure chamber, to increase the amount of oxygen in the blood. The air pressure inside a hyperbaric oxygen chamber is about two and a half times greater than the normal pressure in the atmosphere, which helps the blood carry more oxygen to organs and tissues in the body. Exchange transfusion is a potentially lifesaving procedure that involves slowly removing the patient's blood and replacing it with fresh donor blood or plasma.
In order to protect public health, the U.S. Food and Drug Administration (FDA) alerted healthcare professionals that the agency continues to receive reports of methemoglobinemia associated with benzocaine sprays, with some cases resulting in fatalities. These sprays are used during medical procedures to numb the mucous membranes of the mouth and throat. However, labels of marketed benzocaine sprays were not yet required to warn about the risk of methemoglobinemia. The FDA was continuing to evaluate the safety of benzocaine.
Also, to protect infants from developing methemoglobinemia, the U.S. Environmental Protection Agency has set the Maximum Contaminant Level (MCL) for nitrate in drinking water at 10 milligrams per liter (mg/L). Since this standard takes available health effects information into account, infants are unlikely to develop methemoglobinemia caused by drinking water if the water contains nitrate at or below this level. In addition, community wells throughout the U.S. are required to be tested for nitrate contamination.
If found early, acquired methemoglobinemia can be easily treated with no side effects. After treatment with methylene blue the patient can expect a full recovery.
If a person contracts methemoglobinemia from a specific medication or chemical, then that medication should be avoided in the future. For people with congenital methemoglobinemia, medications or other chemicals that are known to oxidize hemoglobin should not be used. Preventive measures are especially encouraged for pregnant women or women who are breast feeding.
See also Benzene ; Cyanosis .
Surhone, Lambert M., Mariam T. Tennoe, and Susan F. Henssonow, eds. Methemoglobinemia, Seattle, WA: Betascript, 2010.
“Methemoglobinemia” http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001588 .
Judith L Sims