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Toxicology: Methemoglobinemia

It was 5.30 am when I see this word!



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Methemoglobinemia

Methemoglobinemia is a blood disorder in which an abnormal amount of hemoglobin builds up in the blood. Hemoglobin is the oxygen-carrying molecule found in red blood cells. In some cases of methemoglobinemia, the hemoglobin is unable to carry oxygen effectively to body tissues.

(Ps: In this topic I only emphasized on the effects of toxins associated with methemoglobinemia)

Methemoglobinemia is a clinical syndrome caused by an increase in the blood levels of methemoglobin secondary to both congenital (chronic) changes in hemoglobin synthesis or metabolism, or acute imbalances in reduction and oxidation reactions (redox imbalance) induced by the exposure to several chemical agents. Central cyanosis unresponsive to the administration of oxygen, which can cause a reduction in oxygen delivery, is the main characteristic of methemoglobinemia. Its prevalence is difficult to determine because it encompasses mild cases, which are probably underdiagnosed, and fatal cases; it frequently presents in the preoperative period and should be known to every anesthesiologist.

Methemoglobinemia occurs when red blood cells (RBCs) contain greater than 1% methemoglobin. This occurs from either congenital changes in methemoglobin affecting synthesis and metabolism or from exposure to toxins that acutely affect redox reactions involving methemoglobin. It is important to realize that methemoglobin is a naturally occurring oxidized metabolite of hemoglobin and physiologic levels (< 1%) are normal. Problems arise when levels increase, as methemoglobin does not bind oxygen, thus leading to a functional anemia.

The molecule of Hb is a tetramer composed of alpha, beta, gamma, or delta chains. The most common form of Hb in adults (HbA) consists of two α and twoβ chains. Each Hb chain is formed by a globin polypeptide linked to a prosthetic heme group, which is formed by a complex of a protoporfirin IX ring and one atom of ferrous iron (Fe+2). Thus, each Hb molecule has four atoms of iron. Each ferrous iron can reversibly link one O2 molecule, for a total of four molecules of O2 transported by each Hb molecule.


Normal haemoglobin

Methemoglobin has an oxidized ferric iron (Fe +3) rather than the reduced ferrous form (Fe 2+) found in hemoglobin. This structural change is responsible for methemoglobin's inability to bind oxygen. In addition, ferric iron has slightly greater affinity for oxygen due to its chemical structure, thus shifting the oxygen dissociation curve of partially oxidized hemoglobin molecules to the left, resulting in decreased release of oxygen in tissues. The findings of anemia and cyanosis despite oxygen treatment result from both of these effects.




In theory, any oxidizing agent can lead to the formation of MetHb. Hemoglobin is constantly being oxidized; however, natural reducing systems maintain the levels of MetHb under 1%.

NADH-Methemoglobin reductase (NADH-NR) , a system with two enzymes, cytochrome B5 and cytochrome B5-reductase (CB5R), is responsible for the endogenous reduction of MetHb, corresponding to 99% of the reducing activity. NADH-Methemoglobin reductase transfers one electron from NADH to MetHb, changing it into reduced hemoglobin (HHb) (Figure 1). Other systems also help to maintain a low level of MetHb; among them, ascorbic acid, gluthation, and NADPH dehydrogenase should be mentioned. Gluthation reduces several oxidizing substances in the blood before they attack the Hb. However, under normal conditions those pathways are less significant, but become important when NADH-MR is disrupted.

Methemoglobinemia results from a redox imbalance, either due to excessive oxidization of Hb (increased production) or a decrease in the activity of reducing enzymes (decreased metabolism)



Most cases of methemoglobinemia are due to excessive production of methemoglobin following exposure to oxidant drugs, chemicals, or toxins. This increased production of methemoglobin overwhelms the physiologic regulatory mechanisms previously discussed. These agents can cause an increase in methemoglobin levels either by ingestion or by absorption through the skin. Such agents fall into 2 general categories: nitrites or aromatic amines. Dapsone and benzocaine are common causes for methemoglobinemia.


Blood: methemoglobulin(left) and normal blood (right)


Substances that can cause methemoglobinemia

  • Inorganic agents
    • Nitrates – Fertilizers, contaminated well water, preservatives, industrial products
    • Chlorates
    • Copper sulfate – Fungicides
  • Organic nitrites/nitrates
    • Amyl nitrite
    • Isobutyl nitrite
    • Sodium nitrite
    • Nitroglycerin
    • Nitroprusside
    • Nitric oxide
    • Nitrogen dioxide
    • Trinitrotoluene (TNT), combustion products
  • Others
  • Local anesthetics – Benzocaine, lidocaine, prilocaine, phenazopyridine (Pyridium)
  • Antimalarials – Primaquine, chloroquine
  • Rasburicase
  • Antineoplastic agents – Cyclophosphamide, ifosfamide, flutamide
  • Analgesics/antipyretics – Acetaminophen, acetanilid, phenacetin, celecoxib
  • Zopiclone
  • Herbicides – Paraquat (dipyridylium)
  • Methylene blue (high dose or in G6PD deficient patients )
  • Indigo Carmine (Indigotindisulfonate)
  • Resorcinol
  • Antibiotics – Sulfonamides, nitrofurans, P-amino-salicylic acid, Dapsone
  • Industrial/household agents – Aniline dyes, nitrobenzene, naphthalene (moth balls), aminophenol, nitroethane (nail polish remover)


Symptoms of methemoglobinemia

Symptoms are proportional to the methemoglobin concentration and include skin color changes (cyanosis with blue or grayish pigmentation) and blood color changes (brown or chocolate color) at methemoglobin levels up to 15%. As levels of methemoglobin rise above 15%, neurologic and cardiac symptoms arise due to hypoxia. levels above 70% are usually fatal.

Bluish faces





Diagnosis

There are many differential diagmosis, I only emphasize diagnosis in animals only.

The potassium cyanide test can distinguish between methemoglobin and sulfhemoglobin. After the addition of a few drops of potassium cyanide, methemoglobin turns bright red, but sulfhemoglobin remains dark brown. This is due to the binding of methemoglobin to cyanide, forming cyanomethemoglobin, which is bright red in color. Sulfhemoglobin, on the other hand, is inert and does not bind cyanide.


Treatment

If methemoglobinemia is the result of toxin exposure, then removal of this toxin is imperative. Further ingestion or administration of the drug or chemical is to be avoided. If the substance is still present on the skin or clothing, the clothing should be removed and the skin washed thoroughly. These patients may be unstable and should be in a closely monitored situation with oxygen supplementation as needed.


Methylene blue is the primary emergency treatment for documented, symptomatic methemoglobinemia. The methylene blue dose is 1-2 mg/kg administered as a 1% solution in intravenous saline over 3-5 minutes. This dose may be repeated at 1 mg/kg every 30 minutes as necessary to control symptoms. Doses of methylene blue should not exceed 7 mg/kg, because this agent in itself can be toxic and cause dyspnea, chest pain, and hemolysis.

methylene blue antidot

Methylene blue requires G6PD to work. Therefore, it is not effective in patients who have G6PD deficiency with methemoglobinemia. Additionally, methylene blue administration may cause hemolysis in these patients.


Sources: methemoglobulin from diagnosis to treatment; Revista Brasileira de Anesthesiologia, methemoglobinemia,evidence-based care review, Habib Ur Rehman, methemoglobinemia, emedicine.medscape.com



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