METHEMOGLOBINEMIA Palak Parikh Morning Report May 16, 2008
Methemoglobin Altered state of Hg in which the ferrous (Fe 2+) irons of heme are oxidized to the ferric (Fe 3+) state. Ferric hemes of methemoglobin are unable to bind oxygen. Oxygen dissociation curve is “left-shifted”, and oxygen delivery to the tissues is impaired.
Methemoglobinemia >1% of total Hg species is in the oxidized form. Due to imbalance due to either increased methemoglobin production or decreased methemoglobin reduction. High levels can lead to severe and irreversible tissue hypoxia and cell death.
Methemoglobin Reduction toHemoglobin NADH-dependent reaction catalyzed by cytochrome b5 reductase (b5R) – only physiologically important pathway Alternate pathway uses an enzyme utilizing NADPH generated by G6PD in the hexose monophosphate shunt as a source of electrons. Note: This pathway needs an electron acceptor or redox dye, such as methylene blue or flavin
Causes of Methemoglobinemia Hereditary Cytochrome b5 reductase deficiency Hemoglobin M disease Cytochrome b5 deficiency Acquired
Agents that can causeMethemoglobinemia Aniline dyes Local Anesthetic Benzene derivatives Agents Benzocaine, Lidocaine, Chlorates Prilocaine Chloroquine Metoclopramide Dapsone Methylene Blue *** Nitrites Paraquat NTG, Nitric oxide Primaquine Sulfonamides
Blood in Methemoglobinemia Dark-red, chocolate, or brownish to blue in color Does not change in color w/ addition of oxygen, unlike deoxyhemoglobin
Clinical Features ofMethemoglobinemia Cyanosis – detected when methemoglobin concentration exceeds 1.5 g/dL, or 8-12% of total hemoglobin. Early symptoms – headache, fatigue, dyspnea, lethargy At higher methemoglobin levels – respiratory depression, seizures, altered consciousness, shock, death Erythrocytosis – rare
Diagnosis Standard – Co-oximeter Interprets all readings in 630 nm range as methemoglobin (peak absorbance at 631 nm) False positives if sulfhemoglobin and methylene blue present Confirmatory – Evelyn-Malloy method Adds cyanide which binds to positively charged methemoglobin, eliminating peak at 630-635 nm in direct proportion to methemoglobin concentration Subsequently adds ferricyanide to convert entire specimen to cyanomethemoglobin for measurement of total Hg concentration Methemoglobin expressed as percentage of total concentration of Hg.
Treatment of Methemoglobinemia Cytochrome b5r deficiency indicated for cosmetic reasons only methylene blue or ascorbic acid Acquired Methemoglobinemia Discontinue offending agents – especially if dapsone or xylocaine-related med Transfusion of pRBCs if anemic Activated charcoal if overdose Supplemental O2 Methylene Blue – if severe
Methylene Blue Usually given only if methemoglobin level > 40-50% of total hemoglobin. Dose of 1 to 2 mg/kg IV over 5 minutes Dose may be repeated in 1 hr. Large (>7 mg/kg) cumulative doses can cause dyspnea, chest pain, and hemolysis Should not be used in a pt. with G6PD deficiency b/c it may further produce hemolysis.
G6PD Deficiency Populations w/ High Incidence African Americans People of Mediterranean descent Southeast Asians
Severe Methemoglobinemia in G6PDDeficiency If Severe Methemoglonemia, can give: Ascorbic acid (300 – 1000 mg/day PO in divided doses) Risk of hemolysis in very high doses Risk of kidney stone formation in high doses Hyperbaric Oxygen Exchange Transfusion
HIV Patients Have lower glutathione levels in plasma and T lymphocytes, which may predispose them to clinically significant methemoglobinemia. May take primaquine or dapsone for PJP prophylaxis or treatment. If both drugs given within 1-2 days of each other, may increase risk of methemoglobinemia as half life of dapsone exceeds 30 hrs.
Take-Home Points Methemoglobinemia is a condition in which >1% of total Hg species is in oxidized form (Fe 3+). Clinical Triad: Breathlessness, Cyanosis, Chocolate-colored blood. Dapsone and primaquine can cause methemoglobinemia, especially in HIV pts. Usually, if methemoglobin <40% of total Hg, can treat with O2, possibly pRBCs, and discontinuation of any offending agents. If methemoglobin >40% of total Hg, can give methylene blue (unless G6PD deficient).
References Alexander, CM, et al. Principles of oximetry. Anesth Analg. 1989; 68:368. Curry, S. Methemoglobinemia. Annals of Emergency Medicine. 1982; 11:214-221. Darling, R., et al. The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. American Journal of Physiology. 1942; 137:56. Evelyn, K, Malloy, H. Microdetermination of oxyhemoglobin, methemoglobin, and sulfhemoglobin in a single sample of blood. Journal of Biol Chem. 1938; 126:655. Goluboff, N. Methylene blue induced cyanosis and acute hemolytic anemia complicating the treatment of methemoglobinemia. Journal of Pediatrics. 1961; 58:86. Mansouri, A., et al. Concise review; methemoglobinemia. American Journal of Hematology. 1993; 42: 7-12. Prchal, Josef. Diagnosis and treatment of methemoglobinemia. UpToDate. 1/2008. Sin, Don, et al. Dapsone- and primaquine-induced methemoglobinemia in HIV- infected individuals. Journal of Acquired Immune Deficiency. 1996; 12:477-481.