- Author: Mary Denshaw-Burke, MD, FACP; Chief Editor: Emmanuel C Besa, MD more...
Unless methemoglobinemia is severe or symptomatic, treatment is purely for cosmetic or psychological reasons. Various agents can reduce the methemoglobin levels to within the reference range (~1%) or at least to acceptable levels (5-10%).
Methylene blue is the first-line antidotal therapy. Ascorbic acid and riboflavin have been used. N -acetylcysteine reduces methemoglobin levels but is not yet approved for the treatment of methemoglobinemia. Cimetidine can be used in dapsone-induced methemoglobinemia. Hyperbaric oxygen and exchange transfusion should be considered when methylene blue treatment is ineffective or contraindicated.
Antidotes (eg, methylene blue) are used to counteract methemoglobinemia, acting as cofactors in the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent methemoglobin reductase system. Cimetidine may be used in dapsone-induced methemoglobinemia.
Methylene blue increases the activity of nicotinamide adenine dinucleotide (NADH)-methemoglobin reductase in red blood cells (RBCs), assisting in the conversion of ferric (Fe3+) to ferrous (Fe2+) iron. It is available as a 1% solution (10 mg/mL). Most patients require only 1 dose. Resolution of toxicity should be seen within 1 hour, often within 20 minutes.
The US Food and Drug Administration (FDA) warns against using methylene blue concurrently with serotonergic psychiatric drugs, unless such usage is indicated for life-threatening or urgent conditions. Methylene blue may increase central nervous system (CNS) serotonin levels as a result of monoamine oxidase (MAO)-A inhibition, increasing the risk of serotonin syndrome.
Vitamins, Water Soluble
Vitamins are essential for normal metabolic functioning of the body. Important: they act as cofactors in erythrocyte glutathione reductase and NADH dehydrogenase.
Ascorbic acid is an antioxidant and coenzyme for reduction. It may be helpful in the treatment of congenital methemoglobinemia if used daily and on a continual basis. Although it can occasionally reduce the cyanosis associated with chronic methemoglobinemia, it has no role in the treatment of acute acquired methemoglobinemia.
Riboflavin can reduce the cyanosis associated with chronic methemoglobinemia but has no role in the treatment of acute severe acquired methemoglobinemia.
Histamine H2 Antagonists
Cytochrome P-450 inhibitors are recommended only for patients with methemoglobinemia secondary to dapsone.
Cimetidine inhibits conversion of dapsone to its oxidizing metabolite, dapsone hydroxylamine, by the P-450 system, thereby preventing further development of dapsone-induced methemoglobinemia.
Bloom J, ed. Comprehensive Toxicology. Amsterdam, Netherlands: Elsevier; 1997. Vol 4: 62-6.
Curry S. Methemoglobinemia. In: Rosen P, Barkin R, Danzl DF, et al, eds. Emergency Medicine: Concepts and Clinical Practice. 4th ed. St Louis, Mo: Mosby-Year Book; 1997.
Hoffman R, Benz E, Shattil S, Furie B, Cohen H, eds. Hematology Basic Principles and Practice. 4th ed. New York, NY: Churchill Livingstone; 2005. 650-7.
Percy MJ, McFerran NV, Lappin TR. Disorders of oxidised haemoglobin. Blood Rev. 2005 Mar. 19(2):61-8. [Medline].
Mansouri A, Lurie AA. Concise review: methemoglobinemia. Am J Hematol. 1993 Jan. 42(1):7-12. [Medline].
Curry S. Methemoglobinemia. Ann Emerg Med. 1982 Apr. 11(4):214-21. [Medline].
Goluboff N, Wheaton R. Methylene blue induced cyanosis and acute hemolytic anemia complicating the treatment of methemoglobinemia. J Pediatr. 1961 Jan. 58:86-9. [Medline].
Gebara BM, Goetting MG. Life-threatening methemoglobinemia in infants with diarrhea and acidosis. Clin Pediatr (Phila). 1994 Jun. 33(6):370-3. [Medline].
Bento C, Magalhães Maia T, Carvalhais I, Moita F, Abreu G, Relvas L, et al. Transient neonatal cyanosis associated with a new Hb F variant: Hb F Viseu. J Pediatr Hematol Oncol. 2013 Mar. 35(2):e77-80. [Medline].
Allen A, Fisher C, Premawardhena A, Bandara D, Perera A, Allen S. Methemoglobinemia and ascorbate deficiency in hemoglobin E ß thalassemia: metabolic and clinical implications. Blood. 2012 Oct 11. 120(15):2939-44. [Medline].
Ward KE, McCarthy MW. Dapsone-induced methemoglobinemia. Ann Pharmacother. 1998 May. 32(5):549-53. [Medline].
Grauer SE, Giraud GD. Toxic methemoglobinemia after topical anesthesia for transesophageal echocardiography. J Am Soc Echocardiogr. 1996 Nov-Dec. 9(6):874-6. [Medline].
Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). 2004 Sep. 83(5):265-73. [Medline].
Ohashi K, Yukioka H, Hayashi M, Asada A. Elevated methemoglobin in patients with sepsis. Acta Anaesthesiol Scand. 1998 Jul. 42(6):713-6. [Medline].
Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: etiology, pharmacology, and clinical management. Ann Emerg Med. 1999 Nov. 34(5):646-56. [Medline].
Forestier A, Pissard S, Cretet J, Mambie A, Pascal L, Cliquennois M, et al. Congenital Recessive Methemoglobinemia Revealed in Adulthood: Description of a New Mutation in Cytochrome b5 Reductase Gene. Hemoglobin. 2015 Jul 31. 1-4. [Medline].
Fuller TD, Spracklen CN, Ryckman KK, Knake LA, Busch TD, Momany AM, et al. Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy. Pediatr Res. 2015 Mar. 77 (3):472-6. [Medline].
Fan AM, Steinberg VE. Health implications of nitrate and nitrite in drinking water: an update on methemoglobinemia occurrence and reproductive and developmental toxicity. Regul Toxicol Pharmacol. 1996 Feb. 23(1 pt 1):35-43. [Medline].
Erkekoglu P, Baydar T. Evaluation of nitrite contamination in baby foods and infant formulas marketed in Turkey. Int J Food Sci Nutr. 2009 May. 60(3):206-9. [Medline].
[Guideline] Greer FR, Shannon M. Infant methemoglobinemia: the role of dietary nitrate in food and water. Pediatrics. 2005 Sep. 116(3):784-6. [Medline].
Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med. 2004 Jun 14. 164(11):1192-6. [Medline].
Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesth Analg. 2009 Mar. 108(3):837-45. [Medline].
So TY, Farrington E. Topical Benzocaine-induced Methemoglobinemia in the Pediatric Population. J Pediatr Health Care. 2008 Nov-Dec. 22(6):335-9. [Medline].
Kath MA, Shupp JW, Matt SE, Shaw JD, Johnson LS, Pavlovich AR. Incidence of methemoglobinemia in patients receiving cerium nitrate and silver sulfadiazine for the treatment of burn wounds: a burn center's experience. Wound Repair Regen. 2011 Mar-Apr. 19(2):201-4. [Medline].
Chowdhary S, Bukoye B, Bhansali AM, Carbo AR, Adra M, Barnett S, et al. Risk of topical anesthetic-induced methemoglobinemia: a 10-year retrospective case-control study. JAMA Intern Med. 2013 May 13. 173(9):771-6. [Medline].
Skold A, Klein R. Symptomatic-Low Grade Methemoglobinemia Because of Dapsone: A Multiple Hit Hypothesis. Am J Ther. 2011 Jun 3. [Medline].
Henretig FM, Gribetz B, Kearney T, Lacouture P, Lovejoy FH. Interpretation of color change in blood with varying degree of methemoglobinemia. J Toxicol Clin Toxicol. 1988. 26(5-6):293-301. [Medline].
Góth L, Bigler NW. Catalase deficiency may complicate urate oxidase (rasburicase) therapy. Free Radic Res. 2007 Sep. 41(9):953-5. [Medline].
Bauters T, Mondelaers V, Robays H, De Wilde H, Benoit Y, De Moerloose B. Methemoglobinemia and hemolytic anemia after rasburicase administration in a child with leukemia. Int J Clin Pharm. 2011 Feb. 33(1):58-60. [Medline].
Geetha A, Lakshmi Priya MD, Jeyachristy SA, Surendran R. Level of oxidative stress in the red blood cells of patients with liver cirrhosis. Indian J Med Res. 2007 Sep. 126(3):204-10. [Medline]. [Full Text].
Odièvre MH, Danékova N, Mesples B, Chemouny M, Couque N, Parez N, et al. Unsuspected glucose-6-phosphate dehydrogenase deficiency presenting as symptomatic methemoglobinemia with severe hemolysis after fava bean ingestion in a 6-year-old boy. Int J Hematol. 2011 May. 93(5):664-6. [Medline].
Romanovsky A, Djogovic D, Chin D. A case of sodium chlorite toxicity managed with concurrent renal replacement therapy and red cell exchange. J Med Toxicol. 2013 Mar. 9(1):67-70. [Medline].
Warriner DR, Morris P, Ramjiani V, Morton A, Sheridan P. Smells like a heart attack, but is it?. BMJ Case Rep. 2011. 2011:[Medline].
Grundlingh J, Dargan PI, El-Zanfaly M, Wood DM. 2,4-dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J Med Toxicol. 2011 Sep. 7(3):205-12. [Medline].
Severe methemoglobinemia and hemolytic anemia from aniline purchased as 2C-E (4-ethyl-2,5-dimethoxyphenethylamine), a recreational drug, on the Internet - Oregon, 2011. MMWR Morb Mortal Wkly Rep. 2012 Feb 10. 61(5):85-8. [Medline].
Weichert I. Acute management of cocaine-associated methaemoglobinaemia. Case Rep Med. 2011. 2011:136396. [Medline].
Hunter L, Gordge L, Dargan PI, Wood DM. Methaemoglobinaemia associated with the use of cocaine and volatile nitrites as recreational drugs: a review. Br J Clin Pharmacol. 2011 Jul. 72(1):18-26. [Medline].
Carmona-Fonseca J, Alvarez G, Maestre A. Methemoglobinemia and adverse events in Plasmodium vivax malaria patients associated with high doses of primaquine treatment. Am J Trop Med Hyg. 2009 Feb. 80(2):188-93. [Medline].
Loiseau PM, Cojean S, Schrével J. Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance. Parasite. 2011 May. 18(2):115-9. [Medline].
Kunos CA, Radivoyevitch T, Ingalls ST, Hoppel CL. Management of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone-induced methemoglobinemia. Future Oncol. 2012 Feb. 8(2):145-50. [Medline]. [Full Text].
Fung HT, Lai CH, Wong OF, Lam KK, Kam CW. Two cases of methemoglobinemia following zopiclone ingestion. Clin Toxicol (Phila). 2008 Feb. 46(2):167-70. [Medline].
Park JS, Kim H, Lee SW, Min JH. Successful treatment of methemoglobinemia and acute renal failure after indoxacarb poisoning. Clin Toxicol (Phila). 2011 Oct. 49(8):744-6. [Medline].
Mostafazadeh B, Pajoumand A, Farzaneh E, Aghabiklooei A, Rasouli MR. Blood levels of methemoglobin in patients with aluminum phosphide poisoning and its correlation with patient's outcome. J Med Toxicol. 2011 Mar. 7(1):40-3. [Medline].
Rosen PJ, Johnson C, McGehee WG, Beutler E. Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med. 1971 Jul. 75(1):83-6. [Medline].
Grossmann J, Neuwald S, Wiese B. [Acute respiratory failure after metoclopramide for methemoglobinemia - a rare and potentially life-threatening side effect]. Z Gastroenterol. 2012 Jun. 50(6):585-8. [Medline].
Vallurupalli S, Das S, Manchanda S. Infection and the Risk of Topical Anesthetic Induced Clinically Significant Methemoglobinemia after Transesophageal Echocardiography. Echocardiography. 2009 Aug 31. [Medline].
Jiminez MA, Polena S, Coplan NL, Patel K, Gintautas J. Methemoglobinemia and transesophageal echo. Proc West Pharmacol Soc. 2007. 50:134-5. [Medline].
Esbenshade AJ, Ho RH, Shintani A, Zhao Z, Smith LA, Friedman DL. Dapsone-induced methemoglobinemia: a dose-related occurrence?. Cancer. 2011 Aug 1. 117(15):3485-92. [Medline].
Lavezzi AM, Mohorovic L, Alfonsi G, Corna MF, Matturri L. Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers--the possible involvement of maternal methemoglobinemia. BMC Pediatr. 2011 Jul 6. 11:62. [Medline]. [Full Text].
Yano SS, Danish EH, Hsia YE. Transient methemoglobinemia with acidosis in infants. J Pediatr. 1982 Mar. 100(3):415-8. [Medline].
Chaurasia S, Ramappa M, Bhargava A. Corneal epitheliopathy in congenital methemoglobinemia. Cornea. 2014 Apr. 33(4):422-4. [Medline].
Yusim Y, Livingstone D, Sidi A. Blue dyes, blue people: the systemic effects of blue dyes when administered via different routes. J Clin Anesth. 2007 Jun. 19(4):315-21. [Medline].
Zaki SA, Jadhav A, Chandane P. Methaemoglobinaemia during Holi festival. Ann Trop Paediatr. 2009 Sep. 29(3):221-3. [Medline].
Kohli-Kumar M, Zwerdling T, Rucknagel DL. Hemoglobin F-Cincinnati, alpha 2G gamma 2 41(C7) Phe-->Ser in a newborn with cyanosis. Am J Hematol. 1995 May. 49(1):43-7. [Medline].
US Food and Drug Administration. FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. Available at http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. Accessed: December 23, 2015.
Martinez A, Sanchez-Valverde F, Gil F, Clerigué N, Aznal E, Etayo V, et al. 78 Cases Of Methemoglobinemia Induced By Vegetable Intake In Infants In North Spain. A Case-Control Study. J Pediatr Gastroenterol Nutr. 2013 Jan 1. [Medline].
Bergamaschi MM, Alcantara GK, Valério DA, Queiroz RH. Curcumin could prevent methemoglobinemia induced by dapsone in rats. Food Chem Toxicol. 2011 Jul. 49(7):1638-41. [Medline].