Medical Toxicology

, Volume 1, Issue 4, pp 253–260 | Cite as

Drug- and Chemical-Induced Methaemoglobinaemia

Clinical Features and Management
  • Alan H. Hall
  • Kenneth W. Kulig
  • Barry H. Rumack
Toxicology Management Review


Methaemoglobin is haemoglobin with the iron oxidised to the ferric (Fe+++) state from the normal (or reduced) ferrous (Fe++) state. Methaemoglobinaemia refers to the presence of greater than the normal physiological concentration of 1 to 2% methaemoglobin in erythrocytes.

Methaemoglobin is incapable of transporting oxygen. It has an intense dark blue colour; thus, clinical cyanosis becomes apparent at a concentration of about 15%. The symptoms are manifestations of hypoxaemia with increasing concentrations of methaemoglobin. Concentrations in excess of 70% are rare, but are associated with a high incidence of mortality.

Methaemoglobinaemia may be congenital but is most often acquired. Congenital methaemoglobinaemia is of two types. The first is haemoglobin M disease (several variants) which is due to the presence of amino acid substitutions in either the a or β chains. The second type is due to a deficiency of the NADH-dependent methaemoglobin reductase enzyme. This deficiency has an autosomal dominant transmission, and both homozygous and heterozygous forms have been reported. The heterozygous form is not normally associated with clinical cyanosis, but such individuals are more susceptible to form methaemoglobin when exposed to inducing agents.

A wide variety of chemicals including several drugs, e.g. the antimalarials chloroquine and primaquine, local anaesthetics such as lignocaine, benzocaine and prilocaine, glyceryl trinitrate, sulphonamides and phenacetin, have been reported to induce methaemoglobinaemia.

An intense ‘chocolate brown’coloured blood and central cyanosis unresponsive to the administration of 100% oxygen suggests the diagnosis. A simple bedside test using a drop of the patient’s blood on filter paper helps to confirm the clinical suspicion. Methaemoglobin can be quantitated rapidly by a spectrophotometric method.

The intravenous administration of methylene blue (tetramethylthionine chloride) is a specific treatment for acquired methaemoglobinaemia, but may be ineffective in chlorate poisoning. Chlorate poisoning and severe cases of methaemoglobinaemia require exchange transfusion. Hyperbaric oxygen can sustain life during preparations for exchange transfusion.


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  1. Bakshi SP, Fahey JL, Pierce LE. Sausage cyanosis — acquired methemoglobinemic nitrite poisoning. New England Journal of Medicine 277: 1072, 1967PubMedCrossRefGoogle Scholar
  2. Berlin G, Brodin B, Hilden J-O, et al. Acute dapsone intoxication: a case treated with continuous infusion of methylene blue, forced diuresis and plasma exchange. Clinical Toxicology 22: 537–548, 1985CrossRefGoogle Scholar
  3. Bodansky O. Methemoglobinemia and methemoglobin producing compounds. Pharmacological Reviews 3: 144–196, 1951PubMedGoogle Scholar
  4. Bolyai JZ, Smith RP, Gray CT. Ascorbic acid and chemically induced methemoglobinemias. Toxicology and Applied Pharmacology 21: 176–185, 1972PubMedCrossRefGoogle Scholar
  5. Bruton OC. Exchange transfusion for acute poisoning in children. US Armed Forces Medical Journal 9: 1128–1131, 1958Google Scholar
  6. Bucklin R, Myint MK. Fatal methemoglobinemia due to well water nitrates. Annals of Internal Medicine 52: 703–705, 1960PubMedGoogle Scholar
  7. Cartwright GE. Methemoglobin and sulfhemoglobin. In Harrison (Ed.) Principles of internal medicine, 8th ed., pp. 1710–1713, McGraw-Hill, New York, 1977Google Scholar
  8. Chugh KS, Singhal PC, Sharma BK. Methemoglobinemia in acute copper sulfate poisoning. Annals of Internal Medicine 82: 226–229, 1975PubMedGoogle Scholar
  9. Clutton-Brock J. Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. British Journal of Anaesthesiology 39: 388–392, 1967CrossRefGoogle Scholar
  10. Cohen BL, Bovasso GJ. Acquired methemoglobinemia and hemolytic anemia following excessive Pyridium (phenazopyridine hydrochloride) ingestion. Clinical Pediatrics 10: 537–540, 1971PubMedCrossRefGoogle Scholar
  11. Cohen RJ, Sachs JR, Wicker DJ, et al. Methemoglobinemia provoked by malarial chemoprophylaxis in Vietnam. New England Journal of Medicine 279: 1127–1131, 1968PubMedCrossRefGoogle Scholar
  12. Cunningham AA. Resorcin poisoning. Archives of Disease in Childhood 31: 173–176, 1956PubMedCrossRefGoogle Scholar
  13. Curry S. Methemoglobinemia. Annals of Emergency Medicine 11: 214–221, 1982PubMedCrossRefGoogle Scholar
  14. Cushing AH, Smith S. Methemoglobinemia with silver nitrate therapy of a burn. Journal of Pediatrics 74: 613–615, 1969PubMedCrossRefGoogle Scholar
  15. Damergis JA, Stoker JM, Abadie JL. Methemoglobinemia after sulfamethoxazole and trimethoprim therapy. Journal of the American Medical Association 249: 590–591, 1983PubMedCrossRefGoogle Scholar
  16. Done AK. The toxic emergency. Emergency Medicine 8: 283–286, 1976Google Scholar
  17. Donovan JW. Methemoglobinemia. In Haddad & Winchester (Eds) Clinical management of poisoning and drug overdose, pp. 905–909, W.B. Saunders, Philadelphia, 1983Google Scholar
  18. Easley JL, Condon BF. Phenacetin-induced methemoglobinemia and renal failure. Anesthesiology 41: 99–100, 1974PubMedCrossRefGoogle Scholar
  19. Etteldorf JN. Methylene blue in treatment of methemoglobinemia in premature infants caused by marking ink, 8 cases reported. Journal of Pediatrics 38: 24–27, 1951PubMedCrossRefGoogle Scholar
  20. Ewing MC, Mayon-White RM. Cyanosis in infancy from nitrates in drinking-water. Lancet 1: 931–943, 1951PubMedCrossRefGoogle Scholar
  21. Fibuch EE, Cecil WT, Reed WA. Methemoglobinemia associated with organic nitrate therapy. Anesthesia and Analgesia 58: 521–523, 1979PubMedCrossRefGoogle Scholar
  22. Filer LJ, Lower CU, Barness LA, et al. Infant methemoglobinemia: the role of dietary nitrate. Pediatrics 46: 475–478, 1970Google Scholar
  23. Finch CA. Methemoglobin and sulfhemoglobin. New England Journal of Medicine 239: 470–478, 1948PubMedCrossRefGoogle Scholar
  24. Gosselin RE, Smith RP, Hodge HC, et al. Nitrite. In Clinical toxicology of commercial products, 5th ed., pp. III–314–319, Williams & Wilkins, Baltimore, 1984Google Scholar
  25. Grant RS. Well water nitrate poisoning review: a survey in Nebraska 1973 to 1978. Nebraska Medical Journal 66: 197–200, 1981PubMedGoogle Scholar
  26. Graubarth J, Bloom CJ, Coleman FC, et al. Dye poisoning in the nursery. Journal of the American Medical Association 238: 1155–1157, 1945CrossRefGoogle Scholar
  27. Green ED, Zimmerman RC, Ghurabi WH, et al. Phenazopyridine hydrochloride toxicity: a cause of drug-induced methemoglobinemia. Journal of the American College of Emergency Physicians 8: 426–431, 1979PubMedCrossRefGoogle Scholar
  28. Guss DA, Normann SA, Manoguerra AS. Clinically significant methemoglobinemia from inhalation of isobutyl nitrite. American Journal of Emergency Medicine 3: 46–47, 1985PubMedCrossRefGoogle Scholar
  29. Halsted HC. Industrial methemoglobinemia. Journal of Occupational Medicine 2: 591–596, 1960PubMedGoogle Scholar
  30. Harris JC, Rumack BH, Peterson RG, et al. Methemoglobinemia resulting from absorption of nitrates. Journal of the American Medical Association 242: 2869–2871, 1979PubMedCrossRefGoogle Scholar
  31. Jaffe E. Hereditary methemoglobinemia associated with abnormalities in the metabolism of erythrocytes. American Journal of Medicine 41: 786–798, 1966PubMedCrossRefGoogle Scholar
  32. Jaffe ER. Methemoglobinemia and sulfhemoglobinemia. In Beeson et al. (Eds) Cecil textbook of medicine, 15th ed., pp. 1780–1782, W.B. Saunders, Philadelphia, 1979Google Scholar
  33. Jaffe E, Hsieh H-S. DPNH-methemoglobin reductase deficiency and hereditary methemoglobinemia. Seminars in Hematology 8: 417–437, 1971PubMedGoogle Scholar
  34. Keating JP, Lell ME, Strauss AW, et al. Infantile methemoglobinemia caused by carrot juice. New England Journal of Medicine 288: 824–826, 1973PubMedCrossRefGoogle Scholar
  35. Klendshoj NC, Burke WJ, Anthone R, et al. Chlorate poisoning. Journal of the American Medical Association 180: 107–108, 1962CrossRefGoogle Scholar
  36. Marshall JB, Ecklund RE. Methemoglobinemia from overdose of nitroglycerin. Journal of the American Medical Association 244: 330, 1980PubMedCrossRefGoogle Scholar
  37. McGuigan MA. Benzocaine-induced methemoglobinemia. Canadian Medical Association Journal 125: 816, 1981PubMedGoogle Scholar
  38. Miale JB. Laboratory medicine hematology, pp. 528–533, C.V. Mosby, St. Louis, 1977Google Scholar
  39. Miller LW. Methemoglobinemia associated with well water. Journal of the American Medical Association 216: 1642–1643, 1971PubMedCrossRefGoogle Scholar
  40. Mills GC. Hemoglobin catabolism: II. The protection of hemoglobin from oxidative breakdown. Journal of Biological Chemistry 229: 189–197, 1957PubMedGoogle Scholar
  41. Munroe WD, Lawson WJ, Holcomb TM. Hemolytic anemia with methemoglobinemia due to PAS. American Journal of Diseases of Children 108: 425–429, 1969Google Scholar
  42. Nadler JE, Green H, Rosenbaum A. Intravenous injection of methylene blue in man with reference to its toxic symptoms and effect on the electrocardiogram. American Journal of Medical Sciences 188: 15–21, 1934CrossRefGoogle Scholar
  43. Nathan DM, Siegel AJ, Bunn HG. Acute methemoglobinemia and hemolytic anemia with phenazopyridine. Archives of Internal Medicine 137: 1636–1638, 1977PubMedCrossRefGoogle Scholar
  44. O’Donohue WJ, Moss LM, Angelillo VA. Acute methemoglobinemia induced by topical benzocaine and lidocaine. Archives of Internal Medicine 140: 1508–1509, 1980PubMedCrossRefGoogle Scholar
  45. Peters JW. Hydrogen sulfide poisoning in a hospital setting. Journal of the American Medical Association 246: 1588–1589, 1981PubMedCrossRefGoogle Scholar
  46. Poppers PJ, Vosburgh GJ, Finster M. Methemoglobinemia following epidural anesthesia during labor. American Journal of Obstetrics and Gynecology 95: 630–635, 1956Google Scholar
  47. Ramsay DHE, Harvey CC. Marking ink poisoning. An outbreak of methemoglobinaemia cyanosis in newborn babies. Lancet 1: 910–912, 1959PubMedCrossRefGoogle Scholar
  48. Rosen PJ, Johnson C, McGehee WG, et al. Failure of methylene blue treatment in toxic methemoglobinemia. Annals of Internal Medicine 75: 83–86, 1971PubMedGoogle Scholar
  49. Rossi-Fanelli A, Antonini E, Mondovi B. Ferrihemoglobin reduction in normal and methemoglobinemic subjects. Clinica Chimica Acta 2: 476–480, 1957CrossRefGoogle Scholar
  50. Sass MD, Caruso CJ, Farhangi M. TPNH-methemoglobin reductase deficiency: a new red-cell enzyme defect. Journal of Laboratory and Clinical Medicine 70: 760–767, 1967PubMedGoogle Scholar
  51. Schimelman MA, Soler JM, Muller HA. Methemoglobinemia: nitrobenzene ingestion. Journal of the American College of Emergency Physicians 7: 406–408, 1978PubMedCrossRefGoogle Scholar
  52. Scott EM. Congenital methemoglobinemia due to DPNH-diaphorase. In Buetler (Ed.) Hereditary disorders of erythrocyte metabolism, p. 102, Grune & Stratton, New York, 1968Google Scholar
  53. Scott EM, Duncan IW, Ekstrand V. Reduction of methemoglobin Federation Proceedings 22: 467, 1963Google Scholar
  54. Shahidi NT, Hemaidan A. Acetophenetidin-induced methemoglobinemia and its relation to the excretion of diazotizable amines. Journal of Laboratory and Clinical Medicine 74: 581–585, 1969PubMedGoogle Scholar
  55. Shapiro BA, Cane RD, Harrison RA, et al. Methemoglobin levels in the patient population of an acute general hospital. Intensive Care Medicine 8: 295–297, 1982PubMedCrossRefGoogle Scholar
  56. Shesser R, Mitchell J, Edelstein S. Methemoglobinemia from isobutyl nitrite preparations. Annals of Emergency Medicine 10: 262–264, 1981PubMedCrossRefGoogle Scholar
  57. Siggaard-Anderson O, Norgaard-Pederson B, Rem J. Hemoglobin pigments. Spectrophotometric determination of oxy-, carboxy-, met-, and sulfhemoglobin in capillary blood. Clinica Chimica Acta 42: 85–100, 1972CrossRefGoogle Scholar
  58. Smith RP, Olson MV. Drug-induced methemoglobinemia. Seminars in Hematology 10: 253–268, 1973PubMedGoogle Scholar
  59. Strauch B, Buch W, Grey W, et al. Successful treatment of methemoglobinemia secondary to silver nitrate therapy. New England Journal of Medicine 281: 257–258, 1969PubMedCrossRefGoogle Scholar
  60. Ternberg JL, Luce E. Methemoglobinemia: a complication of the silver nitrate treatment of burns. Pediatric Surgery 63: 328–330, 1968Google Scholar
  61. Thienes CH, Haley TJ. Clinical toxicology, pp. 237–239, Lea & Febiger, Philadelphia, 1979Google Scholar
  62. Valaes T, Doxiadis SA, Fessas PO. Acute hemolysis due to naphthalene inhalation. Journal of Pediatrics 63: 904–915, 1963PubMedCrossRefGoogle Scholar
  63. Vigil J, Warburton S, Haynes WS, et al. Nitrates in municipal water supply cause methemoglobinemia in infant. Public Health Reports 80: 1119–1121, 1965PubMedCrossRefGoogle Scholar
  64. Whitwam JG, Taylor AR, White JM. Potential hazard of methylene blue. Anaesthesia 34: 181–182, 1979PubMedCrossRefGoogle Scholar
  65. Wintrobe M, Lee GR, Boggs DR, et al. Clinical Hematology, 8th ed., pp. 97–104, Lea & Febiger, Philadelphia, 1981Google Scholar
  66. Yano SS, Danish EH, Hsia YE. Transient methemoglobinemia with acidosis in infants. Journal of Pediatrics 100: 415–418, 1982PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Limited 1986

Authors and Affiliations

  • Alan H. Hall
    • 1
  • Kenneth W. Kulig
    • 1
  • Barry H. Rumack
    • 1
  1. 1.Rocky Mountain Poison and Drug CenterUniversity of Colorado Health Sciences Center, Denver, General HospitalDenverUSA

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