Skip to main content
SpringerLink
Log in

Drug- and Chemical-Induced Methaemoglobinaemia

Clinical Features and Management

  • Toxicology Management Review
  • Published:
Medical Toxicology Aims and scope Submit manuscript

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bakshi SP, Fahey JL, Pierce LE. Sausage cyanosis — acquired methemoglobinemic nitrite poisoning. New England Journal of Medicine 277: 1072, 1967

    Article  PubMed  CAS  Google Scholar 

  • 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, 1985

    Article  CAS  Google Scholar 

  • Bodansky O. Methemoglobinemia and methemoglobin producing compounds. Pharmacological Reviews 3: 144–196, 1951

    PubMed  CAS  Google Scholar 

  • Bolyai JZ, Smith RP, Gray CT. Ascorbic acid and chemically induced methemoglobinemias. Toxicology and Applied Pharmacology 21: 176–185, 1972

    Article  PubMed  CAS  Google Scholar 

  • Bruton OC. Exchange transfusion for acute poisoning in children. US Armed Forces Medical Journal 9: 1128–1131, 1958

    CAS  Google Scholar 

  • Bucklin R, Myint MK. Fatal methemoglobinemia due to well water nitrates. Annals of Internal Medicine 52: 703–705, 1960

    PubMed  CAS  Google Scholar 

  • Cartwright GE. Methemoglobin and sulfhemoglobin. In Harrison (Ed.) Principles of internal medicine, 8th ed., pp. 1710–1713, McGraw-Hill, New York, 1977

    Google Scholar 

  • Chugh KS, Singhal PC, Sharma BK. Methemoglobinemia in acute copper sulfate poisoning. Annals of Internal Medicine 82: 226–229, 1975

    PubMed  CAS  Google Scholar 

  • 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, 1967

    Article  CAS  Google Scholar 

  • Cohen BL, Bovasso GJ. Acquired methemoglobinemia and hemolytic anemia following excessive Pyridium (phenazopyridine hydrochloride) ingestion. Clinical Pediatrics 10: 537–540, 1971

    Article  PubMed  CAS  Google Scholar 

  • Cohen RJ, Sachs JR, Wicker DJ, et al. Methemoglobinemia provoked by malarial chemoprophylaxis in Vietnam. New England Journal of Medicine 279: 1127–1131, 1968

    Article  PubMed  CAS  Google Scholar 

  • Cunningham AA. Resorcin poisoning. Archives of Disease in Childhood 31: 173–176, 1956

    Article  PubMed  CAS  Google Scholar 

  • Curry S. Methemoglobinemia. Annals of Emergency Medicine 11: 214–221, 1982

    Article  PubMed  CAS  Google Scholar 

  • Cushing AH, Smith S. Methemoglobinemia with silver nitrate therapy of a burn. Journal of Pediatrics 74: 613–615, 1969

    Article  PubMed  CAS  Google Scholar 

  • Damergis JA, Stoker JM, Abadie JL. Methemoglobinemia after sulfamethoxazole and trimethoprim therapy. Journal of the American Medical Association 249: 590–591, 1983

    Article  PubMed  CAS  Google Scholar 

  • Done AK. The toxic emergency. Emergency Medicine 8: 283–286, 1976

    Google Scholar 

  • Donovan JW. Methemoglobinemia. In Haddad & Winchester (Eds) Clinical management of poisoning and drug overdose, pp. 905–909, W.B. Saunders, Philadelphia, 1983

    Google Scholar 

  • Easley JL, Condon BF. Phenacetin-induced methemoglobinemia and renal failure. Anesthesiology 41: 99–100, 1974

    Article  PubMed  CAS  Google Scholar 

  • Etteldorf JN. Methylene blue in treatment of methemoglobinemia in premature infants caused by marking ink, 8 cases reported. Journal of Pediatrics 38: 24–27, 1951

    Article  PubMed  CAS  Google Scholar 

  • Ewing MC, Mayon-White RM. Cyanosis in infancy from nitrates in drinking-water. Lancet 1: 931–943, 1951

    Article  PubMed  CAS  Google Scholar 

  • Fibuch EE, Cecil WT, Reed WA. Methemoglobinemia associated with organic nitrate therapy. Anesthesia and Analgesia 58: 521–523, 1979

    Article  PubMed  CAS  Google Scholar 

  • Filer LJ, Lower CU, Barness LA, et al. Infant methemoglobinemia: the role of dietary nitrate. Pediatrics 46: 475–478, 1970

    Google Scholar 

  • Finch CA. Methemoglobin and sulfhemoglobin. New England Journal of Medicine 239: 470–478, 1948

    Article  PubMed  CAS  Google Scholar 

  • Gosselin RE, Smith RP, Hodge HC, et al. Nitrite. In Clinical toxicology of commercial products, 5th ed., pp. III–314–319, Williams & Wilkins, Baltimore, 1984

    Google Scholar 

  • Grant RS. Well water nitrate poisoning review: a survey in Nebraska 1973 to 1978. Nebraska Medical Journal 66: 197–200, 1981

    PubMed  CAS  Google Scholar 

  • Graubarth J, Bloom CJ, Coleman FC, et al. Dye poisoning in the nursery. Journal of the American Medical Association 238: 1155–1157, 1945

    Article  Google Scholar 

  • 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, 1979

    Article  PubMed  CAS  Google Scholar 

  • Guss DA, Normann SA, Manoguerra AS. Clinically significant methemoglobinemia from inhalation of isobutyl nitrite. American Journal of Emergency Medicine 3: 46–47, 1985

    Article  PubMed  CAS  Google Scholar 

  • Halsted HC. Industrial methemoglobinemia. Journal of Occupational Medicine 2: 591–596, 1960

    PubMed  CAS  Google Scholar 

  • Harris JC, Rumack BH, Peterson RG, et al. Methemoglobinemia resulting from absorption of nitrates. Journal of the American Medical Association 242: 2869–2871, 1979

    Article  PubMed  CAS  Google Scholar 

  • Jaffe E. Hereditary methemoglobinemia associated with abnormalities in the metabolism of erythrocytes. American Journal of Medicine 41: 786–798, 1966

    Article  PubMed  CAS  Google Scholar 

  • Jaffe ER. Methemoglobinemia and sulfhemoglobinemia. In Beeson et al. (Eds) Cecil textbook of medicine, 15th ed., pp. 1780–1782, W.B. Saunders, Philadelphia, 1979

    Google Scholar 

  • Jaffe E, Hsieh H-S. DPNH-methemoglobin reductase deficiency and hereditary methemoglobinemia. Seminars in Hematology 8: 417–437, 1971

    PubMed  CAS  Google Scholar 

  • Keating JP, Lell ME, Strauss AW, et al. Infantile methemoglobinemia caused by carrot juice. New England Journal of Medicine 288: 824–826, 1973

    Article  PubMed  CAS  Google Scholar 

  • Klendshoj NC, Burke WJ, Anthone R, et al. Chlorate poisoning. Journal of the American Medical Association 180: 107–108, 1962

    Article  Google Scholar 

  • Marshall JB, Ecklund RE. Methemoglobinemia from overdose of nitroglycerin. Journal of the American Medical Association 244: 330, 1980

    Article  PubMed  CAS  Google Scholar 

  • McGuigan MA. Benzocaine-induced methemoglobinemia. Canadian Medical Association Journal 125: 816, 1981

    PubMed  CAS  Google Scholar 

  • Miale JB. Laboratory medicine hematology, pp. 528–533, C.V. Mosby, St. Louis, 1977

    Google Scholar 

  • Miller LW. Methemoglobinemia associated with well water. Journal of the American Medical Association 216: 1642–1643, 1971

    Article  PubMed  CAS  Google Scholar 

  • Mills GC. Hemoglobin catabolism: II. The protection of hemoglobin from oxidative breakdown. Journal of Biological Chemistry 229: 189–197, 1957

    PubMed  CAS  Google Scholar 

  • Munroe WD, Lawson WJ, Holcomb TM. Hemolytic anemia with methemoglobinemia due to PAS. American Journal of Diseases of Children 108: 425–429, 1969

    Google Scholar 

  • 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, 1934

    Article  CAS  Google Scholar 

  • Nathan DM, Siegel AJ, Bunn HG. Acute methemoglobinemia and hemolytic anemia with phenazopyridine. Archives of Internal Medicine 137: 1636–1638, 1977

    Article  PubMed  CAS  Google Scholar 

  • O’Donohue WJ, Moss LM, Angelillo VA. Acute methemoglobinemia induced by topical benzocaine and lidocaine. Archives of Internal Medicine 140: 1508–1509, 1980

    Article  PubMed  Google Scholar 

  • Peters JW. Hydrogen sulfide poisoning in a hospital setting. Journal of the American Medical Association 246: 1588–1589, 1981

    Article  PubMed  CAS  Google Scholar 

  • Poppers PJ, Vosburgh GJ, Finster M. Methemoglobinemia following epidural anesthesia during labor. American Journal of Obstetrics and Gynecology 95: 630–635, 1956

    Google Scholar 

  • Ramsay DHE, Harvey CC. Marking ink poisoning. An outbreak of methemoglobinaemia cyanosis in newborn babies. Lancet 1: 910–912, 1959

    Article  PubMed  CAS  Google Scholar 

  • Rosen PJ, Johnson C, McGehee WG, et al. Failure of methylene blue treatment in toxic methemoglobinemia. Annals of Internal Medicine 75: 83–86, 1971

    PubMed  CAS  Google Scholar 

  • Rossi-Fanelli A, Antonini E, Mondovi B. Ferrihemoglobin reduction in normal and methemoglobinemic subjects. Clinica Chimica Acta 2: 476–480, 1957

    Article  CAS  Google Scholar 

  • 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, 1967

    PubMed  CAS  Google Scholar 

  • Schimelman MA, Soler JM, Muller HA. Methemoglobinemia: nitrobenzene ingestion. Journal of the American College of Emergency Physicians 7: 406–408, 1978

    Article  PubMed  CAS  Google Scholar 

  • Scott EM. Congenital methemoglobinemia due to DPNH-diaphorase. In Buetler (Ed.) Hereditary disorders of erythrocyte metabolism, p. 102, Grune & Stratton, New York, 1968

    Google Scholar 

  • Scott EM, Duncan IW, Ekstrand V. Reduction of methemoglobin Federation Proceedings 22: 467, 1963

    Google Scholar 

  • 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, 1969

    PubMed  CAS  Google Scholar 

  • 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, 1982

    Article  PubMed  CAS  Google Scholar 

  • Shesser R, Mitchell J, Edelstein S. Methemoglobinemia from isobutyl nitrite preparations. Annals of Emergency Medicine 10: 262–264, 1981

    Article  PubMed  CAS  Google Scholar 

  • 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, 1972

    Article  Google Scholar 

  • Smith RP, Olson MV. Drug-induced methemoglobinemia. Seminars in Hematology 10: 253–268, 1973

    PubMed  CAS  Google Scholar 

  • 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, 1969

    Article  PubMed  CAS  Google Scholar 

  • Ternberg JL, Luce E. Methemoglobinemia: a complication of the silver nitrate treatment of burns. Pediatric Surgery 63: 328–330, 1968

    Google Scholar 

  • Thienes CH, Haley TJ. Clinical toxicology, pp. 237–239, Lea & Febiger, Philadelphia, 1979

    Google Scholar 

  • Valaes T, Doxiadis SA, Fessas PO. Acute hemolysis due to naphthalene inhalation. Journal of Pediatrics 63: 904–915, 1963

    Article  PubMed  CAS  Google Scholar 

  • Vigil J, Warburton S, Haynes WS, et al. Nitrates in municipal water supply cause methemoglobinemia in infant. Public Health Reports 80: 1119–1121, 1965

    Article  PubMed  CAS  Google Scholar 

  • Whitwam JG, Taylor AR, White JM. Potential hazard of methylene blue. Anaesthesia 34: 181–182, 1979

    Article  PubMed  CAS  Google Scholar 

  • Wintrobe M, Lee GR, Boggs DR, et al. Clinical Hematology, 8th ed., pp. 97–104, Lea & Febiger, Philadelphia, 1981

    Google Scholar 

  • Yano SS, Danish EH, Hsia YE. Transient methemoglobinemia with acidosis in infants. Journal of Pediatrics 100: 415–418, 1982

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rocky Mountain Poison and Drug Center, University of Colorado Health Sciences Center, Denver, General Hospital, Denver, USA

    Alan H. Hall, Kenneth W. Kulig &  Barry H. Rumack

Authors
  1. Alan H. Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth W. Kulig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barry H. Rumack
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hall, A.H., Kulig, K.W. & Rumack, B.H. Drug- and Chemical-Induced Methaemoglobinaemia. Medical Toxicology 1, 253–260 (1986). https://doi.org/10.1007/BF03259842

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03259842

Search

Navigation