THE CLASSIFICATION AND TREATMENT

OF METHEMOGLOBINEMIA I

LEROY DOCTOR2

OXIDATION of hemoglobin leads to the formation of methemoglobin, a

compound which contains the same am~)Unt of oxygen as oxyhemoglobin, but ,,,hlch no longer is capable of dissociation wi th release of oxygen in the tissues. Methemoglobin itself has no toxic effects. The symptoms in methemoglobinemia a re due to the anoxia resulting from the lessened oxygen combining and carrying power of the total blood pigment, and the shift to the left of t.he oxygen dissociation curve with the resultant decreased dis­sociation of the remaining oxyhemoglobin (4, 5, 18, 19, 23).

It is generally agreed (4, 7 8 16 30) that un til 50 to 60 per cent of the h~mo­globin has been oxidized to methemo­globin there a re few symptoms other t.han reduced spontaneous activi ty. Above this level there is a progression of ataxia, excess salivation, and vomit ing. Wi th an 80 per cent methemoglobin level t here are prostration and unconsciousness. Levels ahove 90 per cent a re fatal.

C LASSIFICATION

Clinically, methemoglobinemia can be classified into intracellular and extra­cellular types .

EXTRACELLULAR METHEMOGLOBINEM IA:

Extracellular or plasma methemoglobin­emia is associated with diseases in which there is hemolysis, such as eclampsia, black,mter fever, paroxysmal hemoglo­binuria, sepsis due to anaerobic organ­Isms, and hemolytic icterus (3· 14). In these conditions hemoglobin di~solved in the plasma is changed to methemoglobin. Plasma methemoglobinemia is character-

. IThis project \~'as upported in part by a Cancer Teach­u:g. Grant provlde~ hy the National Cancer Institute, L ll1!ed States PublIc Health Service.

Received for publication, April 22, 1953. 2Student research assis tant, Department of Patholog\"

,""orthwestern L:niversity Medical School. • ,

ized by cyanosis, icterus, hemolysis and methemoglobinuria. '

INTRACELLU LAR METHEMO GLOBINEMIA:

Intracellular methemoglobinemia may be divided into primary and secondary types.

Primary. Primary or idiopathic meth­emoglobinemia is believed to be congen­ital, half of the known cases showing familial tendencies (12, 18, 20, 22, 27). The body normally has mechanisms by which it keeps hemoglobin in its reduced (ferro) form . The principal mechanism, defective in idiopathic methemoglobin­emia, is an intracellular process utilizing carbohydrates as substrates (15). This mechanism is usually sufficiently effec­tive to keep the methemoglobin level at 1 per cent or less. In primary methemo­globinemia, however, because this reduc­ing process is defective, an equilibrium is reached at which 40 per cent of the blood pigment is present as methemoglobin. The blood of a person with idiopathic methemoglobinemia has a 10"'er ascorbic acid content than normal. Furthermore, t he methemoglobin is not reconverted to hemoglobin when allowed to stand in a test tube 24 hours (27).

S econdary. Secondary methemeglobin­emia has an exogenous origin, gener­ally being caused by chemicals. It may also accompany hemolytic anemias (16) or occur as a primary enterogenous type. The principal chemicals responsible for the formation of methemoglobin are the nit rates, sulfonamides, and aniline deriv­atives. Nitrates may be inhaled (amyl nitrate), or ingested as food or medica­t ion [bismuth sub nitrate (16, 31)], or drink [sodium nitrate in well water (9, 25, 32)] . The administration of su lfon­amides may lead to the formation of both methemoglobin and sulfhemoglobin . Ani­line dyes are capable of penetrating the skin and producing methemoglobinemia

134

THE CLASSIFICATION AND TREATMENT

OF METHEMOGLOBINEMIA I

LEROY DOCTOR2

OXIDATION of hemoglobin leads to the formation of methemoglobin, a

compound which contains the same am~)Unt of oxygen as oxyhemoglobin, but ,,,hlch no longer is capable of dissociation wi th release of oxygen in the tissues. Methemoglobin itself has no toxic effects. The symptoms in methemoglobinemia a re due to the anoxia resulting from the lessened oxygen combining and carrying power of the total blood pigment, and the shift to the left of t.he oxygen dissociation curve with the resultant decreased dis­sociation of the remaining oxyhemoglobin (4, 5, 18, 19, 23).

It is generally agreed (4, 7 8 16 30) that un til 50 to 60 per cent of the h~mo­globin has been oxidized to methemo­globin there a re few symptoms other t.han reduced spontaneous activi ty. Above this level there is a progression of ataxia, excess salivation, and vomit ing. Wi th an 80 per cent methemoglobin level t here are prostration and unconsciousness. Levels ahove 90 per cent a re fatal.

C LASSIFICATION

Clinically, methemoglobinemia can be classified into intracellular and extra­cellular types .

EXTRACELLULAR METHEMOGLOBINEM IA:

Extracellular or plasma methemoglobin­emia is associated with diseases in which there is hemolysis, such as eclampsia, black,mter fever, paroxysmal hemoglo­binuria, sepsis due to anaerobic organ­Isms, and hemolytic icterus (3· 14). In these conditions hemoglobin di~solved in the plasma is changed to methemoglobin. Plasma methemoglobinemia is character-

. IThis project \~'as upported in part by a Cancer Teach­u:g. Grant provlde~ hy the National Cancer Institute, L ll1!ed States PublIc Health Service.

Received for publication, April 22, 1953. 2Student research assis tant, Department of Patholog\"

,""orthwestern L:niversity Medical School. • ,

ized by cyanosis, icterus, hemolysis and methemoglobinuria. '

INTRACELLU LAR METHEMO GLOBINEMIA:

Intracellular methemoglobinemia may be divided into primary and secondary types.

Primary. Primary or idiopathic meth­emoglobinemia is believed to be congen­ital, half of the known cases showing familial tendencies (12, 18, 20, 22, 27). The body normally has mechanisms by which it keeps hemoglobin in its reduced (ferro) form . The principal mechanism, defective in idiopathic methemoglobin­emia, is an intracellular process utilizing carbohydrates as substrates (15). This mechanism is usually sufficiently effec­tive to keep the methemoglobin level at 1 per cent or less. In primary methemo­globinemia, however, because this reduc­ing process is defective, an equilibrium is reached at which 40 per cent of the blood pigment is present as methemoglobin. The blood of a person with idiopathic methemoglobinemia has a 10"'er ascorbic acid content than normal. Furthermore, t he methemoglobin is not reconverted to hemoglobin when allowed to stand in a test tube 24 hours (27).

S econdary. Secondary methemeglobin­emia has an exogenous origin, gener­ally being caused by chemicals. It may also accompany hemolytic anemias (16) or occur as a primary enterogenous type. The principal chemicals responsible for the formation of methemoglobin are the nit rates, sulfonamides, and aniline deriv­atives. Nitrates may be inhaled (amyl nitrate), or ingested as food or medica­t ion [bismuth sub nitrate (16, 31)], or drink [sodium nitrate in well water (9, 25, 32)] . The administration of su lfon­amides may lead to the formation of both methemoglobin and sulfhemoglobin . Ani­line dyes are capable of penetrating the skin and producing methemoglobinemia

134

DOCTOR-METHEMOGLOBINEMIA 135

by action of their breakdO\m products, phenylhydroxlamine and aminophenol.

Enterogenous methemoglobinemia may be found in patients with gastrointes­tinal upsets, more commonly diarrhea than constipation (6, 16). Often there is abdominal pain, headache, cyanosis, dyspnea, dizziness, collapse, syncope, and anemia. Normally, ingested nitrates are changed to nitrites which are further broken down to ammonia and excreted without being absorbed. However, when a gastrointestinal disturbance is present, the process proceeds only as far as nitrate formation , and the nitrates are absorbed through the damaged intestinal mucosa (14).

Methemoglobemia from ingested ni­trates occurs without gastrointestinal dis­turbance in cases where E. coli and A. aerogenes are found in the upper gastro­intestinal tract due to a high pH of gastric juice (10). This occurs most fre­quently in the neonatal period (25).

TREATMENT

The normal reconversion mechanisms convert methemoglobin to hemoglobin at a rate of 0.5 gm. of methemoglobin per hour (15). This is accomplished by an enzymatic process using triosephosphate and lactate as substrates. This oxidation­reduction system requires coenzyme fac­tor I in addition to coenzyme I (DPN) and specific enzymes. In normal erythro­cytes the coenzyme II system is not active in methemoglobin reduction. The follow­ing reactions are thought to occur:

globin . However, in primary methemo­globinemia, where these conversion mech­anisms are reduced, and in secondary methemoglobinemia \\'here one wishes to speed up these conversion mechanisms, certain drugs are employed.

Ascorbic Acid: J n primary methemo­globinemia, methemoglobin is not re­duced with appreciable speed in the presence of triosephosphate (or glucose) or lactate. The erythrocytes in primary methemoglobinemia contain a lower con­concentration of coenzyme factor I than normal cells, causing a slo\\'er rate of re­conversion and thus a higher concentra­tion of methemoglobin (17). The methe­moglobin level , however, does not con­tinue to rise without limitat ion because as its concentration increases, its rate of reaction \\'ith nonspecific reducing agents in the blood also ri ses, and an equilib­rium is thus established. Ascorbic acid is the most important of the nonspecific reducing substances in the blood. It reacts with methemoglobi n yielding hemo­globin and dehydroascorbic acid . The latter is then reduced to ascorbic acid by glutathione.

Ascorbic acid, the most important re­ducing substance normally found in blood , has a reconversion rate of 0.1 to 0.3 gm. of methemoglobin per hour (15), an amount less than the normal recon­version rate of over 0.3 gm. per hour (27) . It thus finds its application in the primary methemoglohinemias, where, in do es of 100 to 500 mg. per Kg. per day (22) , it effectively redu ces methemoglobin

(1) Glucose glycolysis Lactate + 2 MHb dehydrogenase

coenzyme I

2 Hb + pyruvate. coenzyme factor J

(2) Glucose glycolysis Triose phosphate + 2 MHb

dehydrogenase coenzyme I --------------~

coenzyme factor I 2 Hb + phosphoglycerate.

After removal of the offending sub­stance in secondary methemoglobinemia, the normal cell conversion mechanisms will reconvert methemoglobin to hemo-

levels from 40 per cent to 7 to 10 per cent of the total blood pigment (22) in the absence of the normal reducing mechan­ism. It is especially useful in primary

DOCTOR-METHEMOGLOBINEMIA 135

by action of their breakdO\m products, phenylhydroxlamine and aminophenol.

Enterogenous methemoglobinemia may be found in patients with gastrointes­tinal upsets, more commonly diarrhea than constipation (6, 16). Often there is abdominal pain, headache, cyanosis, dyspnea, dizziness, collapse, syncope, and anemia. Normally, ingested nitrates are changed to nitrites which are further broken down to ammonia and excreted without being absorbed. However, when a gastrointestinal disturbance is present, the process proceeds only as far as nitrate formation , and the nitrates are absorbed through the damaged intestinal mucosa (14).

Methemoglobemia from ingested ni­trates occurs without gastrointestinal dis­turbance in cases where E. coli and A. aerogenes are found in the upper gastro­intestinal tract due to a high pH of gastric juice (10). This occurs most fre­quently in the neonatal period (25).

TREATMENT

The normal reconversion mechanisms convert methemoglobin to hemoglobin at a rate of 0.5 gm. of methemoglobin per hour (15). This is accomplished by an enzymatic process using triosephosphate and lactate as substrates. This oxidation­reduction system requires coenzyme fac­tor I in addition to coenzyme I (DPN) and specific enzymes. In normal erythro­cytes the coenzyme II system is not active in methemoglobin reduction. The follow­ing reactions are thought to occur:

globin . However, in primary methemo­globinemia, where these conversion mech­anisms are reduced, and in secondary methemoglobinemia \\'here one wishes to speed up these conversion mechanisms, certain drugs are employed.

Ascorbic Acid: J n primary methemo­globinemia, methemoglobin is not re­duced with appreciable speed in the presence of triosephosphate (or glucose) or lactate. The erythrocytes in primary methemoglobinemia contain a lower con­concentration of coenzyme factor I than normal cells, causing a slo\\'er rate of re­conversion and thus a higher concentra­tion of methemoglobin (17). The methe­moglobin level , however, does not con­tinue to rise without limitat ion because as its concentration increases, its rate of reaction \\'ith nonspecific reducing agents in the blood also ri ses, and an equilib­rium is thus established. Ascorbic acid is the most important of the nonspecific reducing substances in the blood. It reacts with methemoglobi n yielding hemo­globin and dehydroascorbic acid . The latter is then reduced to ascorbic acid by glutathione.

Ascorbic acid, the most important re­ducing substance normally found in blood , has a reconversion rate of 0.1 to 0.3 gm. of methemoglobin per hour (15), an amount less than the normal recon­version rate of over 0.3 gm. per hour (27) . It thus finds its application in the primary methemoglohinemias, where, in do es of 100 to 500 mg. per Kg. per day (22) , it effectively redu ces methemoglobin

(1) Glucose glycolysis Lactate + 2 MHb dehydrogenase

coenzyme I

2 Hb + pyruvate. coenzyme factor J

(2) Glucose glycolysis Triose phosphate + 2 MHb

dehydrogenase coenzyme I --------------~

coenzyme factor I 2 Hb + phosphoglycerate.

After removal of the offending sub­stance in secondary methemoglobinemia, the normal cell conversion mechanisms will reconvert methemoglobin to hemo-

levels from 40 per cent to 7 to 10 per cent of the total blood pigment (22) in the absence of the normal reducing mechan­ism. It is especially useful in primary

136 QUARTERLY BULLETIN, N.U.M.S.

met.hemoglobinemia because of its lasting, non-transitory nature (1, 18). Ascorbic acid has little use in the treatment of secondary methemoglobinemia, where the usual reconversion process is maintained.

Methylene blue: Methylene blue opens a ne\\" reduction pathway within the ery­throcyte, in addition to accelerating the usual mechanism of conversion (16, 31 , 33). With methylene blue, coenzyne II (TPN) and its associated system become effective; without methylene blue, only coenzyme I (DPN) is active. The follow­ing scheme is thought to represent the mechanism of action :

Glucose phosphorylation

dehydrogenase coenzyme II

coenzvme factor II methylene blue

The phosphorylation mechanism must change glucose to hexo ephosphate, which in turn is oxidized, reducing the methe­moglobin.

In idiopathic methemoglobinemia, methylene blue causes increased methe­moglobin reduction by incorporating the coenzyme II- coenzyme factor II system, in \\'hich the erythrocytes a re not defi­cient. In this mechanism lactate causes no increased reduction, as glucose and hexosephosphate must be used as sub­strates (17).

Methylene blue has been the most widely used and the most effective agent in the treatment of methemoglobinemia, both primary and secondary . The quantities used are 1 mg. per Kg. of body weight in adults and 2 mg. per Kg. of body weight in children injected intra­venously over a 5-minute period. Alter­nately 3 to 5 mg. per Kg. of body \\"eight may be given orally. If methylene blue is used in excess (7 mg. pel' Kg.), toxic symptoms such as dyspnea, precordial pain, restlessne s, a sense of oppression, apprehension, and fibrillating tremors occur( 4, 14, 24, 28). There may also be a depressant action on circulatory and respiratory centers.

BAL: British Anti-Lewisite has been

reported to be useful in diminishing secondary methemoglobinemia in animals (4, 11). It must be given, however, in near toxic intravenous doses to be as effective as methylene blue. The dosage suggested is 10 mg. (4 ml. of a 1 :400 suspension) of BAL intravenously. Occa­sionally the effects are only transient and a second injection is needed to avoid a return of methemoglobinemia.

Sodium Thiosulfate: Experimentally, sodium thiosulfate (0.8 mg. per Kg. of body weight) has been found effective in lowering p-aminopropiophenone in­duced methemoglobin levels in dogs. This

hexose phosphate + MHb

Hb.

dosage is believed to be as effective as 0.1 mg. per Kg. of methylene blue (29).

A component of the Green-Williamson preparation (35) is active in the reduc­tion of methemoglobin when t reated with sodium thiosulphate (N a2S204) . It has been suggested (21) that this component is coenzyme factor I (DPN), which, when reduced by sodium thiosulfate, takes an active part in methemoglobin reduction . This suggests a method by which sodium thiosulfate acts as reconverter of met­hemoglobin. If sodium thiosulfate acts solely with coenzyme I , it would not be effective in primary methemoglobinemia.

SUMMARY

1. The various types of methemoglo­binemia are defined, and their causes dis­cussed. Methemoglobinemia may be classified as extracellular or intracellular types, the latter occurring either on a congeni tal or acquired basis.

2. The biochemical phenomena in the formation of methemoglobin are sum­marized, and treatment considered on this basis. Ascorbic acid, or a combination of ascorbic acid and methylene blue, are satisfactory in the t reatment of primary methemoglobinemia; methylene blue alone is effective in the secondary types.

136 QUARTERLY BULLETIN, N.U.M.S.

met.hemoglobinemia because of its lasting, non-transitory nature (1, 18). Ascorbic acid has little use in the treatment of secondary methemoglobinemia, where the usual reconversion process is maintained.

Methylene blue: Methylene blue opens a ne\\" reduction pathway within the ery­throcyte, in addition to accelerating the usual mechanism of conversion (16, 31 , 33). With methylene blue, coenzyne II (TPN) and its associated system become effective; without methylene blue, only coenzyme I (DPN) is active. The follow­ing scheme is thought to represent the mechanism of action :

Glucose phosphorylation

dehydrogenase coenzyme II

coenzvme factor II methylene blue

The phosphorylation mechanism must change glucose to hexo ephosphate, which in turn is oxidized, reducing the methe­moglobin.

In idiopathic methemoglobinemia, methylene blue causes increased methe­moglobin reduction by incorporating the coenzyme II- coenzyme factor II system, in \\'hich the erythrocytes a re not defi­cient. In this mechanism lactate causes no increased reduction, as glucose and hexosephosphate must be used as sub­strates (17).

Methylene blue has been the most widely used and the most effective agent in the treatment of methemoglobinemia, both primary and secondary . The quantities used are 1 mg. per Kg. of body weight in adults and 2 mg. per Kg. of body weight in children injected intra­venously over a 5-minute period. Alter­nately 3 to 5 mg. per Kg. of body \\"eight may be given orally. If methylene blue is used in excess (7 mg. pel' Kg.), toxic symptoms such as dyspnea, precordial pain, restlessne s, a sense of oppression, apprehension, and fibrillating tremors occur( 4, 14, 24, 28). There may also be a depressant action on circulatory and respiratory centers.

BAL: British Anti-Lewisite has been

reported to be useful in diminishing secondary methemoglobinemia in animals (4, 11). It must be given, however, in near toxic intravenous doses to be as effective as methylene blue. The dosage suggested is 10 mg. (4 ml. of a 1 :400 suspension) of BAL intravenously. Occa­sionally the effects are only transient and a second injection is needed to avoid a return of methemoglobinemia.

Sodium Thiosulfate: Experimentally, sodium thiosulfate (0.8 mg. per Kg. of body weight) has been found effective in lowering p-aminopropiophenone in­duced methemoglobin levels in dogs. This

hexose phosphate + MHb

Hb.

dosage is believed to be as effective as 0.1 mg. per Kg. of methylene blue (29).

A component of the Green-Williamson preparation (35) is active in the reduc­tion of methemoglobin when t reated with sodium thiosulphate (N a2S204) . It has been suggested (21) that this component is coenzyme factor I (DPN), which, when reduced by sodium thiosulfate, takes an active part in methemoglobin reduction . This suggests a method by which sodium thiosulfate acts as reconverter of met­hemoglobin. If sodium thiosulfate acts solely with coenzyme I , it would not be effective in primary methemoglobinemia.

SUMMARY

1. The various types of methemoglo­binemia are defined, and their causes dis­cussed. Methemoglobinemia may be classified as extracellular or intracellular types, the latter occurring either on a congeni tal or acquired basis.

2. The biochemical phenomena in the formation of methemoglobin are sum­marized, and treatment considered on this basis. Ascorbic acid, or a combination of ascorbic acid and methylene blue, are satisfactory in the t reatment of primary methemoglobinemia; methylene blue alone is effective in the secondary types.

DOCTOR-METHEMOGLOBINEMIA 137

REFEREN CES

l. Albaum, H. G., Tepperman, J . and Bodan­sky, 0.: A Spectrophotometric Study of the Competition of Methemoglobin and Cyto­chrome Oxidase for Cyanide in vitl·0, J. BioI. Chem., 163:641-647, 1946.

2. Bass, A. D., Frost, L. H. and Salter, W. T .: 2-Anileothanol-an Industrial Hazard. Pro­duction of Methemoglobinemia, J .A.M.A., 123: 761-763, 1943.

3. Bensley, E. H., Rhea, L. J . and Mills, E. S. : Familial Idiopathic Methaemoglobinaemia, Quart. J . Med. , 7:325-330, 1938. .

4. Bodansky, O. and Gutmann, H .: Treatment of Methemoglobinemia, .T. Pharm. & Exper. Therap., 90:46-56, 1947.

5. Brooks, J.: The Oxidation of Haemoglobin to Methaemoglobin by Oxygen, J. Physiol. , 107 :332-335, 1948.

6. Carnick, M., Polis, B. D. and Klein, T. , Methemoglobinemia. Treatment with Ascor­bic Acid, Arch. Int. Med. , 78:296-302, 1946.

7. Clark, B. B. and Van Loon, E. J .: The Acute Effects of Hypoxia Resulting from Methemoglobin Produced by Aniline, Fed­eration Proc., 1 :147, 1942.

8. Clark, B. B., Van Loon, E. J. and Morrissey, R. W.: Acute Experimental Aniline Intox­ication, J. Indust. Hyg. & Toxicol, 15:1-12, 1943.

9. Comly, H. H .: Cyanosis in Infants Caused by Nitrates in Well Water, J.A.M.A., 129:112-116, 1945.

10. Cornblath, M. and Hartman n, A. F.: Methemoglobinemia in Young Infant , J . Pediat. , 33:421-425, 1948.

11. Derobert, L. , Hadengue, A., LeBreton, R., et al: Action in vivo du B.A.L. dans les intox­ications par poisons methemoglobinisants, Ann. de Med. Legale, 30:51-52, 1950.

12. Diekmann, W. J.: Methemoglobinemia, Arch. Int. Med., 50:574-578, 1932.

13. Earle, D. P. , Jr. , Bigelow, F. S., Zubrod, C. G. and Kane, C. A.: Studies on the Chemo­therapy of the Human Malarias. IX. Effect of Pamaquine on the Blood Cells of Man, J. Clin. Investigation, 27:121-129, 1948.

14. Ferrant, M.: Methemoglobinemia. Two Cases in Xewborn Infants Caused by Nitrates in Well Water, J. Pediat. , 29:585-592, 1946.

15. Finch, C. A.: Treatment of Intracellular Methemoglobinemia, Bull. J'lew England M. Center, 9:241-245, 1947.

16. Finch, C. A.: Methemoglobinemia and Sulf­hemoglobinemia, New England.T. Med., 239: 470-478, 1948.

17. Gibson, Q. H.: The Reduction of Methaemo­globin in Red Blood Cells and Studies on the Cause of Idiopathic Methaemoglobinaemia, Riochem. J. , 42:13-23, 1948.

18. Gibson, Q. H. and Harrison, D. C.: Familial Idiopathic Methaemoglobinaemia. Five

Cases in One Family, Lancet, 2:941-943, 1947.

19. Gibson, Q. H. and Harrison, D. C.: Haemo­globin-Methaemoglobin Mixtures, X ature. 162:258-259, 1948.

20. Graybiel, A., Lilienthal, J. L., Jr. and Riley, R. L.: The Report of a Case of Idiopath ic Congenital (and Probably Familial) Methem­oglobinemia, Bull. Johns Hopkins Hosp. , 76:155-162, 1945.

21. Gutmann, H. R., Jandorf, J. B. and Bodan­sky, 0.: The Role of Pyridine Nucleotide in the Reduction of Methemoglobin, J . BioI. Chern., 169: 145-152, 1947.

22. Kin!!;, E. .T ., White, J . C. and Gilchrist, M.: A Case of Idiopathic Methaemoglobinaemia Treated by A cOl·bic Acid and Methylene Blue, J. Path. & Bact., 59:181-188, 1947.

23. Lester, D. and Greenberg, L. A.: The Com­parative Anoxemic Effects from Carbon Mon­oxide Hemoglobin and Methemoglobin , J. Pharmacol. & Expel". Therap. , 81 :182-188, 1944.

24. Macht, D. I. and Harden, W. C.: Toxicology and Assay of Methylene Blue, Ann. Int. Med., 71 :738-745, 1933.

25. Medovy, H.: Well-water Methemoglobin­emia in Infan ts, Journal Lancet, 68:194-196. 1948.

26. Scott, E. P.: Cyanosis Cau ed by Methemo­g~obinemia, Am. J. Dis. Cild., 78:77-79, 1~49.

27. SIevers, R. F. and Ryon, J. B.: Congellltal Idiopathic Methemoglobinemia. Favorable Response to Ascorbic Acid Therapy, Arch. Int. Med., 78:299-307, 1945.

28. Spicer, S. S.: Effect of para-Aminobenzoic Acid on the in vi/Jo Oxidation of Hemo­globin J. Indust. Hyg. & Toxicol., 31: 204-205, 1949.

29. Stevenson, G. F. and Doctor, L.: l:npub­Ii shed data.

30. Vandenbelt, J. M. , Pfeiffer, C., Kaiser, M. and Sibert, M.: Methemoglobinemia after Administration of p-Aminoacetophenone and p-Aminopropiophenone, J . Pharmacol. & Exper. Therap., 80:31-38, 1944.

31. Wallace, W. M.: Methemoglobinemia in an Infant as a Result of the Administration of Bismuth Subnitrate, J .A.M.A., 13:J:1280-1281, 1947.

32. Weart, J . G.: Effect of Nitrates in Rural Water Supplies on Infant Health , Illinois M. J ., 93:131-132, 1948-

33. Wendel, W. B.: The Control of Methemo­globinemia with Methylene Blue, J. Olin. Investigation, 18 :179-185, 1939.

34. Wendel, W. B.: Methemoglobinemia: Sig­nificance and Treatment, Memphis M. J. , 14 :3-5, 1939.

35. Williamson, S. and Green, D. E. : The Prepa­ration of Coenzyme I from Yeast, J . BioI. Chem., 135:345-346, 1940.

DOCTOR-METHEMOGLOBINEMIA 137

REFEREN CES

l. Albaum, H. G., Tepperman, J . and Bodan­sky, 0.: A Spectrophotometric Study of the Competition of Methemoglobin and Cyto­chrome Oxidase for Cyanide in vitl·0, J. BioI. Chem., 163:641-647, 1946.

2. Bass, A. D., Frost, L. H. and Salter, W. T .: 2-Anileothanol-an Industrial Hazard. Pro­duction of Methemoglobinemia, J .A.M.A., 123: 761-763, 1943.

3. Bensley, E. H., Rhea, L. J . and Mills, E. S. : Familial Idiopathic Methaemoglobinaemia, Quart. J . Med. , 7:325-330, 1938. .

4. Bodansky, O. and Gutmann, H .: Treatment of Methemoglobinemia, .T. Pharm. & Exper. Therap., 90:46-56, 1947.

5. Brooks, J.: The Oxidation of Haemoglobin to Methaemoglobin by Oxygen, J. Physiol. , 107 :332-335, 1948.

6. Carnick, M., Polis, B. D. and Klein, T. , Methemoglobinemia. Treatment with Ascor­bic Acid, Arch. Int. Med. , 78:296-302, 1946.

7. Clark, B. B. and Van Loon, E. J .: The Acute Effects of Hypoxia Resulting from Methemoglobin Produced by Aniline, Fed­eration Proc., 1 :147, 1942.

8. Clark, B. B., Van Loon, E. J. and Morrissey, R. W.: Acute Experimental Aniline Intox­ication, J. Indust. Hyg. & Toxicol, 15:1-12, 1943.

9. Comly, H. H .: Cyanosis in Infants Caused by Nitrates in Well Water, J.A.M.A., 129:112-116, 1945.

10. Cornblath, M. and Hartman n, A. F.: Methemoglobinemia in Young Infant , J . Pediat. , 33:421-425, 1948.

11. Derobert, L. , Hadengue, A., LeBreton, R., et al: Action in vivo du B.A.L. dans les intox­ications par poisons methemoglobinisants, Ann. de Med. Legale, 30:51-52, 1950.

12. Diekmann, W. J.: Methemoglobinemia, Arch. Int. Med., 50:574-578, 1932.

13. Earle, D. P. , Jr. , Bigelow, F. S., Zubrod, C. G. and Kane, C. A.: Studies on the Chemo­therapy of the Human Malarias. IX. Effect of Pamaquine on the Blood Cells of Man, J. Clin. Investigation, 27:121-129, 1948.

14. Ferrant, M.: Methemoglobinemia. Two Cases in Xewborn Infants Caused by Nitrates in Well Water, J. Pediat. , 29:585-592, 1946.

15. Finch, C. A.: Treatment of Intracellular Methemoglobinemia, Bull. J'lew England M. Center, 9:241-245, 1947.

16. Finch, C. A.: Methemoglobinemia and Sulf­hemoglobinemia, New England.T. Med., 239: 470-478, 1948.

17. Gibson, Q. H.: The Reduction of Methaemo­globin in Red Blood Cells and Studies on the Cause of Idiopathic Methaemoglobinaemia, Riochem. J. , 42:13-23, 1948.

18. Gibson, Q. H. and Harrison, D. C.: Familial Idiopathic Methaemoglobinaemia. Five

Cases in One Family, Lancet, 2:941-943, 1947.

19. Gibson, Q. H. and Harrison, D. C.: Haemo­globin-Methaemoglobin Mixtures, X ature. 162:258-259, 1948.

20. Graybiel, A., Lilienthal, J. L., Jr. and Riley, R. L.: The Report of a Case of Idiopath ic Congenital (and Probably Familial) Methem­oglobinemia, Bull. Johns Hopkins Hosp. , 76:155-162, 1945.

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