METHEMOGLOBINEMIA

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) METHEMOGLOBINEMIA
2) HEREDITARY METHEMOGLOBINEMIA
3) HEMOGLOBIN M DISEASE
4) CDNB (DINITROCHLOROBENZENE)
5) CHLORODINITRO BENZENE
6) DIMETILANILINA
7) DNCB (DINITROCHLOROBENZENE)
8) DWUMETYLOANILINA
9) METHEMOGLOBINEMIA INDUCERS
10) NITROGEN FLUORIDE (TRIFLUORIDE)
11) NITROGEN TRIFLUORIDE, COMPRESSED
12) NITROTOLUENE (ORTHO ISOMER)
13) PESTICIDES, BENZOYLPHENYL UREA
14) UREA PESTICIDES, BENZOYLPHENYL
15) XILIDENO
16) XILIDINE
17) XYLIDIN (ALLE ISOMEREN)
18) XYLIDINEN
19) XYLIDINES

Available Forms Sources

1) ACQUIRED METHEMOGLOBINEMIA

a) The following is a list of agents or toxins that have been associated with methemoglobinemia either by therapeutic or toxic exposure.
b) The descriptive paragraphs that follow provide further detail regarding select toxins or agents that can produce methemoglobinemia in certain settings or patient populations.
c) SUMMARY

1) Acetanilid
2) Alloxans
3) Alpha-naphthol
4) Aminophenols
5) Amyl nitrate
6) Amyl nitrite
7) Aniline compounds
8) Aniline dyes

a) Laundry dyes
b) Shoe dyes

9) Anilinoethanol
10) Antipyrine
11) Aromatic amines (some)
12) Arsine
13) Artificial fingernail removers containing nitroethane
14) Artificial fingernails containing N,N-dimethyl-p-toluidine
15) Cetrimide
16) Chloranilines
17) Chlorates
18) Chlorobenzene
19) Chloronitrobenzene
20) Clofazimine
21) Cobalt preparations
22) Copper sulfate
23) Corning extract
24) Dapsone
25) Diaminodiphenylsulfone
26) Diesel fuel additives
27) Dimethylamine
28) Dimethylaniline
29) Dimethyl-p-toluidine, N,N-(1,3-dinitrobenzene)
30) Dinitrobenzene
31) Dinitrophenol
32) Dinitrotoluene
33) Flutamide
34) Herbicides (e.g. Metobromuron)
35) Hydroquinone
36) Hydroxylacetanilid
37) Hydroxylamine
38) Indoxacarb
39) Inks, marking
40) Kiszka
41) Local anesthetics

a) Benzocaine
b) Cetacaine
c) Lidocaine
d) Prilocaine
e) Procaine

42) Menadione (vitamin K3)
43) Menthol
44) Meta-chloraniline
45) Metoclopramide
46) Methylacetanilid
47) Methylene blue
48) Monochloroaniline
49) Moth balls
50) Naphthalene
51) Nitric Oxide
52) Nitrites/nitrates

a) Ammonium nitrite
b) Amyl nitrate
c) Amyl nitrite
d) Bismuth subnitrate
e) Butyl/isobutyl nitrite
f) Contaminated well water
g) Food additives/curing agents
h) Methyl nitrite
i) Nitroglycerin
j) Silver nitrate
k) Sodium nitrate
l) Sodium nitrite
m) Sodium nitroprusside
n) Sulfasalazine
o) Vegetables (carrots, spinach) in infants

53) Nitrobenzene
54) Nitroethane
55) Nitrofurans
56) Nitrogen oxide
57) Nitrophenol
58) Nitrosobenzene
59) N,N-dimethyl-p-toluidine
60) Paraquine
61) Para-aminopropiophenone
62) Para-aminosalicylic acid
63) Para-bromoaniline
64) Para-chloroaniline
65) Para-nitroaniline
66) Para-toluidine
67) Pentaerythritol tetranitrate
68) Phenacetin
69) Phenazopyridine
70) Phenetidin
71) Phenols
72) Phenylazopyridine
73) Phenylenediamine
74) Phenylhydrazine
75) Phenylhydroxylamine
76) Phenytoin
77) Piperazine
78) Potassium permanganate
79) Prilocaine
80) Primaquine
81) Procaine
82) Pyridine
83) Pyrogallol
84) Quinones

a) Chloroquine
b) Primaquine

85) Resorcinol
86) Shoe dye or polish
87) Sulfonal
88) Sulfonamides
89) Sulfones
90) Sulfonethylmethane
91) Tetranap
92) Tetranitromethane
93) Thiocyanates

a) Nitroglycerin
b) Nitroprusside
c) Thiocyanate

94) Toluenediamine
95) Toluidine
96) Toluylhydroxylamine
97) Trichlorocarbanilide
98) Trinitrotoluene
99) Trional
100) Valproate
101) Zopiclone

d) ACQUIRED METHEMOGLOBINEMIA

1) The following is a list of agents that can produce methemoglobinemia.

e) 4-AMINOPROPIOPHENONE

1) 4-AMINOPROPIOPHENONE has produced methemoglobinemia (Bright & Marrs, 1982).

f) 4-DIMETHYLAMINOPHENOL

1) 4-DIMETHYLAMINOPHENOL has produced methemoglobinemia (van Dijk et al, 1987).

g) ANILINE AND OTHER AMINOPHENOLS

1) Methemoglobinemia may result from exposure to aniline. Used in manufacture of synthetic rubber, dyes, varnishes, shoe polish, perfumes, paint remover, photographic chemicals, explosives, herbicides, and fungicides (Phillips et al, 1990).
2) Methemoglobinemia developed in a 35-year-old man after dermal contact with an octane booster (80% aniline 20% toluene) (Cummings et al, 1994).

h) ANTIMALARIALS

1) Chloroquine and primaquine have been associated with methemoglobinemia (Cohen & Bovasso, 1971; Kantor, 1992).

i) ARTIFICIAL FINGERNAIL PRODUCTS

1) Solutions containing N,N-Dimethyl-p-Toluidine (Potter et al, 1988; Kao et al, 1997).
2) ARTIFICIAL FINGERNAIL REMOVER - Pediatric ingestion of solutions containing nitroethane have resulted in severe methemoglobinemia (Shepherd et al, 1998; Osterhoudt et al, 1994; Hornfeldt & Rabe, 1994).

j) BANKED BLOOD

1) In one study, 312 units of banked blood were examined and it was noted that the risk of methemoglobin increased during blood storage and was present in levels up to 4.2% (Uchida et al, 1990).

k) CELECOXIB

1) Celecoxib-induced methemoglobinemia was reported in an adult with osteoarthritis. The patient was treated for approximately one month when he developed a methemoglobin level of 9% (Kaushik et al, 2004).

l) CETRIMIDE

1) Methemoglobinemia occurred following a surgical procedure using cetrimide as a disinfectant (Baraka et al, 1980).

m) CHLORATES

1) Methemoglobinemia has been reported following chlorate poisoning (Klendshoj et al, 1962).

n) CLEANERS

1) Sodium nitrate containing cleaners have produced methemoglobinemia (Rieder et al, 1989).

o) CLOFAZIMINE

1) A child developed methemoglobinemia (33%) after receiving clofazimine 300 mg/day for 13 days for lichenoid lesions (Moreira et al, 1998).

p) COPPER-8-HYDROXYQUINOLATE

1) Prolonged hemolysis and methemoglobinemia was reported in an adult following a 50 mL ingestion of an organic copper fungicide (Sesamine(R)) which contained copper-8-hydroxyquinolate (Yang et al, 2004).

q) COPPER SULFATE

1) Acute poisoning with copper sulfate produced methemoglobinemia (Chugh et al, 1975).

r) DAPSONE

1) Dose related increases in methemoglobin by a process of reduction of oxyhemoglobin and molecular oxygen to superoxide anions and hydrogen peroxide can occur with therapeutic use of dapsone (Chawla et al, 1998). Two grams of dapsone ingested as a suicide attempt resulted in a methemoglobin level of 38% (Shadnia et al, 2006).
2) Numerous cases of dapsone-induced methemoglobinemia have been reported (Ward & McCarthy, 1998; Hansen et al, 1994; Sheela et al, 1993; Erstad, 1992; Gallant et al, 1991; Reiter & Cimoch, 1987; Mayo et al, 1987; Woodhouse et al, 1983; Woodhouse et al, 1983) .

s) DIETARY SOURCES

1) Foods high in nitrate preservatives (especially meats) may induce methemoglobinemia in infants (Geffner et al, 1981) Keating, 1973; Filer, 1970; Bakshi et al, 1980; (Kaplan et al, 1990) or in persons with hereditary NADH-dependent methemoglobin reductase deficiency.
2) Vegetables, especially when fed to infants, including carrots, squash, green beans, beets, fennel (Bosset Murone et al, 2005; Bryk et al, 2003; Keating et al, 1973) and spinach can produce methemoglobinemia (Filer et al, 1970).

a) Infants younger than 6 months are more susceptible because of higher gastric pH, ease of oxidation of fetal hemoglobin, presence of nitrite-reducing bacteria and an immature methemoglobin reductase system.

3) FENNEL - Methemoglobinemia occurred in several infants fed fennel puree, which is a popular food source in Switzerland, found to contain high levels of nitrates (nitrate concentration was greater than 2000 mg/kg almost 10 times the acceptable concentration for nitrate in infant foods {limit value: 250 mg/kg}). Fennel is given as a puree to reduce colic, and is also used as a tea by women to enhance lactation (Bosset Murone et al, 2005).

t) DINITROBENZENE

1) Dinitrobenzene can produce methemoglobinemia (CDC, 1988). A case of cutaneous spraying of dinitrobenzene and potassium perchlorate from an unintentional mining shell blast caused methemoglobinemia (Laure & Stierle, 1993).

u) FLUTAMIDE

1) Methemoglobinemia developed in an 80-year-old man taking therapeutic doses of flutamide (Schott et al, 1991).

v) HERBICIDES

1) Herbicides have been associated with methemoglobinemia (Proudfoot, 1982). A 59-year-old man developed methemoglobinemia (52%) after ingesting a "mouth full" of a herbicide containing monolinuron (140 g/L) and paraquat (100 g/L) (Casey et al, 1994).

a) METOBROMURON - A 22-year-old female developed methemoglobinemia 12 hours after ingesting 500 mL of a herbicide containing 25% metobromuron and 25% metolachlor (Yang et al, 1995).
b) Propanil [N-(3,4-dichlorphenyl) proanamide] has produced methemoglobinemia. In one case series, 16 patients developed severe methemoglobinemia following intentional propanil poisoning with 9 deaths reported. The authors noted, that the lack of adequate healthcare resources may have limited treatment measures (Eddleston et al, 2002).

w) HYDROXYLAMINE

1) HYDROXYLAMINE may produce methemoglobinemia (Kruszyna et al, 1982).

x) INDOXACARB

1) TOXICITY: Three cases of methemoglobinemia after the ingestion of indoxacarb insecticide have been reported. All patients recovered following supportive care, including treatment with methylene blue (Wu et al, 2010; Chhabra et al, 2010; Prasanna et al, 2008).

y) INDUSTRIAL SALTS

1) Industrial nitrate salts have produced methemoglobinemia during dermal exposure (Harris et al, 1979).

z) LOCAL ANESTHETICS

1) BENZOCAINE - has produced numerous accounts of methemoglobinemia (McGuigan, 1981; Potter & Hillman, 1979; Kotler et al, 1989; Anderson et al, 1988; Ferraro et al, 1988; Grum & Rice, 1990; Buckley & Newman, 1987; Bhutani et al, 1992; Rodriguez et al, 1994; McKinney et al, 1992; Muchmore & Dahl, 1992; Brown et al, 1994; Eldadah & Fitzgerald, 1993; Dinneen et al, 1994; Guerriero, 1997).

a) CASE REPORT: A 16-month-old boy developed severe toxic methemoglobinemia after dermal application of a pomade containing benzocaine, resorcin, and hydroxyquinoline. Following supportive care, including methylene blue therapy, he recovered (Bouziri et al, 2010).
b) TOPICAL - Severe methemoglobinemia was reported in a toddler following topical use of benzocaine for an endoscopic procedure (Hegedus & Herb, 2005).
c) SWISH AND SWALLOW - Benzocaine used as a local agent ("swish and swallow") during an outpatient transesophageal echocardiography produced methemoglobinemia (Wurdeman et al, 2000).
d) SPRAY - A patient developed severe methemoglobinemia after the use of benzocaine spray during an endoscopic procedure. Following treatment with methylene blue, critical rebound phenomenon occurred which required further methylene blue (Fitzsimons et al, 2004) .

1) In one case series, benzocaine-induced methemoglobinemia developed in 37 (53%) of 69 patients treated with a single spray (recommended dose) of benzocaine (Moore et al, 2004).

e) ADULTERATION - Severe methemoglobinemia (a methemoglobin level of 37%) was reported in an adult following a "large" ingestion of street cocaine that was adulterated with benzocaine used as a cutting substance (McKinney et al, 1992a).
f) EAR DROPS - Benzocaine toxicity may have been resulted with the death of a 4-month-old infant. The infant received 3 times the prescribed dose of ear drops containing 0.25% w/v benzocaine and 5.4% w/v antipyrine. Postmortem methemoglobin was 36% (Logan & Gordon, 2005).

2) LIDOCAINE - methemoglobinemia has been associated with lidocaine use (Hansen-Flaschen, 1990; Kotler et al, 1989).

a) Severe methemoglobinemia occurred after topical lidocaine was used in patients prior to transesophageal echocardiography (Karim et al, 2001).

3) BUPIVACAINE/LIDOCAINE - A patient developed clinical methemoglobinemia following an axillary block with bupivacaine and an additional injection of lidocaine in the operative field (Schroeder et al, 1999).
4) PROPITOCAINE may produce methemoglobinemia (Poppers et al, 1956).
5) PRILOCAINE has produced methemoglobinemia (Ludwig, 1981; Mandel, 1989; Bardoczky et al, 1990; CDC, 1994; Lloyd, 1992; Marks & Desgrand, 1991; Bellamy et al, 1992).
6) CETACAINE may cause methemoglobinemia (Gregory & Matsuda, 2000; Ferraro et al, 1988a).
7) EMLA CREAM - Application of 150 g EMLA cream, which contained prilocaine and lidocaine, caused methemoglobinemia; symptoms developed within 1 hour (Hahn et al, 1999). In another case, EMLA cream that was left in place for 5 hours produced a methemoglobin level of 16% (Sinisterra et al, 2002).

aa) LOXOSCELISM

1) In a case series of 25 patients with the cutaneous form of loxoscelism, an increase in methemoglobin was observed in over 50% of patients and 20% had a methemoglobin level between 4.1% to 8% (Barretto et al, 1990).

ab) METHYLENE BLUE

1) METHYLENE BLUE can produce methemoglobinemia (Lamont et al, 1986). Administration of methylene blue for a diagnostic procedure produced methemoglobinemia in a 26-year-old woman with G-6-PD deficiency (Bilgin et al, 1998).

ac) METOCLOPRAMIDE

1) METOCLOPRAMIDE - Methemoglobinemia developed in a 23-year-old woman with pheochromocytoma 3 months after beginning therapy with metoclopramide (Grant et al, 1994). Other medications included: senna, penoxybenzamine, glibenclamide, magnesium sulfate, and propranolol chronically.

ad) METHYL NITRITE

1) METHYL NITRITE - Used in production of phenylpropanolamine (Wax, 1993; Wax & Hoffman, 1994).

ae) NAPHTHALENE

1) NAPHTHALENE (Valaes et al, 1963)

af) NITRATES (NO3-)/NITRITES (NO2-)

1) AMYL NITRITE/SODIUM NITRITE - As contained in cyanide antidote kits (Pierce & Nielsen, 1989). In rat studies, percutaneous absorption of sodium nitrite through abraded skin consistently produced elevations in methemoglobin which was NOT dependent on nitrite concentration (Saito et al, 1997).
2) Lin et al (2005) reported a case of near-fatal methemoglobinemia after recreational inhalation of amyl nitrite aerosolized with a compressed gas blower (Lin et al, 2005). Another life-threatening methemoglobinemia after ingestion of large amounts of amyl nitrite has been reported (Edwards & Ujma, 1995).
3) UNUSUAL EXPOSURE - An 18-year-old man, with a history of infantile autism and moderate mental retardation, developed methemoglobinemia after compulsive urine drinking. The authors speculated that the condition was caused by drinking urine which contains nitrate, which is the main by-product of nitric oxide metabolism (Chan et al, 2004).
4) BUTYL/ISOBUTYL NITRITES

a) Abuse of organic nitrites sold over-the-counter as euphorics (butyl nitrite; "Rush") or found in room deodorizers (isobutyl nitrite), or recreational use of amyl nitrite, to stimulate and prolong the sensation of orgasm, has resulted in significant methemoglobinemia and death.

1) (Shesser et al, 1981; Smith et al, 1980; White & Weiss, 1991; Pierce & Nielsen, 1989; White & Weiss, 1991; Forsyth & Moulden, 1991; Machabert et al, 1994; Bradberry et al, 1994)

b) A young adult survived a 3-fold lethal dose of isobutyl-nitrite after therapy with hyperbaric oxygen and exchange blood transfusion (Jansen et al, 2003).
c) Symptomatic methemoglobinemia may be caused by both inhalation and ingestion of these products in patients with normal methemoglobin reductase activity (Guss et al, 1985).
d) SILVER NITRATE - Therapy in burn patients (Strauch et al, 1969). Nitrate salts may be absorbed from burned skin in quantities sufficient to cause a methemoglobin level of 60%, resulting in death (Harris et al, 1979a).

5) NITROBENZENE

a) NITROBENZENE (Schimelman et al, 1978):

1) Industrial solvents
2) Gun cleaning products

6) NITRIC OXIDE

a) NITRIC OXIDE - Inhaled nitric oxide was given for suspected pulmonary hypertension in a newborn; symptomatic methemoglobinemia developed within 46 hours of initiating therapy (Nakajima et al, 1997).

7) NITROGLYCERIN

a) NITROGLYCERIN - Oral, sublingual or transdermal nitrates for cardiac disease (Marshall & Ecklund, 1980; Bojar et al, 1987).

ag) NITROUS OXIDE

1) NITROUS OXIDE - Contaminants of nitrous oxide canisters used in anesthesia (Clutton-Brock, 1967; Young et al, 1994).

ah) PARA-AMINOSALICYLIC ACID

1) PARA-AMINOSALICYLIC ACID has produced methemoglobinemia (Munroe, 1969).

ai) PARA-CHLORANILINE

1) PARA-CHLORANILINE - inadvertent exposure of premature infants to a humidifying fluid containing para-chloraniline while in an incubator produced methemoglobinemia (van der Vorst et al, 1990).

aj) PHENACETIN

1) Phenacetin is metabolized to nitroso compounds, which may cause methemoglobinemia.
2) Although acetaminophen is a metabolite of phenacetin, acetaminophen does not cause methemoglobin formation because of the absence of nitroso metabolites.

ak) PHENAZOPYRIDINE

1) PHENAZOPYRIDINE - Methemoglobinemia has been reported after therapeutic use and overdose (Nathan et al, 1977; Cohen & Bovasso, 1971; Fincher & Campbell, 1989; Truman et al, 1994).

a) A 2-year-old toddler ingested 600 mg of phenazopyridine (50 mg/kg) which resulted in a methemoglobin level of 29% (Gold & Bithoney, 2003).

al) PRODUCTS OF COMBUSTION

1) Products of combustion have been associated with methemoglobinemia (Hoffman & Sauter, 1989).
2) A 10-week-old infant developed methemoglobinemia (71%) believed to be secondary to exposure to pine tar fumes from a wood burning stove (Dean et al, 1992).
3) AUTOMOBILE EXHAUST FUMES

a) A 28-year-old man developed methemoglobinemia after exposure to automobile exhaust fumes (Laney & Hoffman, 1992).

am) RASBURICASE

1) Hemolytic anemia and methemoglobinemia were reported in one adult with rasburicase to treat acute renal failure secondary to hyperuricemia. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was subsequently confirmed (Browning & Kruse, 2005).

an) RESORCINOL

1) RESORCINOL has produced methemoglobinemia (Cunningham, 1956).

a) CASE REPORT: A 16-month-old boy developed severe toxic methemoglobinemia after the dermal application of a pomade containing benzocaine, resorcin, and hydroxyquinoline. Following supportive care, including methylene blue therapy, he recovered (Bouziri et al, 2010).

ao) SODIUM BETANAPHTHOL DISULFONATE

1) SODIUM BETANAPHTHOL DISULFONATE (R salt) may cause methemoglobinemia (Johnson et al, 1987a).

ap) SULFONAMIDES

1) SULFONAMIDES - Several sulfonamides, including sulfathiazole, sulfasalazine, sulfapyridine, and co-trimoxazole have been reported to produce methemoglobinemia (Dunn, 1998; Damergis et al, 1983; Iserson, 1985).

aq) TNT

1) 2,4,6-TRINITROTOLUENE (TNT) - A 17-year old man developed methemoglobinemia following cutaneous exposure to TNT after manipulating a bomb that exploded (Yazbeck-Karam et al, 2004).

ar) TRIAPINE

1) Severe methemoglobinemia occurred in a patient after being treated with triapine, an experimental anti-cancer drug (Foltz et al, 2006).

as) VALPROATE

1) Symptomatic methemoglobinemia has been described after acute valproate ingestion in a 3-year-old child. The child was admitted to the ED approximately 6 hours post-ingestion with initial oxygen saturation by pulse oximetry of 75% on an FiO2 of 1.00. Arterial blood was dark brown in color. Significant metabolic acidosis (pH 7.23) was noted. Initial methemoglobin level was 38.8%. Complete resolution of methemoglobinemia occurred after administration of a total of 4 mg/kg of methylene blue over 90 minutes (Lynch & Tobias, 1998).

at) ZOPICLONE

1) Two patients developed methemoglobinemia after ingesting up to 1500 mg of zopiclone (100 to 200 tablets of 7.5 mg zopiclone). Both patients recovered following supportive care (Fung et al, 2008).

au) WATER

1) DIALYSIS WATER - Patients undergoing hemodialysis are more susceptible to development of methemoglobinemia, which has occurred with concentrations of 21 mg/L of nitrate-nitrogen in the dialysis fluid. A water standard of 2 ppm of nitrate has been recommended for dialysis fluid (Fan et al, 1987).
2) DRINKING WATER - The current US federal maximum contaminant level of nitrate in drinking water is 45 ppm for nitrate or 10 ppm for nitrate-nitrogen.

a) Infant methemoglobinemia is unlikely at levels below this standard (Fan et al, 1987). Methemoglobinemia has been documented in infants ingesting municipal water containing 13.3 to 24.4 ppm of nitrate-nitrogen (Virgil et al, 1965; Jones et al, 1973).
b) Outbreaks of methemoglobinemia have been reported due to nitrite contamination of drinking water from corrosion inhibitor or boiler additives (Bradberry et al, 1994; Askew et al, 1994; Shih et al, 1995).

3) WELL WATER - With high nitrogen content, especially in rural (agricultural) areas (Miller, 1971; Johnson et al, 1987; Grant, 1981; CDC, 1993).

a) Infants who are fed formula and infant foods prepared with contaminated well water are at high risk of developing methemoglobinemia; significant cyanosis in infants can result from ingestion of well water containing as little as 90 ppm of nitrate and death at 150 ppm (Greer & Shannon, 2005; Johnson et al, 1987).

2) INFANTS

a) Infants 2 to 4 weeks of age have been reported to develop an idiopathic syndrome characterized by methemoglobinemia, vomiting, diarrhea, acidosis and leukocytosis. The highest reported methemoglobin level in one study was 67%; one infant died after methemoglobinemia recurred.

1) References: (Yano et al, 1982; Dagan et al, 1988; Fandre et al, 1962; Hanukoglu et al, 1983; Heyman, 1954; Kohne et al, 1974; Yano et al, 1982; Kay et al, 1990; Avner et al, 1990a; Lebby et al, 1993; Gebara & Goetting, 1994).

b) Cause for methemoglobin is uncertain; unidentified oxidants may have been present in the gastrointestinal tract, resulting in diarrhea and the oxidation of fetal hemoglobin to methemoglobin (Yano et al, 1982).
c) Regardless of absolute methemoglobin level, methemoglobinemia associated with gastroenteritis produces a more severe illness than does that resulting from drug exposure (Avner et al, 1990).
d) Methemoglobinemia and transient organic aciduria with acute gastroenteritis have been described in neonates (Kay et al, 1990).
e) In a study of 43 infants less than 6 months old with a history of diarrhea lasting more than 24 hours, 13 were cyanotic and 27 (64%) had methemoglobin levels greater than 1.5% (Pollack & Pollack, 1994). Children at or below the tenth percentile of weight for age were more likely to develop methemoglobinemia.
f) A 3-week-old infant developed methemoglobinemia (40%) associated with vomiting, diarrhea, and a urinary tract infection (Luk et al, 1991).
g) In a series of 17 infants hospitalized for dietary protein intolerance, 6 had transient methemoglobinemia (maximum methemoglobin level 10 to 35%) (Murray & Christie, 1993).
h) A 1-month-old infant developed methemoglobinemia (43%) associated with probable renal tubular acidosis (Sager et al, 1995).
i) DEHYDRATION - Serious illness, such as gastrointestinal infections with accompanying dehydration, has produced methemoglobinemia (Ash-Bernal et al, 2004).
j) FOOD SOURCE - Several infants developed methemoglobinemia following ingestion of fennel puree (high in nitrates), which is a popular food used to reduce infant colic and used as a tea by women to enhance lactation in Switzerland (Bosset Murone et al, 2005). Other implicated foods can include carrots, spinach, squash, green beans and beets.

3) CONGENITAL

a) METHEMOGLOBIN REDUCTASE DEFICIENCY - REDUCED NADH-CYTOCHROME B5 REDUCTASE DEFICIENCY

1) May be due to deficiency in NADH-dependent methemoglobin reductase (Prchal et al, 1990). Transmitted by an autosomal recessive gene; individuals homozygous for the trait may have 50% to 60% of their hemoglobin present as methemoglobin. Individuals heterozygous for the trait may have only 1% to 2% methemoglobin but are more susceptible to methemoglobin-producing drugs and chemicals.
2) Cyanosis is congenital, with a positive family history.
3) Glucose-6-phosphate dehydrogenase deficiency

a) Individuals with a glucose-6-phosphate dehydrogenase (G-6-PD) deficiency which is a sex-linked defect can develop methemoglobinemia following methylene blue administration (Bilgin et al, 1998). The prevalence in the general population is 2.5 to 25% in the Mediterranean region; the prevalence among African-Americans is approximately 11%.

b) HEMOGLOBIN M DISORDERS

1) Rare cause of hereditary methemoglobinemia (Khakoo et al, 1993). Carriers are heterozygous for the trait; the homozygous state is evidently fatal.
2) Cyanosis is congenital, with methemoglobin levels of 25% to 30%.
3) Mildly affected individuals are generally asymptomatic, and the condition may not have clinical significance until the patient is exposed to an oxidizing drug or chemical.

Overview

Life Support

Clinical Effects

0.2.1)

A) TOXICOLOGY: Oxidization of iron in the hemoglobin ring to the ferric form leads to the inability of hemoglobin to bind or transport oxygen. Heme in the ferric (Fe3+) state also induces a hemoglobin conformational change increasing oxygen affinity of the remaining binding sites and decreasing the oxygen dissociation. Cyanosis occurs when more than 1.5 g/dL of hemoglobin is in the methemoglobin form, compared to 5 g/dL of deoxyhemoglobin to yield similar cyanosis. Methemoglobinemia may result from acquired or congenital causes (hemoglobin M or cytochrome b5 reductase deficiency). Acquired methemoglobinemia is caused by strong oxidizing agents, most commonly local anesthetics and dapsone, though many drugs have been implicated. In addition, recreational drugs, industrial chemicals, as well as medical conditions such as pediatric gastrointestinal infections, sepsis, surgery, or sickle cell crisis are rarely capable of inducing acquired methemoglobinemia.
B) EPIDEMIOLOGY: Methemoglobinemia is common, but clinically significant symptoms are uncommon, and severe toxicity is rare.
C) WITH POISONING/EXPOSURE

1) The severity of the clinical effects observed is dependent on the quantity of methemoglobin present and are referable to the decreased oxygen-carrying capacity of the blood.
2) MILD TO MODERATE TOXICITY: Cyanosis occurs at methemoglobin levels more than 1.5 g/dL. However, most patients do not have the severe ischemic symptoms that might be expected from other disease processes with the same degree of cyanosis. Cyanosis that is unresponsive to supplemental oxygen, or significant cyanosis in a patient with minimal symptoms should raise the suspicion of methemoglobinemia.
3) SEVERE TOXICITY: Clinical severity increases with increased methemoglobin levels. Patients that have methemoglobin levels greater than 30% are more likely to develop severe symptoms.
4) ACID/BASE: Metabolic acidosis may develop secondary to tissue hypoxia or seizures.
5) CARDIOVASCULAR: Tachycardia is common. Dysrhythmias and hypotension may occur in severe cases. Myocardial infarction and abrupt cardiac arrest are rare manifestations of severe methemoglobinemia.
6) GASTROINTESTINAL: Nausea and vomiting may occur.
7) HEMATOLOGIC: Chocolate brown blood is classic. Hemolytic anemia may develop with some agents that cause methemoglobinemia. Hemolysis may occur in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
8) NEUROLOGIC: CNS effects include headache, dizziness, altered consciousness, confusion, lethargy progressing to coma, seizures and syncope which usually occurs secondary to hypoxia at levels typically of 20% or greater.
9) RESPIRATORY: Dyspnea and tachypnea may occur.
10) RISK FACTORS: Patients with underlying medical conditions such as chronic obstructive pulmonary disease (COPD), anemia or coronary artery disease, recent surgery, or increased metabolic demand (ie, shock, infection) are more susceptible to developing symptoms. The very young (less than 3 months old) and the elderly are at greater risk of developing symptomatic methemoglobinemia. In addition, individuals with a genetic deficiency of G-6-PD or nicotinamide adenine dinucleotide methemoglobin reductase are at greater risk of developing methemoglobinemia.

0.2.20)

A) In the United States, commercially prepared formulas and foods for infants do not put the infant at risk for methemoglobinemia; however, infants fed formula prepared with well water remain at risk for methemoglobinemia secondary to nitrate poisoning.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients with mild to moderate toxicity can be treated with supportive care. The offending agent should be withdrawn. Intravenous fluids should be given to maintain urine output and supplemental oxygen applied.

B) MANAGEMENT OF SEVERE TOXICITY

1) Patients with evidence of end-organ ischemia should be treated with methylene blue regardless of the methemoglobin concentration. However, patients are unlikely to have end-organ ischemia with concentrations less than 20%. Treatment with methylene blue should result in resolution of all symptoms attributable to methemoglobinemia within 2 hours. The administration of cimetidine may also shorten the course of dapsone-induced methemoglobinemia. Patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or children younger than 3 months may require exchange transfusion or treatment with hyperbaric oxygen as they may not respond to methylene blue. Treat seizures with IV benzodiazepines or barbiturates.

C) DECONTAMINATION

1) PREHOSPITAL: Patients should be placed on oxygen. Following dermal exposure, skin should be thoroughly washed with soap and water. Contaminated clothing and shoes should be discarded. Otherwise, no field decontamination is required.
2) HOSPITAL: Overdose of drug tablets implicated in causing methemoglobinemia can be treated with 50 grams of activated charcoal, if the patient presents early and the patient’s mental status is amenable to taking the charcoal. However, this is rarely necessary as patients generally do not develop methemoglobinemia until hours after an acute ingestion. Following dermal exposure, skin should be thoroughly washed with soap and water. Contaminated clothing and shoes should be discarded.

D) AIRWAY MANAGEMENT

1) Patients with severe dyspnea, tachypnea, seizure, or evidence of end-organ ischemia may require intubation for airway protection or to minimize excessive work of breathing.

E) ANTIDOTE

1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg. DAPSONE: See dapsone management for treatment of patients with significant methemoglobinemia following dapsone overdose. CONTRAINDICATIONS: Known hypersensitivity to methylene blue and methemoglobin reductase deficiency. Patients with G-6-PD deficiency may develop hemolysis, however, enzyme deficiency is usually not complete and most toxicologists would still recommend methylene blue for severely symptomatic patients.

F) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with any degree of cyanosis should be referred to a health care facility. Patients with mild headache or nausea may be managed at home.
2) OBSERVATION CRITERIA: Patients should be observed for 8 hours after methylene blue administration to rule out recurrence of methemoglobinemia or adverse reaction to the antidote. Some chemicals (eg, aniline, nitrobenzene) may require biochemical transformation before causing methemoglobinemia. Observation of asymptomatic or mildly symptomatic individuals following exposure to these chemicals may be advisable. Slow absorption of some chemicals may also contribute to delayed methemoglobinemia. When doubt exists, it is probably best to admit the patient for continued observation.
3) ADMISSION CRITERIA: Patients with recurrent methemoglobinemia should be admitted. Patients exposed to etiologic agents with a slow clearance, such as dapsone, should be admitted.
4) CONSULT CRITERIA: A medical toxicologist or poison control center should be consulted for patients with methemoglobin concentrations above 30% or for symptomatic patients with lower concentrations. Consultation is recommended for patients with familial methemoglobinemia or G-6-PD deficiency.

G) PITFALLS

1) Failure of the patient to improve following two doses of methylene blue suggests: inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M, sulfhemoglobinemia, or G-6-PD deficiency. Failure to stabilize and treat the sequelae of end-organ ischemia can lead to significant morbidity and mortality. Patients with methemoglobinemia from agents such as dapsone may require repeated doses or continuous infusion of methylene blue.

H) TOXICOKINETICS

1) Dependent on the etiologic agent. The elimination half-life of methemoglobin averages 15 to 20 hours. Following treatment with methylene blue, the half-life decreases to 40 to 90 minutes. Methemoglobinemia due to dermal exposure to local anesthetics generally resolves within several hours depending upon the clearance of the parent compound. Dapsone may cause symptoms for more than 24 hours due to the formation of an active metabolite.

I) DIFFERENTIAL DIAGNOSIS

1) Sulfhemoglobinemia is clinically indistinguishable from methemoglobinemia. This diagnosis should be considered if a patient is unresponsive to 2 doses of methylene blue. Sulfhemoglobin is a very stable entity and may require exchange transfusion, although patients usually have minimal symptoms and often require no treatment. Other medical conditions that lead to cyanosis, such as emphysema, congestive heart failure, pulmonary shunts, as well as, other primary lung pathologies, must be considered.
2) The following list also includes the differential diagnosis of low oxygen saturation by pulse oximetry: Hypoxia, IV dyes (methylene blue/indocyanine green), hemoglobinopathies, methemoglobin (acquired/congenital), carboxyhemoglobin, abnormal hemoglobin variants (Hemoglobin M), ambient light contamination, dark nail polish, low perfusion/poor signal/venous pulsations, or motion artifact.

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) Some methemoglobinemia-producing chemicals are readily absorbed through the skin to produce adverse systemic effects. Aniline and related compounds may be rapidly absorbed by all routes. Skin contact with contaminated clothing or shoes may result in adverse systemic effects.

a) Skin should be thoroughly washed with soap and water. Contaminated clothing and shoes should be discarded. Seek medical attention. Administer 100% humidified supplemental oxygen with assisted ventilation as required. Treat for methemoglobinemia and sequelae. Signs and symptoms of methemoglobinemia may be delayed.

Range Of Toxicity

1) Less than 3% (normal): No symptoms
2) 3% to 15%: Possibly no symptoms or slate gray cutaneous coloration
3) 15% to 30%: Cyanosis, chocolate brown blood
4) 30% to 50%: Dyspnea, headache, fatigue, dizziness, syncope and weakness; a pulse oximetry reading of approximately 85%
5) 50% to 70%: Tachypnea, metabolic acidosis, seizures, CNS depression and coma
6) Greater than 70%: Severe hypoxic symptoms; death
7) In some individuals, signs may precede symptoms.

Clinical Effects

Vital Signs

3.3.2)

A) TACHYPNEA is a compensatory mechanism as the methemoglobin level increases; this may be the first sign of metabolic acidosis (White & Weiss, 1991; Sheela et al, 1993; Hansen et al, 1994)

3.3.4)

A) HYPOTENSION may occur in severe methemoglobinemia secondary to tissue hypoxia and acidosis (Forsyth & Moulden, 1991; Rodriguez et al, 1994; CDC, 1994)

1) Nitrites and related compounds are potent peripheral vasodilators. Hypotension associated with a reflex tachycardia may be noted after exposure.

3.3.5)

A) TACHYCARDIA is common (Bradberry et al, 1994; Cummings et al, 1994; CDC, 1994; Eldadah & Fitzgerald, 1993; Sheela et al, 1993; Hansen et al, 1994)

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) Hypotension may occur in severe methemoglobinemia secondary to tissue hypoxia and acidosis (Forsyth & Moulden, 1991; Rodriguez et al, 1994; CDC, 1994).
2) Nitrites and related compounds are potent peripheral vasodilators, and hypotension associated with a reflex tachycardia may be noted after exposure.

B) TACHYARRHYTHMIA

1) Tachycardia is common (Bradberry et al, 1994; Cummings et al, 1994; CDC, 1994; Eldadah & Fitzgerald, 1993; Sheela et al, 1993; Hansen et al, 1994).

C) CONDUCTION DISORDER OF THE HEART

1) Dysrhythmias may occur secondary to tissue hypoxia and acidosis in severe cases (levels > 55 percent).
2) CASE REPORTS

a) ADULT - Ventricular tachycardia and fibrillation unresponsive to resuscitation efforts developed in a 67-year-old man with methemoglobinemia (80 percent) who ingested a laxative solution contaminated with sodium nitrate (Ellis et al, 1992).

D) SUPRAVENTRICULAR TACHYCARDIA

1) PEDIATRIC - A 6-month-old developed pallor and perioral cyanosis 3 hours after eating a mixed vegetable puree containing potatoes, carrots, squash and celery that had been prepared five days previously and refrigerated; methemoglobin level was 25%. Supplemental oxygen and maintenance fluids were begun. The infant developed supraventricular tachycardia (SVT) with a heart rate of 230 beats/minute with two further episodes reported, which all resolved spontaneously (Bryk et al, 2003).

E) MYOCARDIAL INFARCTION

1) CASE REPORT - Acute myocardial infarction developed in a 46-year-old man with a history of peripheral vascular disease who developed methemoglobinemia (66%) after receiving benzocaine (Rynn et al, 1995).

F) ISCHEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT - A 71-year-old man with a past medical history of severe peripheral vascular disease, type 2 diabetes mellitus, Crohn disease, and sigmoid adenocarcinoma status post resection and ileo-colic anastomosis developed cyanosis, dyspnea (oxygen saturations 76% on pulse oximetry), and chest pain within minutes after the administration of a topical benzocaine 20% solution (3 sprays) during an elective esophageogastroduodenoscopy. . Cardiac enzyme estimation revealed a mild elevation of cardiac troponin I levels (0.71 ng/mL) and an ECG revealed ST depression in the lateral leads V4, V5, and V6. Co-oximetry showed a methemoglobin concentration of 17% and an oxyhemoglobin concentration of 82.2% He was treated with methylene blue (1 mg/kg IV over 5 minutes) and his methemoglobinemia resolved, his chest pain improved and his troponin levels declined to normal (Saha et al, 2006).

Respiratory

3.6.2)

A) DYSPNEA

1) Dyspnea and tachypnea are common compensatory mechanisms as methemoglobin levels increase and acidosis develops; these are noted with levels of 20% to 45% (White & Weiss, 1991; Sheela et al, 1993; Hansen et al, 1994; Wentworth et al, 1999)

B) APNEA

1) CASE REPORT - Thirty minutes after receiving benzocaine and midazolam for an endoscopic procedure, a 15-year-old girl became cyanotic, short of breath and comatose with a methemoglobin level of 54%(Bhutani et al, 1992).

Neurologic

3.7.2)

A) HEADACHE

1) Headache is common secondary to CNS hypoxia and often occurs when the methemoglobin level is 20% to 45% (Shih et al, 1995).

B) DIZZINESS

1) Dizziness, weakness and fatigue are common complaints and occur secondary to hypoxia which has been reported at methemoglobin levels of 20% to 45% (Bellamy et al, 1992; CDC, 1994; Bradberry et al, 1994; Wax & Hoffman, 1994; Shih et al, 1995).

C) ALTERED MENTAL STATUS

1) CONFUSION occurs secondary to CNS hypoxia when the methemoglobin level reaches 45% to 55%.
2) COMA: Decreased mentation progressing to coma secondary to hypoxia has been commonly reported when the methemoglobin level exceeds 50% (Caudill et al, 1990; Bhutani et al, 1992; Ellis et al, 1992; Forsyth & Moulden, 1991; Wax & Hoffman, 1994).

D) SYNCOPE

1) Syncope may occur secondary to hypoxia (CDC, 1994).

E) SEIZURE

1) Seizures may occur in severe cases at methemoglobin levels greater than 50% (Rodriguez et al, 1994; Eldadah & Fitzgerald, 1993).

Gastrointestinal

3.8.2)

A) GASTRITIS

1) Nausea, vomiting, diarrhea and abdominal pain may occur (Bradberry et al, 1994; Askew et al, 1994).

B) GASTROENTERITIS

1) SUMMARY - Infants 2 to 4 weeks of age have been reported to develop an idiopathic syndrome characterized by methemoglobinemia, vomiting, diarrhea, acidosis and leukocytosis. The highest reported methemoglobin level in one study was 67 percent; one infant died after methemoglobinemia recurred (Lebby et al, 1993; Gebara & Goetting, 1994; Yano et al, 1982; Dagan et al, 1988; Smith et al, 1988; Fandre et al, 1962; Hanukoglu et al, 1983; Heyman, 1954; Kohne et al, 1974; Yano et al, 1982; Kay et al, 1990; Avner et al, 1990a).
2) ETIOLOGY - Cause for methemoglobin is uncertain; unidentified oxidants may have been present in the gastrointestinal tract, resulting in diarrhea and the oxidation of fetal hemoglobin to methemoglobin (Yano et al, 1982).
3) In one report, methemoglobinemia was associated with infectious (rotavirus) diarrhea in a 1-month old (Totapally et al, 1998).
4) Regardless of the absolute methemoglobin level, methemoglobinemia associated with gastroenteritis produces a more severe illness than does that resulting from drug exposure (Avner et al, 1990).
5) Methemoglobinemia and transient organic aciduria with acute gastroenteritis have been described in neonates (Kay et al, 1990).
6) CASE SERIES - In a study of 43 infants less than 6 months old with a history of diarrhea lasting more than 24 hours, 13 were cyanotic and 27 had methemoglobin levels greater than 1.5% (Pollack & Pollack, 1994).
7) Children at or below the tenth percentile of weight for age were more likely to develop methemoglobinemia.
8) CASE REPORT - A 3-week-old infant developed methemoglobinemia (40%) associated with vomiting, diarrhea and a urinary tract infection (Luk et al, 1991).
9) CASE SERIES - In a series of 17 infants hospitalized for dietary protein intolerance, 6 had transient methemoglobinemia (maximum methemoglobin levels of 10% to 35%) (Murray & Christie, 1993).

Acid-Base

3.11.2)

A) ACIDOSIS

1) Metabolic acidosis occurs when methemoglobin levels are high enough to result in tissue hypoxia (generally greater than 50%) (Lynch & Tobias, 1998; Eldadah & Fitzgerald, 1993; Ellis et al, 1992; Truman et al, 1994; Dean et al, 1992).

B) RESPIRATORY ALKALOSIS

1) Respiratory alkalosis has been reported (Hansen et al, 1994).

Hematologic

3.13.2)

A) ABNORMAL COLOR

1) BLOOD COLOR - Blood is chocolate brown if the methemoglobin level is greater than 15%.

B) HEMOLYSIS

1) Many agents causing methemoglobinemia also can cause immediate or delayed hemolysis (Fincher & Campbell, 1989; Erstad, 1992). Typically, the enzyme defect that is often responsible for oxidant-induced hemolysis is glucose-6-phosphate dehydrogenase (G6PD) deficiency.
2) Agents often associated with both methemoglobinemia and hemolysis include dapsone, phenazopyridine, amyl nitrite, and aniline. It is not possible; however, to predict when hemolysis might occur in the presence of methemoglobinemia (Price, 2006).

C) INCREASED METHEMOGLOBIN

1) DELAYED METHEMOGLOBIN RISE - Delayed increases in methemoglobin concentration and recurrent increases in methemoglobin levels after methylene blue therapy have been reported after dapsone, phenazopyridine, and benzocaine (Erstad, 1992; Rodriguez et al, 1994; Truman et al, 1994; Hansen et al, 1994).

Dermatologic

3.14.2)

A) CYANOSIS

1) Cyanosis is a typical clinical finding and usually occurs with a methemoglobin of 1.5 g/dL, which represents only 10% conversion of hemoglobin to methemoglobin if the baseline hemoglobin is 15 g/dL (Price, 2006).
2) The cyanosis is central, with involvement of the proximal extremities and trunk as well; it is described as "slate gray" in appearance or as "chocolate cyanosis". Infants with methemoglobinemia may have a peculiar lavender color (Johnson et al, 1987; Wentworth et al, 1999)
3) Methemoglobinemia should be suspected in patients with central cyanosis that does not respond to the administration of oxygen or with marked cyanosis without respiratory symptoms (Henretig et al, 1988; Wentworth et al, 1999)
4) This may be seen in patients with sulfhemoglobinemia when the sulfhemoglobin level is greater than 5% (Lambert et al, 1982).
5) CASE REPORT - Acquired methemoglobinemia (methemoglobin 23.1% on admission) with mild bluish discoloration of the gums was associated with urine drinking in a young adult male with a history of infantile autism and moderate mental retardation. Treatment included intravenous methylene blue for 2 days with clinical improvement of both signs and symptoms of cyanosis. Behavioral therapy was initiated and no further episodes of cyanosis were reported (Chan et al, 2004).

B) EXCESSIVE SWEATING

1) Profuse diaphoresis may develop (Cummings et al, 1994).

Summary Of Exposure

Reproductive

3.20.1)

3.20.3)

A) LACK OF EFFECT

1) In a review of the literature, a causal relationship between exposure to nitrates in drinking water and adverse reproductive effects has not been determined. Data are insufficient on the incidence of methemoglobinemia among infants in the United States and on the effects that exposure to nitrate levels above the maximum contaminant limit (MCL) may have on select populations such as pregnant women (Manassaram et al, 2006).

3.20.4)

A) BREAST MILK

1) Although infants fed formula prepared with well water remain a high-risk group for nitrate poisoning, breastfed infants do not appear to be at risk for methemoglobinemia even when mothers consume water with high concentrations of nitrate (100 ppm). The authors suggested the continued need for testing of well water for nitrate content (Manassaram et al, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) In a cyanotic patient, a methemoglobin level should be obtained to confirm the diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
B) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
C) An ECG should be obtained to screen for myocardial ischemia. Cardiac biomarkers should be obtained if evidence of ischemia is present on ECG.
D) A CBC with microscopy should be performed to evaluate for hemolysis.
E) Blood with more than 15% methemoglobinemia will appear chocolate brown and may be an early bedside indication of methemoglobinemia.
F) If chronic cyanosis (not due to pulmonary disease) is present, especially if a family history of cyanosis is suggested, hemoglobin electrophoresis, methemoglobin reductase level, and/or G-6-PD activity may be indicated.

4.1.2)

A) ACID/BASE

1) Obtain arterial blood gases on patients who are cyanotic or symptomatic; significant disparity between the calculated and measured O2 saturation suggests methemoglobinemia.

a) PO2 is usually normal, even in the presence of severe methemoglobinemia.
b) METHEMOGLOBIN LEVEL (% of total hemoglobin): Diagnostic; levels greater than 15% usually produce symptoms; cyanosis may be present with level of 15%. Methemoglobin levels will be reduced if blood is not analyzed rapidly (few hours) by endogenous methemoglobin reductase. The development of methemoglobinemia may be delayed with some chemical exposures.

2) Methemoglobin is incapable of binding with oxygen. Metabolic acidosis occurs when the methemoglobin level is high enough to result in tissue hypoxia (generally greater than 50%). Partial respiratory compensation for the metabolic acidosis usually occurs.
3) OXYGEN SATURATION: The PO2 and calculated O2 saturation percentages are usually normal. Measured O2 saturation will be decreased.

a) PO2 is a measurement of the partial pressure of oxygen dissolved in plasma. Calculated oxygen saturation (O2 saturation of SO2) is computed fro pH and PO2 utilizing a standardized oxygen dissociation curve and assuming normal hemoglobin. Calculated O2 saturation is unreliable in cases of abnormal hemoglobin (methemoglobin, sulfhemoglobin, carboxyhemoglobin) or in some cases of abnormal pH, temperature or DPG concentrations.
b) Hypoxia may result from loss of respiratory drive if the patient is comatose.

4) A disparity between the oxygen saturation calculated from PO2 values and pulse oximetry readings may provide an important clue to the presence of methemoglobinemia (Marks & Desgrand, 1991).

a) Pulse oximetry overestimates oxygen saturation in patients with significant methemoglobinemia and should not be used to reflect arterial oxygen content or tissue oxygen delivery (Watcha et al, 1989; Bardoczky et al, 1990; Barker et al, 1989; Varon, 1992; Delwood et al, 1991).

1) Although pulse oximetry is considered inaccurate in the presence of methemoglobin, it may have a role in the unsuspected case of methemoglobinemia. Because digital pulse oximetry is not an accurate reflection of oxyhemoglobin, a pulse oximetry value at or trending towards 85% despite supplemental oxygen may actually be an early indication to suspect methemoglobinemia.

b) Treatment of methemoglobinemia should be guided by patient signs and symptoms. Monitor therapy with direct measurements of oxyhemoglobin using a co-oximeter and not on the basis of measurements using pulse oximetry or on estimates of saturations calculated from the PO2 and the oxyhemoglobin dissociation curve (Watcha et al, 1989). Pulse oximetry may actually register a transient decrease following treatment with methylene blue.

1) Pulse oximetry; however, may have a role in comparing the arterial blood gas findings. If a difference between the measured oxyhemoglobin saturation of the pulse oximeter (SpO2) and the calculated oxyhemoglobin saturation of the arterial blood gas (pO2) is different than a saturation gap exists. In this setting, the calculated SpO2 will be greater than the measured SpO2 if methemoglobin is present (Price, 2006).

5) Hemoglobin should be obtained; anemic patients may have greater symptoms and require treatment at lower methemoglobin levels because of decreased oxygen carrying capacity.
6) Chronic familial methemoglobinemia should prompt a search for an abnormal hemoglobin or enzyme deficiency. Hemoglobin electrophoresis, methemoglobin reductase activity and G-6-PD activity may be diagnostic.

B) HEMATOLOGIC

1) If the patient is not cyanotic but has ingested or been exposed to a methemoglobin-inducing substance, a methemoglobin level may be drawn as a baseline.

a) Serial methemoglobin levels should be obtained because continued absorption of the inducing agent may occur for up to 24 hours (Hall et al, 1986).

2) Hemoglobin should be measured because anemic patients may have greater symptoms and require treatment at lower methemoglobin levels due to decreased oxygen-carrying capacity.
3) Chronic familial methemoglobinemia should prompt a search for an abnormal hemoglobin or enzyme deficiency. Hemoglobin electrophoresis, methemoglobin reductase activity and G-6-PD activity may be diagnostic.

C) BLOOD/SERUM CHEMISTRY

1) Plasma levels of the suspected inducing agent(s) generally are not useful (Hall et al, 1986).
2) If the patient is cyanotic, obtain hemoglobin level, electrolytes, ABGs and methemoglobin level.

4.1.3)

A) URINALYSIS

1) May show brown or black discoloration, casts and protein.

4.1.4)

A) OTHER

1) MONITORING

a) Patients may be asymptomatic shortly after exposure. The development of severe methemoglobinemia has been delayed 1 to 10 hours after pediatric ingestion of artificial fingernail products containing nitroethane (Hornfeldt & Rabe, 1994; Osterhoudt et al, 1994) or N,N-dimethyl-p-toluidine (Potter et al, 1988). Close observation 24 hours after exposure may be advisable in cases of suspected nitroethane (Osterhoudt et al, 1994) or N,N-dimethyl-p-toluidine ingestion. Observation of asymptomatic individuals may be advisable with exposure to other chemicals (such as aniline, nitrobenzene) that may require biochemical transformation before causing methemoglobinemia (Smith, 1991).

2) ECG

a) Cardiac monitoring is recommended, especially in patients with underlying diseases known to increase susceptibility.
b) Sinus tachycardia is frequently present and may be secondary to anxiety, tissue hypoxia or acidosis. If the acidosis and tissue hypoxia are severe enough, ischemic changes, ventricular dysrhythmias and cardiac arrest may result.

Methods

1) If a rapid methemoglobin determination cannot be done, a simple test can help to confirm methemoglobinemia. Both sample and control blood are placed on filter paper and exposed to room air; the control blood will be red, whereas the blood containing large amounts of methemoglobin (greater than 15%) will have a deep chocolate brown color.

a) In clinical practice, physicians may delay diagnosis of methemoglobinemia through overreliance on their bedside acumen in detecting chocolate-brown blood. Subtle changes in the appearance of sampled blood may be easily missed if the clinician is not looking specifically for them. In addition, the chocolate-brown color is difficult to identify (Henretig et al, 1988).
b) In an asymptomatic but cyanotic patient in whom methemoglobinemia is suspected, none of the bedside techniques commonly recommended are completely reliable. Diagnosis should be pursued with a spectrophotometric analysis.
c) One study recommended a bedside test using a color chart (red, green, and blue) to provide an accurate quantitative estimate of the percentage of methemoglobin present in a blood sample. A 10 microliter drop of blood is placed on white absorbent paper and compared with the color chart; in clinical use the color chart showed good agreement with measured methemoglobin concentration (Shihana et al, 2010).

2) The methemoglobin level will be reduced if blood is not analyzed rapidly (few hours) by endogenous methemoglobin reductase.
3) BUBBLING OXYGEN: This involves bubbling 100% oxygen through a sample of venous blood. Whereas normal hemoglobin will turn bright red, methemoglobin will not.
4) POTASSIUM CYANIDE: Venous blood containing significant methemoglobin concentrations diluted by 1:100 with deionized water will turn bright pink with the addition of a crystal of potassium cyanide, secondary to production of cyanomethemoglobin (Done, 1976).
5) A spectrophotometric method for measuring methemoglobin in the presence of cyanide has been described (Kruszyna et al, 1993).
6) OXIMETERS: Dotsch et al (1999) conducted an in vitro study to compare 6 different commercially available oximeters used to measure hemoglobin derivatives with a manual conventional (photometric) method (Dotsch et al, 1999).

a) It was found that each device was comparable in accuracy and reproducibility, whereas the photometric method failed to produce accurate methemoglobin concentrations. Methylene blue interfered with methemoglobin measurements in all devices in a dose-dependent manner.
b) The oximeters tested were the CO-Oximeter 270 (Chiron Diagnostics, Fernwald, Germany); CO-Oximeter 865 (Chiron Diagnostics); ABL 520 Hemioximeter (Radiometer, Frankfurt, Germany); AVL omni 6 (AVL, Bad Homburg, Germany); Stat Profil Ultra C (NOVA, Rodermark, Germany); AVOXImeter 1000E (Avox Systems, San Antonio, TX).

1) A 82-year-old man developed severe methemoglobinemia (70%) after ingesting 250 mL of an unknown substance and died 3 days after admission despite therapy. GC-FID (flame ionization detection) for screening analysis and quantitation (GC-MS was used for confirmation) was rapidly able to determine the suspected substance; nitrobenzene was confirmed in whole blood (Martinez et al, 2003).

1) The following clinical clues can help in the diagnosis of methemoglobinemia in the anesthetized patient (Cortazzo & Lichtman, 2014):

a) Hypoxia that does not improve with increased fraction of inspired oxygen (FIO2)
b) Abnormal color of blood
c) Physiologically appropriate PaO2 on blood gas sample with low pulse oximeter saturation: "saturation gap"
d) New-onset cyanosis and/or hypoxia after ingestion of an agent with oxidative properties

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with recurrent methemoglobinemia should be admitted. Patients exposed to etiologic agents with a slow clearance, such as dapsone, should be admitted.
B) Any cyanotic or dyspneic patient with clinically significant methemoglobinemia, or any patient with a methemoglobin level greater than 20%, should be admitted to the intensive care unit, even if improvement has occurred after appropriate emergency department management.
C) Patients with altered mental status should be observed continuously on an inpatient basis because of the possibility of mixed ingestion of toxic substances. Sudden deterioration may occur in cases of toxic ingestion.
D) In less severe cases of methemoglobinemia, the possibility of continued absorption of the toxin must be ruled out before the patient may be safely discharged. When doubt exists, it is probably best to admit the patient.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients with any degree of cyanosis should be referred to a health care facility. Patients with mild headache or nausea may be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) A medical toxicologist or poison control center should be consulted for patients with methemoglobin concentrations above 30% or for symptomatic patients with lower concentrations. Consultation is recommended for patients with familial methemoglobinemia or G-6-PD deficiency.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) SUMMARY: Patients should be observed for 8 hours after methylene blue administration to rule out recurrence of methemoglobinemia or adverse reaction to the antidote. Some chemicals (eg, aniline, nitrobenzene) may require biochemical transformation before causing methemoglobinemia. Observation of asymptomatic or mildly symptomatic individuals following exposure to these chemicals may be advisable. Slow absorption of some chemicals may also contribute to delayed methemoglobinemia. When doubt exists, it is probably best to admit the patient for continued observation.

1) Patients may be asymptomatic shortly after exposure. The development of severe methemoglobinemia has been delayed 1 to 10 hours after pediatric ingestion of artificial fingernail products containing nitroethane (Hornfeldt & Rabe, 1994; Osterhoudt et al, 1994) or N,N-dimethyl-p-toluidine (Potter et al, 1988). Close observation 24 hours post exposure may be advisable in cases of suspected nitroethane (Osterhoudt et al, 1994) or N,N-dimethyl-p-toluidine ingestion.
2) Some chemicals (eg, aniline, nitrobenzene) may require biochemical transformation before causing methemoglobinemia. Observation of asymptomatic or mildly symptomatic individuals following exposure to these chemicals may be advisable (Smith, 1991). Slow absorption of some chemicals may also contribute to delayed methemoglobinemia. When doubt exists, it is probably best to admit the patient for continued observation.

6.3.3)

6.3.3.1) ADMISSION CRITERIA/INHALATION

6.3.3.2) HOME CRITERIA/INHALATION

A) Patients with any degree of cyanosis should be referred to a health care facility. Patients with mild headache or nausea may be managed at home.

6.3.3.3) CONSULT CRITERIA/INHALATION

6.3.3.5) OBSERVATION CRITERIA/INHALATION

Monitoring

Oral Exposure

6.5.1)

A) PREHOSPITAL: Patients should be placed on oxygen. Following dermal exposure, skin should be thoroughly washed with soap and water. Contaminated clothing and shoes should be discarded. Otherwise, no field decontamination is required.

6.5.2)

A) SUMMARY: Overdose of drug tablets implicated in causing methemoglobinemia can be treated with 50 grams of activated charcoal, if the patient presents early and the patient’s mental status is amenable to taking the charcoal. However, this is rarely necessary as patients generally don’t develop methemoglobinemia until hours after an acute ingestion. Following dermal exposure, skin should be thoroughly washed with soap and water. Contaminated clothing and shoes should be discarded.
B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Patients with mild to moderate toxicity can be treated with supportive care. The offending agent should be withdrawn. Intravenous fluids should be given to maintain urine output and supplemental oxygen applied.

2) MANAGEMENT OF SEVERE TOXICITY

a) Patients with evidence of end-organ ischemia should be treated with methylene blue regardless of the methemoglobin concentration. However, patients are unlikely to have end-organ ischemia with concentrations less than 20%. Treatment with methylene blue should result in resolution of all symptoms attributable to methemoglobinemia within 2 hours. The administration of cimetidine may also shorten the course of dapsone-induced methemoglobinemia. Patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency or children younger than 3 months may require exchange transfusion or treatment with hyperbaric oxygen as they may not respond to methylene blue. Treat seizures with IV benzodiazepines or barbiturates.

3) DIFFERENTIAL DIAGNOSIS: The following list includes the differential diagnosis of low oxygen saturation by pulse oximetry: Hypoxia, IV dyes (methylene blue/indocyanine green), hemoglobinopathies, methemoglobin (acquired/congenital), carboxyhemoglobin, abnormal hemoglobin variants (Hemoglobin M), ambient light contamination, dark nail polish, low perfusion/poor signal/venous pulsations, or motion artifact (Cortazzo & Lichtman, 2014).

B) OXYGEN

1) INDICATIONS: 100% oxygen should be administered to all cyanotic patients until the methemoglobin level is below 20% and the patient is in no respiratory distress.
2) The lack of clinical response to 100% oxygen indicates the presence of dyshemoglobinemia (methemoglobinemia or sulfhemoglobinemia) or the presence of an anatomic or physiologic shunt.

a) With a normal circulation, the inhalation of 100% oxygen rapidly improves peripheral cyanosis (nail beds, mucous membranes, distal extremities) associated with cardiovascular or pulmonary disease. In patients with methemoglobinemia, cyanosis does not improve when 100% oxygen is administered. Likewise, cyanotic patients with sulfhemoglobinemia will not respond to inhalation of 100% oxygen.

C) MONITORING OF PATIENT

1) In a cyanotic patient, a methemoglobin level should be obtained to confirm diagnosis. Methemoglobin levels will be artificially low if blood is not analyzed within a few hours.
2) Pulse oximetry may give a false reading in the 80% to low 90% range. An arterial blood gas test will reveal a falsely normal calculated oxygen saturation despite low measured pulse oximetry. If oxygen saturation is measured, it will be low relative to the pO2. This saturation gap suggests methemoglobinemia.
3) An ECG should be obtained to screen for myocardial ischemia. Cardiac biomarkers should be obtained if evidence of ischemia is present on ECG.
4) A CBC with microscopy should be performed to evaluate for hemolysis.
5) Blood with more than 15% methemoglobinemia will appear chocolate brown and may be an early bedside indication of methemoglobinemia.
6) If chronic cyanosis (not due to pulmonary disease) is present, especially if a family history of cyanosis is suggested, hemoglobin electrophoresis, methemoglobin reductase level, and/or G-6-PD activity may be indicated.

D) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999a). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

4) DAPSONE: Dapsone has a long half-life which provides a continuing oxidative stress that can cause rebound methemoglobinemia. In patients with significant methemoglobinemia following an overdose of dapsone, treatment with methylene blue should begin with a bolus dose (1 to 2 mg/kg). A continuous infusion of methylene blue may be necessary following the bolus. An initial rate 0.1 to 0.15 mg/kg is appropriate, with further titration of the dose based on the concentration of methemoglobin (Dawson & Whyte, 1989).
5) INTRAOSSEOUS INFUSION

a) A 6-week-old infant with acquired methemoglobinemia (probably from well water used in formula preparation or a diarrheal illness) was successfully treated with intraosseous administration of standard doses of methylene blue after multiple failed attempts at intravenous access (Herman et al, 1999). Symptoms improved one hour after receiving methylene blue, with no signs of extravasation.
b) INTERMITTENT vs CONTINUOUS THERAPY: In one study of 11 children with accidental dapsone ingestion (dose range: 350 to 600 mg), continuous intravenous methylene blue therapy was more effective in reducing the blood methemoglobin level than intermittent regimen. Children were randomized to receive either intermittent methylene blue therapy (group 1; n=5; 2 mg/kg/doses every 6 hours) or continuous intravenous regimen (group 2; n=6; 2 mg/kg over 6 hours). On admission, the mean blood methemoglobin levels for group 1 and 2 were 52.7 +/- 2.5 and 52.8 +/- 3.02, respectively. The reduction in methemoglobin levels in group 2 was statistically significant after 12, 24, 36, 48 and 72 hours of methylene blue therapy as compared to group 1. After 72 hours, the mean methemoglobin levels for group 1 and 2 were 20.1 +/- 1.5 and 11.2 +/- 1.4, respectively (p= 0.001) (Prasad et al, 2008).

6) ADVERSE EFFECTS

a) METHEMOGLOBINEMIA: Although methylene blue itself has been reported to cause methemoglobin formation up to about 7% of total hemoglobin (Whitwam et al, 1979; Goluboff & Wheaton, 1961; Nadler et al, 1934), this hypothesis has been disputed (Stossel & Jennings, 1966; Rentsch & Wittekind, 1967), and the amounts said to be induced are clinically insignificant (Hall et al, 1986).
b) HEMOLYSIS

1) Repeated large doses (up to 15 milligrams/kilogram) may cause hemolysis (Jaffe, 1979; Harvey & Keitt, 1983), particularly in the presence of G-6-PD deficiency. Methylene blue may be ineffective in patients with G-6-PD deficiency (Rosen et al, 1971).
2) The dangers of repeated appropriate doses of methylene blue (1 to 2 milligrams/kilogram) are uncertain, but it is recommended that, with rare exceptions, the total dosage should not exceed 7 milligrams/kilogram (Wintrobe, 1974; Harvey & Keitt, 1983).

c) OTHER: Include chest pain, dyspnea, anxiety, and tremors (Nadler et al, 1934).

7) FALSE POSITIVE CO-OXIMETER RESULTS: Methylene blue may cause a false-positive methemoglobin level when a co-oximeter is used to measure arterial blood gases (Kirlangitis et al, 1990).

E) SEIZURE

1) Seizures occur generally secondary to tissue hypoxia; treatment of seizures in this setting should be focused on relieving tissue hypoxia and treating methemoglobinemia. Administer 100% supplemental oxygen and administer methylene blue as described above. Anticonvulsant therapy may be used as an adjunct.
2) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

3) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

4) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

5) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

6) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

7) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

F) HYPERBARIC OXYGEN THERAPY

1) INDICATIONS

a) In life-threatening cases, hyperbaric oxygen therapy allows dissolving of sufficient oxygen in the blood to maintain life, even without the oxygen-carrying capacity of hemoglobin.
b) It is indicated as adjunctive therapy in patients with severe symptomatic methemoglobinemia who do not respond to methylene blue as it can sustain life during preparation for exchange transfusion.
c) CASE REPORT: An 18-year-old man inadvertently ingested 30 mL of isobutyl nitrate (concentration unknown), and developed severe cyanosis and evidence of myocardial ischemia, which was unresponsive to 200 milligrams of methylene blue. The patient was then treated with hyperbaric oxygen and exchange transfusion. No neurological deficits were evident one year after exposure (Jansen et al, 2003a).

G) EXCHANGE TRANSFUSION

1) INDICATIONS

a) Should be done immediately if the methemoglobinemia is not responsive to methylene blue and is progressive in a symptomatic individual.
b) Should be considered if the methemoglobin level approaches 70% and cannot be controlled by the use of methylene blue.
c) CASE REPORT: An 18-year-old man inadvertently ingested 30 mL of isobutyl nitrate (concentration unknown), and developed severe cyanosis and evidence of myocardial ischemia, which was unresponsive to 200 milligrams of methylene blue. The patient was then treated successfully with exchange transfusion and hyperbaric oxygen. No neurological deficits were evident one year after exposure (Jansen et al, 2003a).

H) ASCORBIC ACID

1) May be useful in chronic congenital methemoglobinemia but is not recommended in acutely toxic patients (Jaffe, 1979; Smith, 1967).

I) CIMETIDINE

1) Coadministration of cimetidine has been demonstrated to reduce methemoglobin concentrations in patients on chronic dapsone therapy, by the inhibition of a cytochrome P450-dependent metabolite of dapsone (Coleman et al, 1992; Ahmadi et al, 1996).
2) Animal studies have shown a decrease in methemoglobin formation when cimetidine was given concurrently with a once a day dosing (Coleman et al, 1991). When tested in humans given 400 mg of cimetidine 3 times daily for 3 days before and 4 days after dapsone, drug concentrations increased 30% (less metabolism) (Coleman & Tingle, 1992). This has not been tried in the overdose situation.
3) Another in vitro study showed no inhibition of methemoglobin formation by cimetidine (Tingle et al, 1990).

J) ACETYLCYSTEINE

1) Based on an in vitro study, chemically-induced methemoglobinemia declined at a linear rate following NAC administration (Wright et al, 1996). The authors suggested that NAC may be able to reduce methemoglobin directly or through glutathione production (a minor pathway of endogenous methemoglobin reduction) by acting as a precursor to its synthesis.
2) NITRIC OXIDE-INDUCED METHEMOGLOBINEMIA: In vitro, medium (1 mcM) and high (10 mcM) concentrations of methylene blue and high concentrations of riboflavin were effective in reducing methemoglobin concentrations; however, n-acetylcysteine and low concentrations of riboflavin had no beneficial effect on methemoglobin reduction (Dotsch et al, 2000).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) OXYGEN

1) Oxygen should be administered to all cyanotic patients. Cyanosis secondary to methemoglobinemia or sulfhemoglobinemia will not respond to oxygen therapy.
2) Profound cyanosis may occur in individuals with methemoglobinemia or sulfhemoglobinemia who appear to be in no respiratory distress. The blood should be examined and compared to normal blood to identify chocolate-brown color, signifying a methemoglobin level of at least 15%.

B) SEIZURE

1) SUMMARY

2) DIAZEPAM

3) NO INTRAVENOUS ACCESS

4) LORAZEPAM

5) PHENOBARBITAL

6) OTHER AGENTS

C) METHEMOGLOBINEMIA

1) SUMMARY

2) METHYLENE BLUE

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

4) CASE REPORT/REBOUND METHEMOGLOBINEMIA: A 39-year-old man developed acute methemoglobinemia (55%) after use of benzocaine spray. Methylene blue 100 mg was given intravenously, and the methemoglobin level decreased to 25.2%; a second dose of methylene blue was given. However, 3 hours later the level increased to 59.9%, a third dose of 80 mg was given with a subsequent decline, and no further increase in methemoglobin level. The authors suggested that the patient likely received an overdose of benzocaine resulting in rapid systemic absorption and that benzocaine, which is highly lipophilic, resulted in prolonged release of the drug causing recurrent methemoglobinemia (Fitzsimons et al, 2004).
5) ADVERSE EFFECTS

a) METHEMOGLOBINEMIA: Although methylene blue itself has been reported to cause methemoglobin formation up to about 7% of total hemoglobin (Whitwam et al, 1979; Goluboff & Wheaton, 1961; Nadler et al, 1934), this hypothesis has been disputed (Stossel & Jennings, 1966; Rentsch & Wittekind, 1967) and the amounts said to be induced are clinically insignificant (Hall et al, 1986).
b) HEMOLYSIS

c) OTHER : Include chest pain, dyspnea, anxiety, and tremors (Nadler et al, 1934).

6) FALSE POSITIVE CO-OXIMETER RESULTS: Methylene blue may cause a false positive methemoglobin level when measuring arterial blood gases using a co-oximeter (Kirlangitis et al, 1990).

D) HYPERBARIC OXYGEN THERAPY

1) If the patient is not responsive to methylene blue, hyperbaric oxygen has been recommended as adjunctive therapy in severe cases (Donovan, 1983). In animals, HBO has been shown to decrease mortality alone and in combination with methylene blue (Sheehy & Way, 1974; Goldstein & Doull, 1971).

E) EXCHANGE TRANSFUSION

1) Exchange transfusion should be done if the methemoglobinemia is not responsive to methylene blue and is progressive in a symptomatic individual. The mortality rate from methemoglobin levels greater than 70% is high, and exchange transfusion should be considered if levels approach this figure, and cannot be controlled by the use of methylene blue.

F) ASCORBIC ACID

1) May be useful in chronic congenital methemoglobinemia, but is not recommended in acutely toxic patients (Jaffe, 1979; Smith, 1967).

G) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

6.9.2)

A) DECONTAMINATION

B) SKIN ABSORPTION

1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.

C) METHEMOGLOBINEMIA

1) SUMMARY

2) METHYLENE BLUE

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

D) OXYGEN

1) Administer 100% supplemental oxygen to patients with symptomatic methemoglobinemia. Hyperbaric oxygen therapy can be considered to support patients who are refractory to methylene blue therapy. Exchange transfusion could be necessary. Hemodialysis may be considered to remove the chemical (eg, aniline) in severe cases.

E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

1) CASE REPORT: A 51-year-old woman who underwent a total abdominal hysterectomy and salpingo-oophorectomy for a right adnexal mass, presented 4 weeks later with abdominal pain and diarrhea. A CT scan revealed a large obstructing descending aortic thrombus. While undergoing a transesophageal echocardiogram (TEE), she developed severe methemoglobinemia after receiving IV sedation and topical benzocaine anesthesia (HurriCaine 20% spray). She recovered after receiving methylene blue (Cortazzo & Lichtman, 2014).
2) UNUSUAL EXPOSURE: An 18-year-old man with a history of infantile autism and moderate mental retardation developed methemoglobinemia after compulsive urine drinking. Upon physical exam he was noted to have mild bluish discoloration of the gums, along with a pulse oximetry reading of 84% and a methemoglobin level of 23.1%. Intravenous methylene blue was administered over 2 days with marked improvement of his cyanosis; oxygen saturation improved to 92% and the methemoglobin level decreased to 0.3%. Treatment also included behavior modification therapy. Although the mechanism remains unknown, the authors speculated that the nitrate (a by-product of nitric oxide metabolism) found in the urine caused the methemoglobinemia observed in this patient (Chan et al, 2004).
3) REGLAN-INDUCED METHEMOGLOBINEMIA - A 53-year-old male restrained driver presented to the ED after a high-speed head-on collision. Multiple long bone fractures were noted on plain radiographs. On hospital day 3, open reduction and internal fixation of extremity fractures was performed . Routine postoperative medications included cefazolin, lorazepam, morphine, and metoclopramide (Emran et al, 2004).

a) On hospital day 5 the patient was transferred to the surgical intensive care unit for urgent intubation due to progressive respiratory distress and midsternal chest pain. Topical benzocaine spray was used during intubation. The patient remained profoundly hypoxic despite increasing positive end-expiratory pressure from 5 cm H2O to 15 cm H2O and FIO2 to 100%. Dark, chocolate-brown blood was aspirated from a femoral arterial line; methemoglobin level was 38%. Methylene blue 200 mg (1.5 mg/kg) was given and within 60 minutes there was a dramatic improvement in oxygen saturation and mixed venous oxygen saturation. After treatment, methemoglobin level was 3.4%. The authors noted that this event was most consistent with Reglan-induced methemoglobinemia exacerbated by the benzocaine spray (Emran et al, 2004).

1) A 3-year-old child ingested up to 2 ounces of ICK Away aquarium product (containing 0.075% of malachite green (45 mg)) and developed generalized cyanosis approximately 30 minutes postingestion. An initial arterial blood gas revealed an O2 saturation of 47.4% and a methemoglobin level of 50.6%. The patient improved rapidly following an infusion of methylene blue (2 mg/kg), with a repeat methemoglobin level of 6.5%, obtained 2.5 hours postingestion (Spiller et al, 2008).

Range Of Toxicity

Summary

Minimum Lethal Exposure

1) Because of great individual variation in susceptibility to methemoglobin formation, estimates of lethal amounts of any particular drug or chemical are of doubtful value.

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) Correlation of methemoglobin fraction and signs and symptoms observed in most individuals (Haymond et al, 2005):

2) METHEMOGLOBIN BLOOD CONCENTRATIONS AND SIGNS AND SYMPTOMS

a) Correlation of methemoglobin blood concentration and signs and symptoms observed in most individuals (Cortazzo & Lichtman, 2014):

1) Methemoglobin concentration: Less than 1.5 g/dL; % of total hemoglobin less than 10%; Symptoms: None.
2) Methemoglobin concentration: 1.5 to 3 g/dL; % of total hemoglobin: 10% to 20%; Symptoms: Cyanotic skin discoloration.
3) Methemoglobin concentration: 3 to 4.5 g/dL; % of total hemoglobin: 20% to 30%; Symptoms: Anxiety, lightheadedness, headache, tachycardia.
4) Methemoglobin concentration: 4.5 to 7.5 g/dL; % of total hemoglobin: 30% to 50%; Symptoms: Fatigue, confusion, dizziness, tachypnea, increased tachycardia.
5) Methemoglobin concentration: 7.5 to 10.5 g/dL; % of total hemoglobin: 50% to 70%; Symptoms: Coma, seizures, dysrhythmias, acidosis.
6) Methemoglobin concentration: Greater than 10.5 g/dL; % of total hemoglobin: Greater than 70%: Symptoms: Death.

3) CASE REPORTS

a) Survival of 2 patients with methemoglobin levels of 72% and 81.5%, respectively, who were treated with methylene blue has been reported (Kotler et al, 1989; Caudill et al, 1990).

Pharmacology Toxicology

Toxicologic Mechanism

                       Oxidation
        Hgb Fe+2 -----------------> Met Hgb Fe+3

Physicochemical

Animal Toxicology

Clinical Effects

11.1.6)

A) Cat hemoglobin is extremely susceptible to the oxidizing action of drugs and chemicals. Signs of methemoglobinemia include rapid heart beat and respiratory rate, mucous membrane cyanosis, and dark brown blood (Wilkie & Kirby, 1988).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

5) Because of lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only. In the case of a poisoning involving large animals, consult a veterinary poison control center.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) CAT

a) EMESIS - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
b) ACTIVATED CHARCOAL - Dose is 2 grams/kilogram per os or via stomach tube. For treatment of acetaminophen poisoning: due to controversy over adsorption of N-acetylcysteine, do not give activated charcoal and NAC within 2 hours of each other.
c) CATHARTIC - If the animal is not experiencing life-threatening symptoms, administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

2) DOG

a) EMESIS -

1) If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os or one tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times.

b) ACTIVATED CHARCOAL - Dose is 2 grams/kilogram per os or via stomach tube. For treatment of acetaminophen poisoning, due to controversy over adsorption of N-acetylcysteine, do not give activated charcoal and NAC within 2 hours of each other.
c) CATHARTIC - If the animal is not experiencing life-threatening symptoms, administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution (Kirk, 1986).

11.2.5)

A) CAT

1) SUMMARY - Treatment of methemoglobinemia in cats is controversial, because methylene blue causes Heinz body anemia in both cats and dogs (Schalm, 1978; Schechter et al, 1973). Rumbeiha et al (1992), however, studied 40 cats given methylene blue in single or limited therapeutic doses following nitrite-induced methemoglobinemia in which NO cats developed symptoms of hemolytic anemia. The authors suggested that earlier studies examined only cats exposed for prolonged periods to methylene blue.

a) Methylene blue may be useful in cats without pre-existing Heinz body formation. If used, the blood should be monitored for at least one week (Wilkie & Kirby, 1988).
b) Maintain vital functions: secure airway, supply oxygen if cyanotic, and begin supportive fluid therapy.
c) Decontaminate as specified above.
d) N-ACETYLCYSTEINE -

1) For animals with methemoglobinemia secondary to severe acetaminophen poisoning, load with 140 to 280 milligrams/kilogram per os or intravenously (Hjelle & Grauer, 1986). Dilute in D5W to 5% solution and give either via stomach tube or intravenously slowly over a period of 15 to 20 minutes.
2) Thereafter, give 70 milligrams/kilogram per os every 4 hours for up to 17 doses; if clinical picture is good can instead dose with 70 milligrams/kilogram per os four times daily for three days.
3) Sodium sulfate or methylene blue can be given instead of NAC.
4) NOTE - Oral formulations of N-acetylcysteine are used intravenously in the clinical treatment of animals, although not tested or approved for this use.

e) SODIUM SULFATE - Sodium sulfate has been used as an alternative to NAC. Dose: 50 milligrams/kilogram of a 1.6% solution in water given intravenously every 4 hours for a total of 3 to 6 treatments. Sodium sulfate was reported to be as effective as oral or intravenous NAC for reducing methemoglobinemia (Savides et al, 1985).
f) METHYLENE BLUE -

1) Prepare a solution of 10 percent methylene blue in sterile saline (1 gram methylene blue in 10 milliliters saline). Administer the solution intravenously to provide a dose of 1.5 milligrams/kilogram methylene blue. For an average 4.5 kg (10 pounds) cat, the dosage volume of 10 percent solution would be 0.07 milliliters.
2) This agent effectively reverses methemoglobinemia. The dosage may be repeated two or three times without causing anemia (Personal Communication, 1991; Rumbeiha & Oehme, 1992).
3) Monitor blood smears for one week post-treatment for Heinz body anemia.

g) ASCORBIC ACID - Ascorbic acid converts methemoglobin to oxyhemoglobin. Dose is 30 milligrams/kilogram subcutaneously every 6 hours for 7 treatments. This is an adjuncting therapy.
h) Corticosteroids and antihistamines are contraindicated. Limit physical activity to reduce anoxia hazard. Drinking water always should be available, and food may be offered 24 hours after beginning treatment.
i) TRANSFUSION - If necessary, transfuse with whole blood or plasma, 25 milliliters/kilogram.

B) DOG

1) Maintain vital functions: Secure airway, supply oxygen if cyanotic, and begin supportive fluid therapy.
2) Decontaminate as specified above.
3) N-ACETYLCYSTEINE (Use cat dosages for dogs weighing 10 kilograms and less):

a) For animals with methemoglobinemia secondary to severe acetaminophen poisoning, load with 280 milligrams/kilogram per os or intravenously (Hjelle & Grauer, 1986). Dilute in D5W to 5% solution and give either via stomach tube or intravenously slowly over a period of 15 to 20 minutes.
b) Thereafter, give 140 milligrams/kilogram per os every 4 hours for up to 17 doses; if clinical picture is good can instead dose with 140 milligrams/kilogram per os four times daily for three days.

4) ASCORBIC ACID - Ascorbic acid converts methemoglobin to oxyhemoglobin. If methemoglobinemia is present, dose at 30 milligrams/kilogram subcutaneously every 6 hours for 7 treatments.
5) Corticosteroids and antihistamines are contraindicated. Limit physical activity to reduce anoxia hazard. Drinking water should always be available, and food may be offered 24 hours after beginning treatment.

Range Of Toxicity

11.3.1)

A) CAT

1) PRODUCTS CONTAINING ACETAMINOPHEN or PHENACETIN SHOULD NEVER BE ADMINISTERED TO CATS. No dose is safe, due to cats inability to metabolize acetaminophen.

11.3.2)

A) CAT

1) PRODUCTS CONTAINING ACETAMINOPHEN or PHENACETIN SHOULD NEVER BE ADMINISTERED TO CATS. No dose is safe, due to cats inability to metabolize acetaminophen.

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) CAT

2) DOG

a) EMESIS -

References

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FeedBack

METHEMOGLOBINEMIA

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Vital Signs

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Acid-Base

Hematologic

Dermatologic

Summary Of Exposure

Reproductive

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Case Reports

Summary

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicologic Mechanism

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

General Bibliography