MetHB concentration

Signs and Symptoms

0-3% (normal)

None

3-10%

Blue-grey skin appearance (cyanosis), may be asymptomatic

10-20%

Cyanosis, chocolate brown colour of blood

20-50%

Mental changes (headache, fatigue, anxiety, confusion, dizziness), syncope, tachycardia, dyspnea and tachypnea, weakness, exercise tolerance

50-70%

Metabolic acidosis, seizures, coma, dysrhythmias

>70%

Potentially lethal

A

Acetaminophen

Acetaminophen rarely causes MeHb in humans at therapeutic doses, but it can in overdoses or in combination with other MeHb inducers.

Atovaquone¹³

MeHb is mentioned as an adverse effect of Mepron® (product monograph)

B 

Benzocaine^14-17

Benzocaine is one of the most common causes of significant MeHb. Most of the serious cases involve use of topical sprays used in anesthesia. While the majority of children who accidental ingest teething gels remain asymptomatic, life-threatening MeHb (~70%) has occurred

Buprenorphine-naloxone¹³

MeHb is mentioned as an adverse effect of Suboxone

C

Celecoxib¹⁸

Cloroquine¹⁹

Cotrimoxazole^20,21

Cyclophosphamide³

Celecoxib 100 mg BID resulted in MeHb of 9% and confusion in one patient.
Cotrimoxazole has caused MeHb on its own and when given with other MeHb inducers.

D 

Dapsone²

Dapsone is another frequently cited cause of MeHb. Because of the long half-life of dapsone and its hydroxylamine metabolite, prolonged or repeated antidote treatment or exchange transfusion may be required.

Disulfiram²²

Disulfiram was suspected to cause MeHb of 53% in one fatality. The metabolite diethylthiocarbamate can produce MeHb in vitro.

E

EMLA (lidocaine-prilocaine)²³

Application of a large amount of EMLA for laser hair removal resulted in symptomatic elevated MeHb (20%) requiring treatment.

F

Flutamide^24,25

MeHb is mentioned as a possible side effect in the product monograph and is usually mild. Sulfhemoglobinemia has occurred that is mistaken for MeHb but does not respond to methylene blue.

H

Hydrogen peroxide^26-28

Hydrogen peroxide disinfection of dialysis machines has been linked to MeHb. Topical application of hydrogen peroxide to mucous membranes caused MeHb in a patient deficient of the enzyme catalase. See rasburicase.

I  

Ibuprofen²⁹

Cyanosis with MeHb levels of 27.2% occurred in a 7-month-old infant, eight hours after a dose of ibuprofen 7.5 mg/kg. Other causes were ruled out.

Ifosfamide³⁰

Marked MeHb (~50%) occurred in a patient receiving ifosfamide who was also taking phenobarbital for seizures. Enzyme induction with increased formation of MeHb inducing metabolites was suspected to be involved.

Interactions^12,21,31

Oxidative stress may be additive when more than one potential MeHb inducers are used together (e.g. sulfonamides and prilocaine; nitric oxide and cotrimoxazole; acetaminophen and sodium nitrate).

L

Lidocaine¹⁶ (and other local anesthetics)

Lidocaine appears to be much less likely to cause MeHb compared to benzocaine, considering the frequency of lidocaine use.

M

Metoclopramide^32,33

Metoclopramide has occasionally been reported to cause MeHb in neonates and less frequently in adults, although significant MeHb (>40%) has been reported.

N 

Nitrites and nitrates (amyl nitrite, silver nitrate, nitroglycerin, nitroprusside)^34-36

Environmental and industrial nitrites and nitrates are common inducers of MeHb; therapeutic nitrates can cause MeHb as well.

Nitric Oxide

Therapeutic inhaled nitric oxide at less than 40 ppm usually causes only a mild elevation in MeHb.

P  

Phenazopyridine^2,37,38

Phenazopyridine is another common cause of MeHb in both children and adults. The resemblance to candy and sugar coating makes phenazopyridine tablets attractive to children.

Prilocaine¹⁶

Prilocaine is the next most common local anesthetic reported to cause MeHb (after benzocaine).

Primaquine³⁹

Primaquine causes a usually mild MeHb when used as an antimalarial but MeHb levels >30% can be seen occasionally.

R 

Rasburicase⁴⁰

Rasburicase (recombinant urate oxidase) catalyses the conversion of urate to allantoin, producing hydrogen peroxide in the process which may contribute to development of MeHb.

Riluzole^41,42

MeHb levels of 12 to 18% have been seen following overdoses of riluzole.

S

Sulfonamides (sulfadiazine, sulphanilamide, sulfapyridine, sulfasalazine)^43-45

Topical silver sulfadiazine burn dressings caused MeHb in a young boy with thalassemia. Sulfanilamide is not available for human use in Canada anymore. The sulfapyridine portion is responsible for MeHb seen with sulfasalazine.

T

Tetracaine⁴⁶

Self-medication with tetracaine lozenges caused MeHb in one case. Tetracaine by itself appears to have a low propensity to cause MeHb.

Z

Zopiclone^48,49

MeHb levels ranging from 10.4% to 23.8% have been reported in patients following large overdoses of zopiclone.