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PubMed1977

Benzocaine-induced methemoglobinemia.

Severe methemoglobinemia developed in a healthy 14-month-old infant following the topical application of a benzocaine-containing gel administered for the relief of the discomfort of teething. Congenital methemoglobinemia and hemoglobin M disease were excluded by appropriate laboratory studies. The patient is considered to have a normal methemoglobin-reducing capacity and her response to the drug is one that presumably could occur in any other child of comparable age on receiving an equivalent dose of benzocaine. Parents should be cautioned against the indiscriminate use of similar medications, particularly since the process for which these medications are administered is both benign and physiologic.

Administration, Topical↗

PubMed1993

Concise review: methemoglobinemia.

The ferrous iron of hemoglobin is exposed continuously to high concentrations of oxygen and, thereby, is oxidized slowly to methemoglobin, a protein unable to carry oxygen. To restore hemoglobin function, methemoglobin (ferrihemoglobin) must be reduced to hemoglobin (ferrohemoglobin). Under physiological conditions, methemoglobin reduction is accomplished mainly by red cell NADH-cytochrome b5 reductase (NADH-methemoglobin reductase) so efficiently that there is insignificant amounts of methemoglobin in the circulating blood. However, should methemoglobin formation be increased--e.g., due to the presence of oxidant drugs, or an abnormal methemoglobin not amenable to reduction (hemoglobin M), or a deficiency in red cell cytochrome b5 reductase--methemoglobinemia will result. Most methemoglobinemias have no adverse clinical consequences and need not be treated. Under certain conditions, such as exposure to large amounts of oxidant or in young infants, rapid treatment is necessary. In hereditary cytochrome b5 deficiency, treatment is often directed at improving the poor cosmetic effect of persistent cyanosis with the minimum amount of drugs to give satisfactory clinical results.

Hemoglobin M↗

PubMed2001

Molecular basis of recessive congenital methemoglobinemia, types I and II: Exon skipping and three novel missense mutations in the NADH-cytochrome b5 reductase (diaphorase 1) gene.

Hereditary methemoglobinemia due to reduced nicotin amide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5r) deficiency is classified into an erythrocyte type (I) and a generalized type (II). We investigated the b5r gene of three unrelated patients with types I and II and found four novel mutations. The patient with type I was homozygous for a c.535 G-->A exchange in exon 6 (A179T). The patients with type II were found to be homozygous for a c.757 G-->A transition in exon 9 (V253M) and compound heterozygous for two mutations, respectively. One allele presented a c.379 A-->G transition (M127V). The second allele carried a sequence difference at the invariant 3' splice-acceptor dinucleotide of intron 4 (IVS4-2A-->G) resulting in skipping of exon 5. To characterize a possible effect of this mutation on RNA metabolism, poly(A)(+) RNA was analyzed by RT-PCR and sequencing. The results show that RNA is made from the allele harboring the 3'-splice site mutation. Furthermore, western blot analysis revealed a complete absence of immunologically detectable b5r in skin fibroblasts of this patient. The compound heterozygosity for the splice site and the missense mutations apparently caused hereditary methemoglobinemia type II in this patient. Hum Mutat 17:348, 2001.

Alleles↗

PubMed1997

Methemoglobinemia associated with dapsone treatment in solid organ transplant recipients: a two-case report and review.

Dapsone, a sulfone antibiotic, has been increasingly used in solid-organ transplant recipients for the primary prevention of Pneumocystis carinii pneumonia, especially in patients with documented sulfa allergy. A known side effect of dapsone therapy, however, is methemoglobinemia, a condition leading to impaired tissue oxygen delivery. This report documents two cases of dapsone-induced methemoglobinemia in patients after solid organ transplantation with emphasis on the importance of clinical recognition and benefits of treatment. Further, the pathophysiology and causes of this condition are extensively reviewed.

Aged↗

PubMed1996

Health implications of nitrate and nitrite in drinking water: an update on methemoglobinemia occurrence and reproductive and developmental toxicity.

In 1987, an evaluation of the nitrate drinking water standard was performed with a primary focus on the effects of nitrate on methemoglobinemia and reproductive/developmental effects (Fan et al. (1987). Regul. Toxicol. Pharmacol. 7, 135-148). The present review presents an updated overview and evaluation of the available information on the same health effects of nitrate and nitrite with an emphasis on data not included in the previous review, which should be used as a compendium to this report. Recent epidemiologic data have suggested an association between developmental effects in offspring and the maternal ingestion of nitrate from drinking water, but a definite conclusion on the cause and effect relationship cannot be drawn. Animal experimental data have shown reproductive toxicity associated with high exposure levels to nitrate or nitrite, which are not likely to be encountered in drinking water. No teratogenic effects were observed in rats, mice, rabbits, and hamsters tested. Several cases of methemoglobinemia have been reported in infants in the United States using water containing nitrate at levels higher than the current maximum contaminant level (MCL) of 45 ppm (mg/liter) nitrate (NO3) or 10 ppm nitrate-nitrogen (nitrate-N), but none at or lower than the MCL. The uncertainties in the data base are discussed, noting that no uncertainty factor was applied in deriving the MCL in order to account for the uncertainties that exist in the data base.

Animals↗

PubMed2002

Decrease in 4-aminobiphenyl-induced methemoglobinemia in Cyp1a2(-/-) knockout mice.

Methemoglobin formation, as well as hemoglobin or DNA adducts, are useful biomarkers of occupational exposure to certain arylamines. It has been suggested that, in liver from animals not treated with a cytochrome P450 (CYP) inducer, hepatic CYP1A2 is the major P450 involved in N-hydroxylation. This is the first step in the metabolic activation of many arylamines, such as the human urinary bladder carcinogen 4-aminobiphenyl (ABP). The product of this catalytic step, N-hydroxy-4-ABP, reacts in the blood with oxyhemoglobin to form methemoglobin and nitrosobiphenyl. We therefore examined the role of CYP1A2 in causing methemoglobinemia in ABP-treated Cyp1a2(-/-) knockout mice. Application of ABP (100 micromol/kg body wt) to the skin resulted in a marked depletion in the levels of the hepatic thiols (reduced glutathione and cysteine) after 2 h, which rebounded to basal levels 24 h later, and we found no differences between the Cyp1a2(-/-) and wild-type Cyp1a2(+/+) animals. Unexpectedly, the methemoglobin levels were significantly (p < 0.05) higher in Cyp1a2(-/-) than Cyp1a2(+/+) mice at 2, 7, and 24 h following topical ABP. Treatment with dioxin, 24 h prior to ABP, decreased methemoglobin levels by about half at each of the time points in both the Cyp1a2(-/-) and Cyp1a2(+/+) mice. These data suggest that CYP1A2 does not play a positive role in methemoglobin formation via the activation of ABP; rather, the absence of CYP1A2 enhances ABP-induced methemoglobinemia. Because liver CYP1A2 levels are known to vary more than 60-fold between humans, our findings may be relevant to patients who are exposed to arylamines in the workplace.

Administration, Topical↗

PubMed2003

[Methemoglobinemia due to prilocaine after plexus anesthesia. Reduction by prophylactic administration of ascorbic acid?].

OBJECTIVE: This study investigated in vivo and in vitro kinetics of o-toluidine-induced methemoglobinemia and the influence of ascorbic acid on resulting methemoglobin concentrations. o-Toluidine is a metabolite of prilocaline and ascorbic acid is recommended for treatment of methemoglobinemia as an alternative to methylene blue. METHODS: We measured the formation of methemoglobin in vitro in a whole blood culture system of 8 healthy individuals 30, 60, and 360 min after the addition of different concentrations of o-toluidine (0.5, 5, 50 micrograms/ml) with and without addition of ascorbic acid (0.5 and 5 mg/ml). In a prospective randomized clinical study, a total of 72 patients of ASA risk I-III were investigated. The 3 groups of 24 patients received either an axillary, an infraclavicular vertical brachial plexus, or a combined femoral and ischiadic blockade. In each plexus anesthesia group, 12 patients were given 2,000 mg ascorbic acid intravenously before applying the local anesthetics. For surgery of the upper limb the patients received 40 ml 1% prilocaine and 10 ml 0.5% bupivacaine, for surgery of the lower limb they received 60 ml 1% prilocaine and 0.25 mg adrenaline. Blood samples for measurement of methemoglobin concentrations were taken before and 30, 60, 120, 180 and 360 min after the injection of the regional anesthetic. A p < 0.05 was considered to be significant. RESULTS: There was a dose-dependent increase of methemoglobin due to addition of o-toluidine after 360 min in vitro. The application of 0.5 mg/ml ascorbic acid to the whole blood samples with 0.5 and 5 micrograms/ml o-toluidine resulted in a further increase of methemoglobin formation whereas there was no difference in the samples with 50 micrograms/ml. The higher concentration of 5 mg/ml ascorbic acid attenuated the methemoglobin formation only with 50 micrograms/ml o-toluidine. No effect was observed with lower concentrations of o-toluidine. In the in vivo study plexus anesthesia with prilocaine resulted in an increase of the methemoglobin concentration with a maximum after 120-180 min. The highest measured methemoglobin concentration found was 11.3%. The methemoglobin concentration already showed a decrease 360 min after the application of the regional anesthetic 2,000 mg ascorbic acid given intravenously before plexus anesthesia was not able to influence the resulting methemoglobin concentrations. CONCLUSIONS: In vitro high concentrations of ascorbic acid are able to reduce the resulting methemoglobin concentration 360 min after addition of 50 micrograms/ml o-toluidine. The application of 2,000 mg ascorbic acid i.v. before plexus anesthesia with prilocaine does not reduce the concentration of methemoglobin.

Adult↗

PubMed1982

Blood nitrates and infantile methemoglobinemia.

Infantile methemoglobinemia is of much more frequent occurrence among hospitalized newborns and young infants than is generally appreciated. When present, acute diarrhoea of different etiologies is almost exclusively the cause of hospitalization. No correlation between this condition and ingestion of food or water containing high concentrations of nitrates or nitrites was found. This study demonstrates for the first time that high blood nitrates are a regular part of the syndrome. The evidence presented is interpreted as indicating that diarrhoea results in endogenous, de novo synthesis of nitrites, and this is the principal cause of infantile methemoglobinemia.

Acute Disease↗

PubMed1990

Methemoglobinemia as a complication of 20% benzocaine spray for endoscopy.

Topical 20% benzocaine (Hurricaine, Beutlich, Inc., Niles, Ill.) spray is frequently used for oral anesthesia before upper endoscopy. Side effects attributed to this agent are exceedingly rare. The author reports one of these rare complications, drug-induced methemoglobinemia, in a patient with methemoglobin reductase deficiency. The mechanisms for the development of methemoglobinemia and its treatment are reviewed.

Adult↗

PubMed1983

Life-threatening toxic methemoglobinemia induced by prilocaine.

Methemoglobinemia is reviewed briefly with particular reference to prilocaine. One case of prilocaine induced toxic methemoglobinemia is presented and discussed to remind the practitioner that although rare, this condition can be life threatening, and should be considered in the differential diagnosis of cyanosis.

Adult↗

PubMed1990

Metabolism of the arylamide herbicide propanil. I. Microsomal metabolism and in vitro methemoglobinemia.

Methemoglobinemia produced by exposure to the herbicide propanil (3,4-dichloropropionanilide) is thought to be mediated by toxic metabolites formed during the hepatic clearance of the parent compound. We examined the metabolism of propanil and 3,4-dichloroaniline in rat liver microsomes to identify metabolites that may be involved in propanil-induced methemoglobinemia. The major pathway of propanil metabolism in microsomal incubations was acylamidase-catalyzed hydrolysis to 3,4-dichloroaniline. The reaction did not require NADPH, and was inhibited by the acylamidase inhibitors paraoxon and sodium fluoride. Oxidized metabolites were isolated by high-performance liquid chromatography, and identified as 2'-hydroxypropanil and 6-hydroxypropanil by comparison of their mass and nuclear magnetic resonance spectra to those of synthetic standards. Major microsomal metabolites of 3,4-dichloroaniline were 6-hydroxy-3,4-dichloroaniline and N-hydroxy-3,4-dichloroaniline. Both N-hydroxy-3,4-dichloroaniline and 6-hydroxy-3,4-dichloroaniline directly oxidized hemoglobin in rat erythrocyte suspensions in a concentration-dependent manner; however, the potency of N-hydroxy-3,4-dichloroaniline was at least an order of magnitude greater than that of 6-hydroxy-3,4-dichloroaniline.

Anilides↗

PubMed1992

Methemoglobinemia secondary to automobile exhaust fumes.

Methemoglobinemia is an uncommon cause of cyanosis. A 28-year-old male presented to the emergency department cyanotic and short of breath after exposure to noxious automobile fumes. He did not improve with the administration of 100% oxygen therapy. The initial arterial blood gas with cooximetry was: pH of 7.38, PaCO2 of 43 mm Hg, PaO2 of 118 mm Hg, measured oxygen saturation of 70%, and a methemoglobin level of 24.8%. Methylene blue was given (2 mg/kg intravenously) and the patient's symptoms resolved. On the following day he was discharged home without complication. A comprehensive review of the literature revealed no reported cases of methemoglobinemia secondary to accidental exposure to exhaust fumes.

Adult↗

PubMed1993

Infantile methemoglobinemia associated with acute diarrheal illness.

A case of an infant with diarrhea and acidosis associated with methemoglobinemia is presented. Of interest is that the association of diarrhea and acidosis with methemoglobinemia is more common than previously thought and can produce dangerously high methemoglobin levels. A review of the literature of this unusual occurrence along with clues to making the diagnosis are discussed.

Acidosis↗

PubMed2004

Cytochrome b5 reductase: the roles of the recessive congenital methemoglobinemia mutants P144L, L148P, and R159*.

Recessive congenital methemoglobinemia (RCM, OMIM 250800) arises from defects in either the erythrocytic or microsomal forms of the flavoprotein, cytochrome b5 reductase (cb5r) and was the first disease to be directly associated with a specific enzyme deficiency. Of the 33 verified mutations in cb5r that give rise to either the type I (erythrocytic) or type II (generalized) forms of RCM, three of the mutations, corresponding to P144L, L148P, and R159*, are located in a segment of the primary sequence composed of residues G143 to V171 which serves as a "hinge" or "linker" region between the FAD- and NADH-binding lobes of the protein. With the exception of R159*, which produces a truncated non-functional cb5r resulting in type II RCM, the type I methemoglobinemias resulting from the P144L or L148P mutations have been proposed to be due to decreased enzyme stability. Utilizing a recombinant form of the rat cb5r enzyme, we have generated the P144L, L148P, and P144L/L148P mutants, purified the resulting proteins to homogeneity and characterized their spectroscopic, kinetic, and thermodynamic properties. The three mutant proteins retained full complements of FAD with the P144L and L148P variants being spectroscopically indistinguishable from wild-type cb5r. In contrast, kinetic analyses revealed that the P144L, L148P, and P144L/L148P variants retained only 28, 31, and 8% of wild-type NADH:cytochrome b5 reductase activity, respectively, together with significant alterations in affinity for both NADH and NAD+. In addition, FAD oxidation-reduction potentials were 32, 19, and 65 mV more positive for the mutants than the corresponding FAD/FADH2 couple in native cb5r (E0'=-272 mV). Thermal and proteolytic stability measurements indicated that all three mutants were less stable than the wild-type protein while differential spectroscopy indicated altered pyridine nucleotide binding in all three variants. These results demonstrate that the "hinge" region is important in maintaining the correct orientation of the flavin- and pyridine nucleotide-binding lobes within the protein for efficient electron transfer and that the P144L and L148P mutations disrupt the normal registration of the FAD- and NADH-binding lobes resulting in altered affinities for both the physiological reducing substrate, NADH and its product, NAD+.

Amino Acid Sequence↗

PubMed2006

Acute methemoglobinemia following attempted suicide by Dapson.

This report describes the case of an otherwise healthy young adult female, with oral ingestion of 40 unknown tablets. Her clinical course included progressive bluish discoloration of lips and limbs, hemolysis and jaundice. A high PaO2 in the presence of cyanosis and dark blood lead to suspicion of methemoglobinemia. Laboratory results showed methemoglobin level to be 3.8 g/dL (38%). The etiology was traced to dapsone according to patient history; after 3 days it became evident that she had ingested 2 g dapsone in suicidal intent. The therapeutic and diagnostic approach in such patients is discussed. In conclusion, acute methemoglobinemia is an uncommon but potentially treatable disorder.

Acute Disease↗

PubMed2005

Identification and characterization of the novel FAD-binding lobe G75S mutation in cytochrome b(5) reductase: an aid to determine recessive congenital methemoglobinemia status in an infant.

NADH-cytochrome b(5) reductase deficiency results clinically in either type I or type II recessive congenital methemoglobinemia. The more severe type II form is associated with a global deficiency of cytochrome b(5) reductase and is characterized by cyanosis with neurological dysfunction. In contrast, the only symptom for type I is cyanosis. We have identified a novel G to A mutation at position 15,635 in the DIAI gene of a 4-month-old baby that results in a glycine to serine substitution at codon 75 in the cytochrome b(5) reductase protein. The G75S mutation, located in the FAD-binding lobe of cytochrome b(5) reductase, was found in association with the previously described V252M variant. The V252M mutation is present in the NADH-binding domain and associated with both types I and II recessive congenital methemoglobinemia. Since the G75S and V252M mutations represent radical changes in differing regions of cytochrome b(5) reductase, generating and characterizing these variants singly and in combination using a rat heterologous expression system would provide insight into the differences between types I and II disease at the molecular level. Although all three variants were found to retain stoichiometric levels of FAD with spectroscopic and thermodynamic properties comparable to those of native cytochrome b(5) reductase, all exhibited decreased catalytic efficiency and reduced protein stability reflecting the position of the mutations in the primary structure. The G75S variant retained only 11% of the catalytic efficiency of the wild-type enzyme. Thus, cytochrome b(5) reductase deficient patients who are heterozygous for either FAD- or NADH-binding lobe mutations can exhibit the clinically less severe type I phenotype.

Amino Acid Sequence↗

PubMed2006

Methemoglobinemia by cerium nitrate poisoning.

Cerium nitrate is a topical antiseptic used with silver sulfadiazine (Flammacerium) for the treatment of serious burns. This topical agent can induce methemoglobinemia, but no cases have been reported in the recent literature. In this article, we present the case of a 16-year old girl, with third-degree burns over 95% of her body. After daily dressings of Flammacerium, on the sixth day she developed a bluish skin coloring. When tested for methemoglobinemia, levels of 31.8% were found. These returned to normal after classic treatment with Methylene blue.

Adolescent↗

PubMed2004

Anesthetic management of a patient with congenital methemoglobinemia.

A knowledge of congenital methemoglobinemia is essential to deliver a safe anesthetic to this group of patients. We report the case of a 33-year-old patient with congenital methemoglobinemia undergoing a gynecological procedure, and discuss the anesthetic implications. The etiology, pathophysiology, classification, diagnosis, clinical manifestations, anesthetic considerations, treatment options, and postoperative management are also discussed.

Adult↗