How does ascorbic acid treat methemoglobinemia

In 1 the disease is of unusual interest in that a spontaneous formation of methemoglobin was apparently the cause of the cyanosis. A similar syndrome was described by Stokvis in and named enterogenous cyanosis. In the other patient sodium nitrite therapy was the cause of the cyanosis. Arch Intern Med Chic. Coronavirus Resource Center. Our website uses cookies to enhance your experience.

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This Issue. September Access through your institution. Add or change institution. Save Preferences. As with methylene blue, intravenous ascorbic acid administration was also effective to treat dapsone-induced methemoglobinemia in a rat model. It is commonly used to treat leprosy, malaria, dermatitis herpetiformis, and other diseases, and has also been administered as a prophylactic treatment of pneumocystis pneumonia and Toxoplasma gondii infection in HIV-positive patients [ 3 , 4 ].

DDS is insoluble in water and is readily absorbed in the gastrointestinal tract. DDS is metabolized via either N-hydroxylation or acetylation through portal circulation in the liver Fig. It has been suggested that the most common adverse effects of DDS—methemoglobinemia and hemolysis—are induced by DDS-hydroxylamine, an N-hydroxylated metabolite of DDS that produces a number of reactive oxygen species and methemoglobin as a result of a cyclic oxidation-reduction reaction between DDS-hydroxylamine and oxyhemoglobin in red blood cells [ 8 - 10 ].

Methemoglobin contains one or more ferric state heme ions oxidized from ferrous ions; accordingly, it is incapable of binding to oxygen [ 11 , 12 ]. Severe methemoglobinemia resulting from a DDS overdose can cause cyanosis, dizziness, dyspnea, tachycardia, altered mental status, and eventually, death [ 13 - 16 ]. The most widely accepted treatment for methemoglobinemia is intravenous injection of methylene blue.

This compound is reduced to colorless leucomethylene blue by nicotinamide adenine dinucleotide phosphate NADPH methylene blue reductase, which then reduces methemoglobin to hemoglobin [ 10 ]. However, methylene blue could induce hemolysis, and should not be administered to patients with known glucosephosphate dehydrogenase G6PD deficiency and non-G6PD deficiency infants [ 17 , 18 ]. As an alternative to methylene blue, ascorbic acid has been used to treat methemoglobinemia, although multiple doses are required, and its response is very slow [ 19 - 21 ].

Methylene blue has been unavailable in most Korean emergency departments because of an import suspension over the past few years. Therefore, we have used ascorbic acid to treat methemoglobinemia. The present study was performed to investigate the effects of ascorbic acid in the treatment of DDS-induced methemoglobinemia by comparing its activity to that of methylene blue in an animal model. The animals were housed in a controlled environment for 3 to 7 days and were allowed free access to food and water.

All animals were fasted for 8 hours before the experiment, but had free access to water. Study protocol The rats were divided into an ascorbic acid group, a methylene blue group, and a control group. Ascorbic acid and methylene blue were diluted in normal saline, and equivalent volumes were administered to the three groups. Blood collection After anesthesia, a thoracotomy was performed, and blood samples were collected from the heart of the rats.

Carbon monoxide oximetry was used to determine the percentage of methemoglobin in a blood sample. The optical density of the samples was measured at nm. CAT is an antioxidant enzyme that converts hydrogen peroxide H 2 O 2 to water and oxygen. Ten microliters of each sample was transferred into the wells of a well plate. After the samples were incubated for 10 minutes, their optical density values were measured at nm.

Statistical analysis The sample size was calculated based on superiority of intravenous ascorbic acid and methylene blue administration over normal saline in DDS-induced methemoglobinemia. The test for normality was performed using a Shapiro-Wilk test. The Kruskal-Wallis test with the Mann-Whitney U post hoc test was used to perform comparisons among the groups if the normality assumption was not satisfied. At 60 minutes, significantly lower concentrations of methemoglobin were measured in the methylene blue 3.

At minutes, the methemoglobin concentration was At minutes, the methemoglobin concentrations of three groups were There were no statistically significant differences among the three groups. The CAT activity in the three groups at 60, , and minutes is shown in Fig. There were also no statistically significant differences among the groups. However, it is unclear whether ascorbic acid is more effective than methylene blue at treating DDS-induced methemoglobinemia.

Methemoglobin is formed by oxidizing normal ferrous heme ions to ferric state ions. Methemoglobin has a reduced ability for oxygen transport to tissues, which causes cellular hypoxia.

However, under conditions of oxidative stress, methemoglobin levels can increase. There are two types of methemoglobinemia: congenital and acquired. Acquired methemoglobinemia is a result of increased methemoglobin formation by exogenous oxidizing agents and is more common; cases of congenital methemoglobinemia are rare.

Normally, low methemoglobin levels are maintained by reducing mechanisms through enzymatic systems and cellular antioxidants. NADH-dependent cytochrome b5 methemoglobin reductase is the major enzyme responsible for the reduction of methemoglobin, and NADPH-dependent methemoglobin reductase is a minor pathway [ 10 ]. Cellular antioxidants, such as ascorbic acid and glutathione, play a minor role in reducing methemoglobin. If significant symptoms e. The standard treatment for methemoglobinemia is intravenous administration of methylene blue, which is currently considered the gold standard of treatment for methemoglobinemia.

Methylene blue reduces toxic levels of methemoglobin to a non-toxic level within 10 to 60 minutes via an NADPH-dependent pathway [ 23 ]. As a result, this treatment is minimally effective, or could be potentially harmful, because it may exacerbate the degree of methemoglobinemia and induce acute hemolysis.

In addition, methylene blue can cause serotonin toxicity. Several case reports of methylene blue-associated serotonin toxicity have been described in which methylene blue was intravenously administered to stain parathyroid glands during parathyroidectomy in patients receiving serotonergic psychotropic drugs [ 24 ].

In one severe case, methylene blue-associated serotonin toxicity was fatal [ 25 ]. When methylene blue is unavailable, ascorbic acid can be used, although multiple doses are required, and its response is less effective. As an alternative to methylene blue, ascorbic acid can be a therapeutic agent for methemoglobinemia in some cases [ 19 - 21 , 26 ].

Ascorbic acid, the most investigated antioxidant and free radical scavenger in the literature, reduces methemoglobin directly [ 27 , 28 ]. Topal and Topal [ 19 ] reported a case in which methemoglobinemia induced by the local anesthetic prilocaine was treated with ascorbic acid instead of methylene blue as an alternative method. A previously healthy day-old male developed toxic methemoglobinemia after local administration of prilocaine for circumcision, and mg of intravenous ascorbic acid was administered slowly over a hour period.

His initial levels of methemoglobin were found to be Park et al. In this case, DDS induced toxic methemoglobinemia, and high doses of ascorbic acid i. Another case series of ascorbic acid treatment for methemoglobinemia was reported by Rino et al. The methemoglobin levels of these patients ranged from 6. Cimetidine and N-acetylcysteine have also been studied for treating methemoglobinemia; however, their therapeutic effects are poorly understood [ 8 , 9 , 29 ].

In this study, we demonstrated that intravenous ascorbic acid administration was effective at reducing methemoglobin levels. However, ascorbic acid was slightly less effective than methylene blue administration. At minutes, the methemoglobin concentration of the ascorbic acid group was not significantly different from that of the control group, whereas the methylene blue group showed a more marked difference.

In actual clinical cases, because the therapeutic response to ascorbic acid is less marked, repeated doses of intravenous ascorbic acid or an oral preparation have been prescribed, whereas we administered a single intravenous dose of ascorbic acid [ 20 , 26 ].

Therefore, a higher dose of ascorbic acid might be needed to achieve better therapeutic results. NO is an important regulatory molecule that is associated with host defense and development, and is produced biologically from the oxidation of L-arginine to L-citrulline, which is catalyzed by NO synthase [ 30 ].

NO is indicative of cytotoxic effects along with other reactive oxygen species, such as H 2 O 2 and superoxide [ 31 ]. Catalase is an antioxidant enzyme that can degrade H 2 O 2 to water and oxygen. The breakdown of H 2 O 2 in the cell by catalase prevents oxidative damage. A number of studies regarding the role of H 2 O 2 in oxidative stress have been conducted [ 32 , 33 ].

Contrary to our expectations, plasma NO levels and CAT activity at 60, , and minutes did not show any statistical differences among any of the groups. Further study is needed with higher doses of ascorbic acid, as well as with measurements of different oxidative stress parameters.

In summary, in the present study, intravenous ascorbic acid administration was effective for the treatment of DDS-induced methemoglobinemia in a murine model. Rodriguez M, Fishman JA. Prevention of infection due to Pneumocystis spp. In human immunodeficiency virus-negative immunocompromised patients.

Clin Microbiol Rev ; Dapsone-induced hemolytic anemia in lung allograft recipients. J Heart Lung Transplant ; Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med ;