American Journal of Therapeutics 21, 240–243 (2014)

Ascorbic Acid for the Treatment of Methemoglobinemia: The Experience of a Large Tertiary Care Pediatric Hospital Pedro Bonifacio Rino, MD,1 Dennis Scolnik, MBChB,2,3 Ana Fustiñana, MD,1 Alexis Mitelpunkt, MD,4 and Miguel Glatstein, MD4,5*

The purpose of reporting this series of patients is to illustrate the role of ascorbic acid in the treatment of severe acquired methemoglobinemia (metHb), especially when methylene blue is not available. Medical records of affected patients were reviewed to collect history of exposures, food ingestion, physical examination, pulse oximetry, blood gas, and co-oximetry results, and outcomes. Five cases of acquired metHb are presented here, all of whom received treatment with ascorbic acid and fully recovered after 24 hours of treatment. Our series emphasizes that ascorbic acid is an effective alternative in the management of acquired metHb if methylene blue is unavailable and suggests that ascorbic acid infusion may be indicated in patients with glucose-6-phosphatase dehydrogenase deficiency. Keywords: ascorbic acid, methemoglobinemia, infants, methylene blue

INTRODUCTION Vitamin C, also known as ascorbic acid, is ingested by approximately 12% of the US adult population.1 This vitamin is involved in several important endothelial cell functions in the vascular bed.2 It has been used as a preventative for the common cold although studies do not demonstrate any therapeutic benefit,3 and it


Division of Pediatric Emergency Medicine, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina; 2Division of Pediatric Emergency Medicine, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada; 3Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, University of Toronto, Ontario, Canada; 4Division of Pediatric Emergency Medicine, Department of Pediatrics, Dana-Dwek Children Hospital, University of Tel Aviv, Tel Aviv, Israel; and 5Division of Clinical Pharmacology and Toxicology, Ichilov Hospital, University of Tel Aviv, Tel Aviv, Israel. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Pediatric Emergency Medicine, Dana-Dwek Children Hospital, Sackler School of Medicine, Tel Aviv University, 6 Weizman St, Tel Aviv 64239, Israel. E-mail: [email protected] 1075–2765 Ó 2014 Lippincott Williams & Wilkins

has also been used experimentally in the prevention and treatment of cardiovascular disease and cancer because of its antioxidant properties.4,5 Vitamin C also has a role as a reducing agent in the treatment of idiopathic methemoglobinemia (metHb), however, it is less effective than standard treatment with methylene blue and is therefore not generally used.6,7 It may be indicated when methylene blue is unavailable, although the rate at which it reduces metHb is considerably slower than normal intrinsic mechanisms.8,9 The objective of this article was to describe 5 cases of children with acquired metHb who were successfully treated with ascorbic acid and to review the literature on the use of this antidote.

MATERIALS AND METHODS We performed a retrospective chart review of 5 patients aged ,18 years with confirmed MetHb seen at the Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina. Charts were identified using the specific International Classification of Diseases 9 code 289.7 (metHb). Inclusion criteria for the study were presentation to the emergency department with MetHb significant enough to cause cyanosis and functional hypoxia.

Ascorbic Acid for Treatment of Methemoglobinemia

Because low concentrations of methemoglobin are found physiologically in the body, we defined metHb as an abnormal elevation of the methemoglobin level above 2%.9 No exclusion criteria, other than age limit, were used. Data were extracted using a structured form. Clinical outcomes such as the extent and duration of clinical manifestations, treatments used, clinical responses, and outcomes were collected and analyzed. Concomitant medications and toxic exposures were recorded.

RESULTS The clinical characteristics of the 5 patients are presented in Table 1. Mean age was 11.2 months (range, 1–46 months), and no patient was febrile. One patient developed symptoms after being treated with dapsone for pemphigus, and 3 of the patients we are sure that became symptomatic after ingestion of water or food that we have suspect contained nitrites because they all received formula made with water from areas that


containing nitrate at levels higher than the current maximum contaminant level of 45 ppm (mg/L) nitrate (NO3). Extensive questioning of the parents of all patients failed to reveal exposure to any other known toxins or drugs. All patients presented to the emergency department with cyanosis, tachycardia of 140–180 beats per minute, and some degree of respiratory distress, as demonstrated by tachypnea and/or intercostal retractions. Oxygen saturation levels, measured using a dNellcor N 550 pulse oximeter, were 75%–86%. Methemoglobin fractions ranged from 6.4% to 43%. Blood gas analysis in patient E, the most severely ill patient, revealed a metabolic acidosis with pH 6.95, bicarbonate 7 mmol/L, and pCO2 32 mm Hg and normal anion gap of 12 mmol/L. One hundred percent oxygen and intravenous ascorbic acid were provided to all patients, resulting in full recovery (Table 1). All patients showed marked improvement within 24 hours. Several patients were kept in hospital for longer than their physical condition mandated because of social reasons. For patients

Table 1. Characteristics of 5 infants with acquired metHb treated with ascorbic acid. Patient A Sex Age (mo) Weight (kg) Clinical findings Cutaneous Respiratory Neurologic Pulse rate (beats/min) Respiratory rate (per min) Maximum methemoglobin (%) by co-oximetry Methemoglobin after 24 h of ascorbic acid treatment Hemoglobin (mg/dL) Ascorbic acid treatment

Patient B

Patient C

Patient D

Patient E

F 46 15.52

M 2 4.4

F 12 9.05

F 1 3.3

M 1 3.25

Severe cyanosis Mild distress Normal 140 28

Mild cyanosis Severe distress Lethargy state 152 58

Severe cyanosis Mild distress Normal 148 24

Severe cyanosis Severe distress Irritability 170 40

Severe cyanosis Severe distress Irritability 140 40











Cause of MetHb

11 1 d: 2 g IV in 4 doses then continued orally Dapsone

10 1 d: 1.5 g IV in 3 doses then continued orally Nitrites water

14 2 d: 2 g IV (4 doses/d) then continued orally Unknown

Days of admission




13.4 13.6 1 d: 1 g IV in 3 2 days: 2 g IV (4 doses then doses/d) then continued continued orally orally Nitrites water Nitrites water Acidosis Diarrhea 1 5

IV, intravenously.

American Journal of Therapeutics (2014) 21(4)


with severe methemoglobin, we used daily doses of 1–2 g intravenously, followed by oral doses of 300– 600 mg/d in divided doses. The ascorbic acid (vitamin C) injection was diluted 1:1 with normal saline and was administered over 10 minutes. No side effects were seen. One patient was discharged after 1 day of hospitalization and the remainder within 5 days. One patient required the administration of bicarbonate for severe acidosis associated with concomitant acute gastroenteritis. On follow-up during the ensuing several days, none of the patients had any additional episodes of cyanosis.

DISCUSSION Cyanosis unresponsive to the administration of 100% oxygen can be due to unrepaired congenital cyanotic heart disease or an abnormality of hemoglobin oxygen binding such as metHb.10 MetHb occurs when the iron atom in hemoglobin is oxidized, by losing an electron to an oxidant, and it transforms from the ferrous (Fe2+) to the ferric (Fe3+) state.11 In the ferric state, the iron in the hemoglobin cannot bind and transport oxygen, causing cellular hypoxia. MetHb is a functional anemia, and it needs to be identified and treated urgently to prevent potentially severe morbidity or mortality. Most cases of metHb are acquired as a result of exposure to exogenous oxidizing agents, including many drugs and their metabolites, but the condition can be difficult to diagnose unless it is considered early in a well thought out differential diagnosis based on response to 100% oxygen.12 Nitrates and nitrites are powerful oxidizing agents and are among the most common methemoglobinforming compounds. The use of nitrate-contaminated drinking water to prepare infant formula is a wellknown risk factor for infant metHb.11 Ingestion of water with nitrites was the probable cause of metHb in 3 of our 5 patients. Nitrituria in a cyanotic infant may suggest the diagnosis of metHb.13 Affected infants develop a peculiar blue–gray skin color and may become irritable or lethargic, depending on the severity of their condition.14 They can progress rapidly to coma and death if the condition is not recognized and treated appropriately. After ingestion, nitrates are converted by fecal organisms to nitrites. Nitrites are absorbed and form methemoglobin, which interferes with the oxygencarrying capacity of hemoglobin. Infants are particularly are susceptible to nitrate poisoning for a variety of reasons: fetal hemoglobin is more readily oxidized American Journal of Therapeutics (2014) 21(4)

Rino et al

to methemoglobin, their methemoglobin reductase system is relatively poorly developed, their stomach acid production is relatively low, and they have large numbers of nitrite-reducing bacteria in their bowel.15 In addition, metHb in children can be exacerbated by common conditions such as diarrhea, dehydration, and acidosis. The initial laboratory test of choice is the measurement of metHb concentration by cooximetry. Venous blood is acceptable, as it provides the same information and is less invasive to obtain. Blood gas analysis is indicated to assess oxygenation, ventilation, and tissue perfusion, and serum electrolytes and lactate should also be measured. Dapsone has been implicated as a cause of metHb. Its effect is related to its long half-life and its slow conversion to its methemoglobin-forming hydroxylamine metabolites.16 Our patient with dapsone intoxication required multiple doses of ascorbic acid both intravenously and orally. The initial treatment of metHb is to assess and stabilize the airway, breathing, and circulation. One hundred percent oxygen should be delivered. Dextrose should be provided, as it is the major source of nicotinamide adenine dinucleotide in the red blood cells.17 The offending agent should be discontinued immediately. After initial stabilization, co-oximetry helps to establish the diagnosis. Patients with abnormal vital signs such as tachycardia and tachypnea, or with elevated lactate concentrations due to tissue hypoxia or the functional anemia of metHb, should be treated aggressively. The presence of significant symptoms or methemoglobin levels .25% are indications for treatment. The most widely accepted definitive treatment of metHb is the administration of 1–2 mg/kg methylene blue intravenously over 5 minutes.6 Glucose-6phosphatase dehydrogenase deficiency is a relative contraindication because methylene blue reduces NADPH and can lead to hemolysis. If methylene blue is unavailable, as is the case in our institution, ascorbic acid can be used, although response is less marked and dramatic. Ascorbic acid reduces the metHb molecule in vitro.18 All of our patients received intravenous ascorbic acid and 3 required subsequent doses of this preparation orally. With this treatment, cyanosis resolved and all the patients were discharged in good condition. Ascorbic acid is a potent antioxidant and reducing agent. Although ascorbic acid–induced methemoglobin reduction is less important under physiological conditions than reduction by the NADH-dependent methemoglobin reductase system, under methemoglobinemic conditions, ascorbic acid is useful because of its effect in scavenging free radicals.19,20

Ascorbic Acid for Treatment of Methemoglobinemia

In the presence of metHb levels .25%, and in symptomatic patients, the treatment of choice for metHb remains methylene blue, however, if this is not available, ascorbic acid seems to be a clinically viable alternative. It may also be the first line of treatment in patients with glucose-6-phosphatase dehydrogenase deficiency.

REFERENCES 1. Radimer K, Bindewald B, Hughes J, et al. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999–2000. Am J Epidemiol. 2004;160:339–349. 2. May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal. 2013; 19:2068–2083. 3. Chalmers TC. Effects of ascorbic acid on the common cold. An evaluation of the evidence. Am J Med. 1975;58: 532–536. 4. Vuyyuri SB, Rinkinen J, Worden E, et al. Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells. PLoS One. 2013;8:e67081. 5. Singh RB, Niaz MA, Bishnoi I, et al. Diet, antioxidant vitamins, oxidative stress and risk of coronary artery disease: the Peerzada Prospective Study. Acta Cardiol. 1994;49:453–467. 6. Skold A, Cosco DL, Klein R. Methemoglobinemia: pathogenesis, diagnosis, and management. South Med J. 2011; 104:757–761. 7. Bolyai JZ, Smith RP, Gray CT. Ascorbic acid and chemically induced methemoglobinemias. Toxicol Appl Pharmacol. 1972;21:176–185. 8. Kortgen A, Janneck U, Vetsch A, et al. Methemoglobinemia due to prilocaine after plexus anesthesia. Reduction by prophylactic administration of ascorbic acid? Anaesthesist. 2003;52:1020–1026.

243 9. Boran P, Tokuc G, Yegin Z. Methemoglobinemia due to application of prilocaine during circumcision and the effect of ascorbic acid. J Pediatr Urol. 2008;4:475–476. 10. Fan AM, Steinberg VE. Health implications of nitrate and nitrite in drinking water: an update on methemoglobinemia occurrence and reproductive and developmental toxicity. Regul Toxicol Pharmacol. 1996;23:35–43. 11. Kross BC, Ayebo AD, Fuortes LJ. Methemoglobinemia: nitrate toxicity in rural America. Am Fam Physician. 1992; 46:183–188. 12. Wilburn-Goo D, Lloyd LM. When patients become cyanotic: acquired methemoglobinemia. J Am Dent Assoc. 1999;130:826–831. 13. Sanchez-Echaniz J, Benito-Fernández J, Mintegui-Raso S. Methemoglobinemia and consumption of vegetables in infants. Pediatrics. 2001;107:1024–1028. 14. Knobeloch L, Salna B, Hogan A, et al. Blue babies and nitrate-contaminated well water. Environ Health Perspect. 2000;108:675–678. 15. Dusdieker LB, Getchell JP, Liarakos TM, et al. Nitrate in baby foods. Adding to the nitrate mosaic. Arch Pediatr Adolesc Med. 1994;148:490–494. Available at: http:// 16. Dawson AH, Whyte IM. Management of dapsone poisoning complicated by methaemoglobinaemia. Med Toxicol Adverse Drug Exp. 1989;4:387–392. 17. Rehman HU. Methemoglobinemia. West J Med. 2001;175: 193–196. 18. Dötsch J, Demirakça S, Cryer A, et al. Reduction of NOinduced methemoglobinemia requires extremely high doses of ascorbic acid in vitro. Intensive Care Med. 1998; 24:612–615. 19. Dunne J, Caron A, Menu P, et al. Ascorbate removes key precursors to oxidative damage by cell-free haemoglobin in vitro and in vivo. Biochem J. 2006;399:513–524. 20. Waller HD, Benöhr HC, Tigges FJ. On the mechanism of ascorbic acid induced methemoglobin reduction of human erythrocytes. Klin Wochenschr. 1977;55:955–964. Available at: 926709.

American Journal of Therapeutics (2014) 21(4)

Ascorbic acid for the treatment of methemoglobinemia: the experience of a large tertiary care pediatric hospital.

The purpose of reporting this series of patients is to illustrate the role of ascorbic acid in the treatment of severe acquired methemoglobinemia (met...
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