Article, Emergency Medicine

High-dose vitamin C management in dapsone-induced methemoglobinemia

Unlabelled imageAmerican Journal of Emergency Medicine 32 (2014) 684.e1-684.e3

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Case Report

High-dose vitamin C management in Dapsone-induced methemoglobinemia?,??

Abstract

Methylene blue is the first-choice treatment of methemoglobinemia, but it is not readily available in most Korean emergency departments because of an import suspension. An 84-year-old woman with dapsone- induced massive methemoglobinemia visited our emergency department for unclear mentality and cyanosis. Because methylene blue was not available, we intravenously administrated vitamin C (VC) for symptomatic methemoglobinemia, although VC is not a universally accepted treatment. Vitamin C (10 g intravenously) administered 6 hourly successfully treated the dapsone-induced methemoglobinemia and did not adversely affect renal functions. Thus, we recommend that if methylene blue is unavailable, 6 hourly intravenous administrations of 10 g of VC should be considered for dapsone-induced methemoglobinemia.

Traditionally, methylene blue is the first-choice treatment of methe- moglobinemia [1]. However, most Korean emergency departments have not stocked methylene blue since July 2010 because of an import suspension. To our knowledge, there is no universally accepted alternative for methylene blue. This present case concerns the successful use of intravenous (IV) vitamin C (VC) in dapsone-induced methemoglobinemia. An 84-year-old woman visited our emergency department for decreased mentality and cyanosis after ingesting 7 tablets of dapsone. Vital signs were as follows: blood pressure, 106/49 mm Hg; body temperature, 36.3?C; pulse, 118 beats/min; respiratory rate, 28 breaths/min; and oxygen saturation, 85% on room air. We provided 15 L of oxygen via a nonrebreathing mask, but the cyanosis was not improved. lung sounds were clear, and an electrocardiography showed sinus tachycardia. Arterial blood gas analysis showed the following: PaCO2, 27.0 mm Hg; PaO2, 113 mm Hg; oxygen saturation, 98.1%; and methemoglobin concentration, 51.9%. Hemoglobin level

was 11.0 g/dL, and routine Laboratory test results were normal.

Despite symptomatic methemoglobinemia, we could not admin- ister methylene blue because it was not available. Decreased mentality and cyanosis persisted, and her methemoglobin concen- tration rose to 64.4% at 7 hours after presentation (Fig. 1). Inevitably, we administered 10 g of VC IV for 10 minutes. Methemoglobin concentration declined to 38% at 15 hours after presentation, but her glomerular filtration rate (GFR) did not decrease (Fig 2). A second 10 g of VC was administered, but methemoglobin concentration rebounded to 46.9% (21 hours after presentation). After a third administration, mentality and cyanosis improved gradually and methemoglobin concentration decreased to 21.5% (27 hours after

? Grant: This study was financially supported by research funds from Yeungnam University.

?? Conflicts of interest: None.

presentation). However, considering the rebound of dapsone-induced methemoglobinemia, we decided to administer 10 g of VC 6 hourly until the methemoglobin concentration fell below 10%. Administra- tions of VC were stopped at approximately 54 hours after presenta- tion. During treatment, the patient occasionally complained of epigastric discomfort and nausea, but her GFR remained above 86.8 mL/min per 1.73 m2 until she was discharged after 6 days (Fig. 2).

Current treatments for methemoglobinemia target the direct reduction of methemoglobin concentration [1]. However, the removal of oxidative stress, the causative factor of methemoglobinemia, offers another possible treatment strategy, and in this respect, VC can effectively treat methemoglobinemia. A recent study showed that VC reduced excessive oxidative stress after hemodialysis and thereby decreased hemodialysis-induced methemoglobinemia [2].

Little is known about the optimal plasma concentration of VC for methemoglobinemia. However, it has been reported that VC can reduce methemoglobinemia at high plasma concentrations. Dotsch et al [3] reported that plasma VC concentrations of 1 mM or less failed to reduce methemoglobinemia, whereas a concentration of 10 mM significantly reduced methemoglobinemia.

A high plasma VC concentration is dependent on administration route, dose, and frequency [4]. Oral route cannot increase plasma VC concentration above ~ 200 uM because of controls by gastrointestinal systems, whereas VC IV administered increase plasma concentration in proportion to dose [4-6]. Therefore, the IV administration is essential for the achievement of high plasma VC concentrations.

Currently, the upper limit dose for VC is 2 g/d [7]. However, 2 g of VC may not reach the pharmacologic plasma concentration. Hong et al [8] reported that the mean plasma concentration of VC in healthy Korean adults is 2.22 +- 0.16 mM. However, recent studies have shown that at least ~ 5 g of VC is required to reach a plasma concentration above 2 mM and that greater than 30 g is required to achieve a concentration of 10 mM [4,6], which was proposed by Dotsch et al [3] for methemoglobi- nemia. Higher doses can be used to achieve pharmacology plasma concentrations, but they increase the possibility of adverse events. Maintaining plasma concentration by frequent administration offers another means of controlling methemoglobinemia using moderate VC doses. Although single doses of 10 g might not maintain pharmacologic concentration, our case indicates that 6 hourly IV administrations of 10 g of VC probably maintained pharmacologic plasma concentrations without inducing adverse events.

Vitamin C can increase the urinary excretion of oxalate; in particular, in the presence of renal insufficiency, high doses of VC can cause renal failure related to hyperoxaluria [1,5]. However, in the absence of renal insufficiency, 10 g of VC probably does not cause adverse renal complications [4,9,10]. The total number of vials of VC (25 g/50 mL) used in 2008 was 354 647 in the United States, and the

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684.e2 S.-Y. Park et al. / American Journal of Emergency Medicine 32 (2014) 684.e1684.e3

Fig. 1. Changes in plasma methemoglobin concentrations according to the administration of 10 g doses of VC. After a dapsone overdose, methemoglobin concentration in our patient increased to 64.4%, but this was effectively reduced by repeated IV administrations of 10 g of VC. Although the methemoglobin concentration rebounded at 21 hours despite the administration of VC, the methemoglobin concentration steadily reduced after the IV implementation of 10 g of VC every 6 hours.

median single IV dose was 50 g, but adverse events related to VC were rare in patients without renal insufficiency [9].

The dose-related adverse effects of VC are not fully understood, and no optimal VC plasma concentration has been determined for methemoglobinemia. Nevertheless, we found that 10 g of VC

administered 6 hourly successfully treated massive methemoglobine- mia without causing renal complications. Thus, we recommend that if methylene blue is unavailable, 6 hourly IV administrations of 10 g of VC should be considered for the treatment of massive methemoglobine- mia in patients without renal insufficiency.

Fig. 2. Changes of renal function before, during, and after VC treatment. At presentation, Blood urea nitrogen and creatinine (Cr) were within their normal ranges, and GFR (calculated using the Modification of Diet in Renal Disease Study equation) was 86.8 mL/min per 1.73 m2. Both BUN and Cr remained in their normal range, and GFR remained stable during the 6 hourly administrations of VC (10 g) for 54 hours. In addition, BUN, Cr, and GFR remained in their normal ranges for 6 days after VC treatment.

S.-Y. Park et al. / American Journal of Emergency Medicine 32 (2014) 684.e1684.e3 684.e3

Sin-Youl Park, MD, PhD

Department of Emergency Medicine

College of Medicine Yeungnam University Daegu, Republic of Korea

Kyung-Woo Lee, MD Tae-Sin Kang, MD

Department of Emergency Medicine Catholic University of Daegu School of Medicine

Daegu, Republic of Korea

http://dx.doi.org/10.1016/j.ajem.2013.11.036

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