Pathophysiologic Mechanisms, Diagnosis, and Management
`of Dapsone-lnduced Methemoglobinemia
`
`John V. Ashurst, OMS IV; Megan N. Wasson, OMS IV; William Hauger, MD; and William T. Fritz, MD
`
`JAm Osteopath Assoc. 2010;110(1):16,19-20
`
`Bes{w[ o¢ Case
`Dapsone is a leprostatic agent commonly prescribed for the
`treatment of patients with leprosy, malaria, and a variety of A white woman aged 68 years presented to the emergency
`blistering skin diseases, including dermatitis herpetiformis,
`department with a several-day history of weakness, chills,
`Methemoglobinemia, a potentially life-threatening condition
`and shortness of breath, as well as a pruritic maculopapular
`in which the oxygen-carrying capacity of blood in body tis-
`rash bilaterally on her lower extremities. She reported recently
`sues is reduced, is a known adverse effect of dapsone use.
`shaving her legs with a new razor that contained an unknown
`The authors report a case of dapsone-induced methe-
`lotion. However, the patient was not able to correlate the
`moglobinemia observed in the emergency department
`appearance of the rash with the use of the new razor.
`during routine workup for contact dermatitis in a patient
`The patient’s medical history was significant for celiac
`with celiac disease. The pathophysiologic mechanisms, diag-
`disease, coronary artery disease requiring four cardiac stents,
`nosis, and management of dapsone-induced methe-
`dermatitis herpetiformis, gastroesophageal reflux disease, and
`moglobinemia are discussed,
`peripheral neuropathy. Her family history was clinically sig-
`nificant for deep vein thrombosis.
`Physical examination revealed that the patient was well
`nourished with no signs of physical deformity, trauma, or
`acute distress. Her vital signs included a blood pressure of
`apsone, a potent anti-inflammatory and antiparasitic
`160/90 mm Hg; a body temperature of 98.1°F (36.7°C); a pulse
`compound, is used worldwide for the treatment of
`of 115 beats per minute; a respiratory rate of 20 breaths per
`patients with leprosy, malaria, and immunosuppression-
`induced infections caused by Pneumocystis carinii and Toxo- minute; and an oxygen saturation of 89% with ambient air.
`plasma gondii.1-3 In the United States, the major application of After supplemental oxygen of 3 L per nasal cannula was
`dapsone is in the treatment of patients with bullous der-
`applied, her oxygen saturation increased to 93%. The patient’s
`matosis and dermatitis herpetiformis3 Potentially life-threat-
`physical examination and laboratory test results at presenta-
`tion are shown in the Table.
`ening adverse effects of dapsone use include dapsone hyper-
`The patient’s lungs were clear to auscultation with
`sensitivity syndrome, dose-dependent hemolytic anemia,
`and methemoglobinemia>Z4-6
`decreased breath sounds bilaterally. Skin examination revealed
`In the present article, we report a case of dapsone-induced multiple areas of excoriation, swelling, and cording of the
`methemoglobinemia in which the diagnosis was made after a
`bilateral lower extremities. Central and peripheral cyanosis
`detailed history and physical examination. The diagnosis led was noted. Abdominal, cardiac, and neurologic examinations
`were unremarkable.
`to prompt treatment and complete recovery of the patient,
`Routine laboratory test data (Table) revealed a high white
`blood cell count (9900 cells/btL) and a normal platelet count
`(313,000 cells/btL), hemoglobin level (12.9 g/dL), and hema-
`tocrit concentration (39%). According to chemistry panel results,
`levels of chloride (106 mEq/L), potassium (3.8 mEq/L), and
`sodium (139 mEq/L) were also normal.
`The patient’s D-Dimer concentration was normal, at
`1.1 mg/L, and her erythrocyte sedimentation rate was ele-
`vated, at 42 mm per hour. Results of electrocardiographic
`examination revealed sinus tachycardia with hyperacute
`T waves in leads V2 through V5.
`After initial evaluation, the patient was tentatively diag-
`nosed as having an acute pulmonary embolism of unknown
`origin. Both a chest radiographic and spiral computed tomo-
`graphic examination were performed, but neither showed
`
`From Lake Erie College of Osteopathic Medicine in Pennsylvania (Mr Ashurst,
`Ms Wasson) and the Department of Internal Medicine (Dr Hauger) and
`Department of Anesthesiology (Dr Fritz) at Conemaugh Memorial Medical
`Center in Johnstown, Pennsylvania.
`The authors have no relevant conflicts of interest or financial relationships
`to disclose,
`Address correspondence to John V. Ashurst, OMS IV, 721 Oak St,
`Northern Cambria, PA 15714-1438.
`E-mail: john.ashurst@lecom.edu
`
`Submitted April 15, 2009; revision received July 20, 2009; accepted November
`11, 2009.
`
`16 . JAOA ¯ Vol 110 . No 1 . January 2010
`
`Ashurst et al ¯ Case Report
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`1 of 3
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`Almirall EXHIBIT 2046
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`Table
`Examination and Laboratory Findings for
`Patient in Case at Presentation and Hospital Admission
`
`[] Discontinuation of dapsone use
`[] Application of supplemental oxygenation by nasal
`Component Value cannula
`
`Treatment for Patient in Case
`
`¯ Examination Findings
`at Presentation
`[] Blood pressure, mm Hg
`[] Body temperature, °F (°C)
`[] Pulse, beats per minute
`[] Respiratory rate, breaths per minute
`[] Oxygen saturation, %
`[] Ot her physica I findings
`- Decreased breath sounds bilaterally
`- Excoriation, swelling, and cording
`of bilateral lower extremities
`- Central and peripheral cyanosis
`¯ Laboratory Findings at Presentation
`[] White blood cells, No. cells/l~L
`[] Platelets, No. cells/l~L
`[] Hemoglobin, g/dL
`[] Hematocrit, %
`[] Chemistry panels, mEq/L
`-Chloride
`- Potassium
`- Sodium
`[] D-Dimer, mg/L
`[] Erythrocyte sedimentation rate, mm per hour
`[] Electrocardiographic examination
`- Sinus tachycardia with hyperacute
`T waves in leads V2-V5
`¯ Findings After Hospital Admission
`and Ventilatory Support
`[] Arterial blood gasses
`- PaCO2, mm Hg
`- PaO2, torr
`- Oxygen saturation, %
`- Bicarbonates, mEq/L
`- Base excess, m Eq/L
`[] Methemoglobin, %
`
`160/90
`98.1 (36.7)
`115
`20
`89
`
`9900
`313,000
`12.9
`39
`
`106
`3.8
`139
`1.1
`42
`
`49
`192
`98.2
`29
`4.2
`6.3
`
`Abbreviations: PaCO2, partial pressure of carbon dioxide in arterial blood;
`PaO2, partial pressure of oxygen in arterial blood.
`
`clinically significant findings. In addition, Doppler ultrasono-
`graphic examination of the veins in the patient’s bilateral lower
`extremities revealed no deep vein thrombosis.
`The patient was admitted to the hospital for ventilatory
`support and further evaluation. Soon after admission, evalu-
`ations of her arterial blood gas and methemoglobin levels
`were performed (Table). These tests revealed elevated levels of
`arterial PaCO2 (49 mm Hg); arterial PaO2 (192 torr); arterial
`oxygen saturation (98.2%); bicarbonate (29 mEq/L); and base
`excess (4.2 mEq/L). The patient’s methemoglobin level was also
`elevated, at 6.3%.
`Further evaluation of the patient’s medical history revealed
`that she had been self-medicating with dapsone in an effort to
`
`[] Use of diphenhydramine (Benadryl) cream to manage
`contact dermatitis
`
`Figure. Treatment successfully used for the patient in the present
`case, a white woman aged 68 years who was diagnosed as having dap-
`sone-induced methemoglobinemia. Before diagnosis, the patient
`had been self-medicating with dapsone in an effort to manage a rash
`on her lower extremities, which she believed to be dermatitis her-
`petiformis.
`
`manage the rash on her lower extremities, which she believed
`to be dermatitis herpetiformis. The patient was treated with dis-
`continuation of dapsone, application of supplemental oxy-
`genation by nasal cannula, and use of diphenhydramine
`(Benadryl) cream for the rash (Figure).
`During the 2 days after treatment initiation, the patient’s
`methemoglobin level decreased to 3.8%, trending toward the
`normal range, and her oxygen saturation also improved. The
`patient was discharged from the hospital with the diagnosis of
`dapsone-induced methemoglobinemia and contact dermatitis.
`She was advised to eliminate her dapsone self-medication
`and to continue to use diphenhydramine for her contact der-
`matitis.
`
`:’:
`Dapsone-induced methemoglobinemia is usually the result
`of acute poisoning secondary to either accidental ingestion or
`suicidal intent. According to recent research at several tertiary
`centers/dapsone has been shown to be the major cause of
`drug-induced methemoglobinemia.
`Dapsone (4,4’-diaminodiphenyl sulfone) is the parent
`compound of many sulfone medications.l,2,3,s It is absorbed
`through the gut and is metabolized by the liver through the oxi-
`dation reactions of N-acetylation and N-hydroxylation.l,2,5,s
`Hydroxylated amine metabolites produced in the oxidation
`reactions are potent oxidants that have been hypothesized to
`cause dapsone’s hematologic adverse effects, including
`hemolytic anemia and methemoglobinemia.l~ Typically, dap-
`sone is excreted by the kidneys. However, dapsone has been
`known to sometimes circulate in the enterohepatic system,
`resulting in a relatively long half-life of the drug in the body
`(ie, 24-30 hours).1
`Methemoglobinemia occurs either as a congenital pro-
`cess in which there is a deficiency of nicotinamide adenine
`dinucleotide plus hydrogen (NADH)-cytochrome b5 reductase
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`Ashurst et al ¯ Case Report
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`JAOA ¯ Vol 110 . No 1 . January 2010 . 19
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`: :::
`or as an acquired disease in which there is an increase in the
`Based on our clinical experience--including the present case
`rate of oxidation of hemoglobin to methemoglobin.2,4.6,9 The
`report--we believe that physicians need to remain alert to the
`newly formed methemoglobin is an aberrant form of
`hemoglobin in which the original ferrous (Fe2+) atom is oxi-
`possible association between dapsone use and methe-
`dized to a ferric (Fe~+) atom¯ The ferric atom then causes an moglobinemia. A high degree of suspicion for this associa-
`allosteric change in the heme portion of the oxidized
`tionmustbe keptinmind when treating patients who have his-
`hemoglobin molecule, resulting in an increase in its oxygen
`tories of dermatitis herpetiformis, leprosy, or malaria¯
`affinity but a decrease in its oxygen binding capacity.4,5,9
`For patients who do not successfully respond to sup-
`portive therapy or who have substantially higher-than-normal
`levels of methemoglobin, methlyene blue with adjuvant acti-
`vated charcoal can be considered as a reasonable and safe
`The diagnosis of methemoglobinemia is based on clinical
`treatment option¯ Early recognition of dapsone toxicity will
`symptoms and laboratory testing¯ Peripheral and central
`allow for appropriate treatment of patients with dapsone-
`cyanosis is almost always present when there is a minimum
`induced methemoglobinemia, thereby preventing further
`methemoglobin level of 15% in the blood.2,4.6,10 These clinical
`signs typically result from the methemoglobin molecule methemoglobin production¯
`causing a functional anemia, as well as from the methe-
`moglobin molecule’s inability to bind to oxygen¯ As the con-
`centration of methemoglobin in the blood increases to 45%,
`symptoms of dizziness, fatigue, headache, tachycardia, and
`weakness are expected.4.o,lo Acidosis, cardiac arrhythmia, dys-
`pnea, seizures, and eventually coma become evident as the
`methemoglobin level approaches 70%.4-6,10
`Arterial blood gas analysis paired with oxygen satura-
`tion analysis by pulse oximetry are now considered the defini-
`tive measures for making a correct diagnosis of methe-
`moglobinemia. Blood gas analyses in patients with
`methemoglobinemia reveal normal to elevated levels of PaO2
`with low oxyhemoglobin saturation.2,4-6
`
`1. Sener o, Doganci L, Safali M, Besirbellioglu B, Bulucu F, Pahsa A. Severe dap-
`sone hypersensitivity syndrome. J Investig Allergol Clin Immunol.
`2006;16(4):268-270. httpy/www.jiaci.org/issues/vo116issue04/10.pdf. Accessed
`November 28, 2009.
`
`2. Turner MD, Karlis V, Glickman RS. The recognition, physiology, and treat-
`ment of medication-induced methemoglobinemia: a case report. Anesth
`prog. 2007;54(3):115-117. http://www.ncbi.nlm.nih.gov/pmc/articles
`/PMC1993865/?tool=pubmed. Accessed November 28, 2009.
`
`3. Coleman MD, Rhodes LE, Scott AK, Verbov JL, Friedman PS, Breckenridge
`AM, et al. The use of cimetidine to reduce dapsone-dependent
`methaemoglobinaemia in dermatitis herpetiformis patients. BrJ Olin Phar-
`macol. 1992;34(3):244-249. http://www.ncbi.nlm .nih.gov/pmc/articles
`/PMC1381395/?tool=pubmed. Accessed November 28, 2009.
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`4. Rehman HU. Methemoglobinemia. West J Med. 2001;175(3):193-196.
`http://www.ncbi.nlm .nih.gov/pm da rt icles/PM C1071541/?tool=pubmed.
`Accessed November 28, 2009.
`
`’~:"~’ ~
`;~’ :,~
`Traditionally, the initial management of methemoglobinemia
`involves ventilator support and removing the offending agent,
`Research has shown that a patient who has symptoms of dys-
`pnea or a methemoglobin level of at least 30% should receive
`methylene blue intravenously at 1 to 2 mg per kilogram of
`body weight over a 5-minute period. Intravenously, methy-
`2,5,6
`lene blue is oxidized into leucomethylene blue by accepting an
`electron from nicotinamide adenine dinucleotide phosphate
`(NADPH) in the presence of NADPH-methemoglobin reduc-
`tase.2,9 Leukomethylene blue acts as an artificial electron
`acceptor to methemoglobin, resulting in methemoglobin’s
`conversion back to hemoglobin.2,9
`Additional studiesn have shown that supplementing
`methylene blue with activated charcoal results in a lower dose
`of methylene blue being required to trigger a reversal of methe-
`moglobinemia symptoms,
`In patients with celiac disease, flares of dermatitis her-
`petiformis can be controlled by the prophylactic use of dapsone.
`However, dapsone use predisposes such patients to the devel-
`opment of methemoglobinemia. In the present case report,
`the patient incorrectly believed that she had a flare of der-
`matitis herpetiformis, and this belief caused her to take the
`wrong medicationMapsone--which led to acute dapsone-
`induced methemoglobinemia.
`
`5. Falkenhahn M, Kannan S, O’Kane M. Unexplained acute severe
`methaemoglobinaemia in a young adult. BrJAnaesth. 2001;86(2):278-280.
`6. Bayard M, Farrow J, Tudiver F. Acute methemoglobinemia after endoscopy.
`J Am Board Fam Pract. 2004;17(3):227-229. http://www.jabfm.org/cgi/con-
`tentlfull117131227. Accessed November 28, 2009.
`
`7. Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinem ia: a retro-
`spective series of 138 cases at 2 teaching hospitals. Medicine. 2004;83(5):265-
`273.
`
`B. Tingle MD, Coleman MD, Park BK. An investigation of the role of metabolism
`in dapsone-induced methaemoglobinaemia using a two compartment in
`vitro test system. BrJ Clin Pharmaco]. 1990;30(6):829-838. httpY/www.ncbi.nlm
`.nih.govlpmdarticleslPMC13683031?tool=pubmed. Accessed November 28,
`2009.
`9. Birchem SK. Benzocaine-induced methemoglobinemia during trans-
`esophageal echocardiography. JAm Osteopath Assoc. 2005;105(8):381-384.
`httpYlwww.jaoa.orglcgVcontentlfulVlO51BI3B1. Accessed November 2B, 2009.
`
`10. Mayo W, Leighton K, Robertson B, Ruedy J. Intraoperative cyanosis: a
`case of dapsone-induced methaemoglobinaemia. Can dAnaesth. 1987;34(1):79-
`82.
`
`11. Hansen DG, Challoner KR, Sm ith DE. Dapsone intoxication: two case
`reports [review]. d Emerg Med. 1994;12(3):347-351.
`
`20 ° JAOA ° Vol 110 ° No 1 ° January 2010
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