CASE REPORT
Pathophysiologic Mechanisms, Diagnosis, and Management
of Dapsone-Induced Methemoglobinemia
John V. Ashurst, OMS IV; Megan N. Wasson, OMS IV; William Hauger, MD; and William T. Fritz, MD
Dapsone is a leprostatic agent commonly prescribed for the
treatment of patients with leprosy, malaria, and a variety of
blistering skin diseases, including dermatitis herpetiformis.
Methemoglobinemia, a potentially life-threatening condition
in which the oxygen-carrying capacity of blood in body tissues is reduced, is a known adverse effect of dapsone use.
The authors report a case of dapsone-induced methemoglobinemia observed in the emergency department
during routine workup for contact dermatitis in a patient
with celiac disease. The pathophysiologic mechanisms, diagnosis, and management of dapsone-induced methemoglobinemia are discussed.
J Am Osteopath Assoc. 2010;110(1):16,19-20
D
apsone, a potent anti-inflammatory and antiparasitic
compound, is used worldwide for the treatment of
patients with leprosy, malaria, and immunosuppressioninduced infections caused by Pneumocystis carinii and Toxoplasma gondii.1-3 In the United States, the major application of
dapsone is in the treatment of patients with bullous dermatosis and dermatitis herpetiformis.1 Potentially life-threatening adverse effects of dapsone use include dapsone hypersensitivity syndrome, dose-dependent hemolytic anemia,
and methemoglobinemia.1,2,4-6
In the present article, we report a case of dapsone-induced
methemoglobinemia in which the diagnosis was made after a
detailed history and physical examination. The diagnosis led
to prompt treatment and complete recovery of the patient.
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: [email protected]
Submitted April 15, 2009; revision received July 20, 2009; accepted November
11, 2009.
16 • JAOA • Vol 110 • No 1 • January 2010
Report of Case
A white woman aged 68 years presented to the emergency
department with a several-day history of weakness, chills,
and shortness of breath, as well as a pruritic maculopapular
rash bilaterally on her lower extremities. She reported recently
shaving her legs with a new razor that contained an unknown
lotion. However, the patient was not able to correlate the
appearance of the rash with the use of the new razor.
The patient’s medical history was significant for celiac
disease, coronary artery disease requiring four cardiac stents,
dermatitis herpetiformis, gastroesophageal reflux disease, and
peripheral neuropathy. Her family history was clinically significant 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
160/90 mm Hg; a body temperature of 98.1°F (36.7°C); a pulse
of 115 beats per minute; a respiratory rate of 20 breaths per
minute; and an oxygen saturation of 89% with ambient air.
After supplemental oxygen of 3 L per nasal cannula was
applied, her oxygen saturation increased to 93%. The patient’s
physical examination and laboratory test results at presentation are shown in the Table.
The patient’s lungs were clear to auscultation with
decreased breath sounds bilaterally. Skin examination revealed
multiple areas of excoriation, swelling, and cording of the
bilateral lower extremities. Central and peripheral cyanosis
was noted. Abdominal, cardiac, and neurologic examinations
were unremarkable.
Routine laboratory test data (Table) revealed a high white
blood cell count (9900 cells/␮L) and a normal platelet count
(313,000 cells/␮L), hemoglobin level (12.9 g/dL), and hematocrit 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 elevated, 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 diagnosed as having an acute pulmonary embolism of unknown
origin. Both a chest radiographic and spiral computed tomographic examination were performed, but neither showed
Ashurst et al • Case Report
CASE REPORT
Table
Examination and Laboratory Findings for
Patient in Case at Presentation and Hospital Admission
Component
䡲 Examination Findings
at Presentation
▫ Blood pressure, mm Hg
▫ Body temperature, °F (°C)
▫ Pulse, beats per minute
▫ Respiratory rate, breaths per minute
▫ Oxygen saturation, %
▫ Other physical findings
– Decreased breath sounds bilaterally
– Excoriation, swelling, and cording
of bilateral lower extremities
– Central and peripheral cyanosis
䡲 Laboratory Findings at Presentation
▫ White blood cells, No. cells/␮L
▫ Platelets, No. cells/␮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
䡲 Findings After Hospital Admission
and Ventilatory Support
▫ Arterial blood gasses
– PaCO2, mm Hg
– PaO2, torr
– Oxygen saturation, %
– Bicarbonates, mEq/L
– Base excess, mEq/L
▫ Methemoglobin, %
Value
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 ultrasonographic 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, evaluations 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
Ashurst et al • Case Report
Treatment for Patient in Case
䡺 Discontinuation of dapsone use
䡺 Application of supplemental oxygenation by nasal
cannula
䡺 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 dapsone-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 herpetiformis.
manage the rash on her lower extremities, which she believed
to be dermatitis herpetiformis. The patient was treated with discontinuation of dapsone, application of supplemental oxygenation 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 dermatitis.
Discussion
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,7 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.1,2,3,8 It is absorbed
through the gut and is metabolized by the liver through the oxidation reactions of N-acetylation and N-hydroxylation.1,2,5,8
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.1,8 Typically, dapsone 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 process in which there is a deficiency of nicotinamide adenine
dinucleotide plus hydrogen (NADH)-cytochrome b5 reductase
JAOA • Vol 110 • No 1 • January 2010 • 19
CASE REPORT
or as an acquired disease in which there is an increase in the
rate of oxidation of hemoglobin to methemoglobin.2,4-6,9 The
newly formed methemoglobin is an aberrant form of
hemoglobin in which the original ferrous (Fe2+) atom is oxidized to a ferric (Fe3+) atom. The ferric atom then causes an
allosteric change in the heme portion of the oxidized
hemoglobin molecule, resulting in an increase in its oxygen
affinity but a decrease in its oxygen binding capacity.4,5,9
Diagnosis of Methemoglobinemia
The diagnosis of methemoglobinemia is based on clinical
symptoms and laboratory testing. Peripheral and central
cyanosis is almost always present when there is a minimum
methemoglobin level of 15% in the blood.2,4-6,10 These clinical
signs typically result from the methemoglobin molecule
causing a functional anemia, as well as from the methemoglobin molecule’s inability to bind to oxygen. As the concentration of methemoglobin in the blood increases to 45%,
symptoms of dizziness, fatigue, headache, tachycardia, and
weakness are expected.4-6,10 Acidosis, cardiac arrhythmia, dyspnea, seizures, and eventually coma become evident as the
methemoglobin level approaches 70%.4-6,10
Arterial blood gas analysis paired with oxygen saturation analysis by pulse oximetry are now considered the definitive measures for making a correct diagnosis of methemoglobinemia. Blood gas analyses in patients with
methemoglobinemia reveal normal to elevated levels of PaO2
with low oxyhemoglobin saturation.2,4-6
Management of Methemoglobinemia
Traditionally, the initial management of methemoglobinemia
involves ventilator support and removing the offending agent.
Research has shown that a patient who has symptoms of dyspnea 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.2,5,6 Intravenously, methylene blue is oxidized into leucomethylene blue by accepting an
electron from nicotinamide adenine dinucleotide phosphate
(NADPH) in the presence of NADPH-methemoglobin reductase.2,9 Leukomethylene blue acts as an artificial electron
acceptor to methemoglobin, resulting in methemoglobin’s
conversion back to hemoglobin.2,9
Additional studies11 have shown that supplementing
methylene blue with activated charcoal results in a lower dose
of methylene blue being required to trigger a reversal of methemoglobinemia symptoms.
In patients with celiac disease, flares of dermatitis herpetiformis can be controlled by the prophylactic use of dapsone.
However, dapsone use predisposes such patients to the development of methemoglobinemia. In the present case report,
the patient incorrectly believed that she had a flare of dermatitis herpetiformis, and this belief caused her to take the
wrong medication—dapsone—which led to acute dapsoneinduced methemoglobinemia.
20 • JAOA • Vol 110 • No 1 • January 2010
Conclusion
Based on our clinical experience—including the present case
report—we believe that physicians need to remain alert to the
possible association between dapsone use and methemoglobinemia. A high degree of suspicion for this association must be kept in mind when treating patients who have histories of dermatitis herpetiformis, leprosy, or malaria.
For patients who do not successfully respond to supportive therapy or who have substantially higher-than-normal
levels of methemoglobin, methlyene blue with adjuvant activated charcoal can be considered as a reasonable and safe
treatment option. Early recognition of dapsone toxicity will
allow for appropriate treatment of patients with dapsoneinduced methemoglobinemia, thereby preventing further
methemoglobin production.
References
1. Sener O, Doganci L, Safali M, Besirbellioglu B, Bulucu F, Pahsa A. Severe dapsone hypersensitivity syndrome. J Investig Allergol Clin Immunol.
2006;16(4):268-270. http://www.jiaci.org/issues/vol16issue04/10.pdf. Accessed
November 28, 2009.
2. Turner MD, Karlis V, Glickman RS. The recognition, physiology, and treatment 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. Br J Clin Pharmacol. 1992;34(3):244-249. http://www.ncbi.nlm.nih.gov/pmc/articles
/PMC1381395/?tool=pubmed. Accessed November 28, 2009.
4. Rehman HU. Methemoglobinemia. West J Med. 2001;175(3):193-196.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1071541/?tool=pubmed.
Accessed November 28, 2009.
5. Falkenhahn M, Kannan S, O’Kane M. Unexplained acute severe
methaemoglobinaemia in a young adult. Br J Anaesth. 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/content/full/17/3/227. Accessed November 28, 2009.
7. Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine. 2004;83(5):265273.
8. 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. Br J Clin Pharmacol. 1990;30(6):829-838. http://www.ncbi.nlm
.nih.gov/pmc/articles/PMC1368303/?tool=pubmed. Accessed November 28,
2009.
9. Birchem SK. Benzocaine-induced methemoglobinemia during transesophageal echocardiography. J Am Osteopath Assoc. 2005;105(8):381-384.
http://www.jaoa.org/cgi/content/full/105/8/381. Accessed November 28, 2009.
10. Mayo W, Leighton K, Robertson B, Ruedy J. Intraoperative cyanosis: a
case of dapsone-induced methaemoglobinaemia. Can J Anaesth. 1987;34(1):7982.
11. Hansen DG, Challoner KR, Smith DE. Dapsone intoxication: two case
reports [review]. J Emerg Med. 1994;12(3):347-351.
Ashurst et al • Case Report