- Email: [email protected]
Recurrent methomoglobinemia after acute dapsone intoxication in a child
The Journal of Emergency Medicine, Vol. 7, pp. 477-480,
RECURRENT
Prlnted in the USA
1989
Copyright 0 1989 Pergamon Press plc
??
METHEMOGLOBINEMIA AFTER ACUTE DAPSONE INTOXICATION IN A CHILD
James G. Linakis, PhD, MD,*Vt+$ Michael Shannon, MD, MPH,*st+§ Alan Woolf, MD, MPH,*+§ CarOlyn Sax, MD* *Program in Clinical Toxicology, tDivision of Emergency Medicine, *Department of Medicine, The Children’s Hospital, Harvard Medical School and the §Massachusetts Poison Control System, Boston, Massachusetts Reprint address: James G. Linakis, PhD, MD, Massachusetts Poison Control System, 300 Longwood Avenue, Boston, MA 02115
0 Abstract - Dapsone is a synthetic sulfone increasingly used in the treatment of a wide variety of dermatologic disorders. The case of a child with dapsone-induced recurrent methemoglobinemia is presented with a discussion of dapsone toxicity and its treatment. In addftion, the diagnostic value of pulse oximetry in the presence of dysfunctional hemoglobins is discussed.
PATIENT REPORT
A 3l/2-year-old white female presented to her pediatrician’s office after the acute onset of acral cyanosis that had progressed over 1l/2 hours to include central cyanosis. She had one episode of vomiting, but was otherwise asymptomatic. In her pediatrician’s office she was markedly cyanotic, but in no respiratory distress; her cardiac history and physical examination were within normal limits. She was referred to the Children’s Hospital Emergency Department for further evaluation and treatment. There was no known drug or toxic exposure, although the child had a history of a previous (nontoxic) drug ingestion. She had not been left unattended except for during a brief period approximately 7 hours prior to presentation. Medications in the household included sulfonamides, oral contraceptives and dapsone. Of note, her parents indicated that the child had an episode of acral cyanosis three weeks previously that had resolved spontaneously within 6 to 7 hours. Upon arrival in the emergency department, the child was noted to be severely cyanotic and moderately agitated. Her respiratory rate was 30, with a pulse of 135 and a blood pressure of 110/60. She had clear and symmetrical breath sounds and a normal cardiac exam. Her peripheral extremities were cyanotic, but warm and well perfused. Electrolytes, complete blood count, and a glucose-
0 Keywords- dapsone; methemoglobinemia; child; methylene blue
INTRODUCTION
Dapsone is a synthetic sulfone that is structurally similar to the sulfonamides. It is considered the drug of choice for the treatment of leprosy, and is being used increasingly for the treatment of various dermatologic diseases. These include dermatitis herpetiformis, pyoderma gangrenosum, pustular psoriasis, lichen planus, pemphigus, subcorneal pustular dermatosis, and brown recluse spider bites (1,2). To date, reports of dapsone toxicity in children have been largely limited to the tropical medicine literature (1,35). However, as dapsone becomes more widely used, accidental ingestions may become more prevalent in the pediatric population (6). We report a case of dapsone-induced, prolonged methemoglobinemia in a 3’12 year old child who required repeated treatment with methylene blue.
Toxicology-one of the most critical and challenging areas confronting the emergency department staff -is coordinated by Kenneth Ku&, MD, of the Rocky Mountain Poison Center. RECEIVED: 21 November 1988; FINALSUBMISSION RECEIVED:14 February 1989; ACCEPTED:9 March 1989
477
0736-4679189 $3.00 + .OO
478
J. G. Linakis, M. Shannon, A. Woolf, C. Sax
6-phosphate dehydrogenase (G6PD) screen were all normal. An arterial blood gas revealed a pH of 7.39, a pC0, of 24 torr, a p0, of 72 torr, and a calculated O2 saturation of 95 A. Pulse oximetry (Nellcor, model N-100, Nellcor Incorporated, Hayward, CA) at the time the blood gas was obtained revealed an O2 saturation of 85%. A toxicology screen of serum and urine was negative. The child’s blood was noted to have a chocolate-brown color that did not change when oxygen was bubbled through. An initial methemoglobin level was reported as 44.7 % . Activated charcoal was given in a dose of 1 g/kg and methylene blue was then administered in a dose of 1 mg/kg IV over 5 minutes. This resulted in rapid, but incomplete, resolution of the cyanosis. The child was subsequently admitted for observation and over the next 24 hours again became increasingly cyanotic. Methemoglobin levels were repeated at 14, 22, 25, 40, and 48 hours post admission (Figure 1). Ascorbic acid, 250 mg po per day, was begun and a second dose of methylene blue was administered (1 mg/kg IV) 22 hours after admission. After administration of the second dose of methylene blue, the child’s cyanosis showed nearly complete resolution except for mild circumoral cyanosis while crying. Over the next 24 hours, she again experienced a mild increase in the degree of cyanosis coinciding with a gradual increase in the methemoglobin level; however, no further methylene blue was given. The child was discharged 66 hours after admission with residual mild cyanosis that resolved over the next 2 to 3 days. A methemoglobin level performed 3l/2 weeks after discharge was 0.2%. Methemoglobin levels obtained from each of the child’s parents were reported as 0.4% in each. Serum from the time of admission and from 24 hours after admission was assayed for dapsone, ni-
40Methykne Blue gi, $
p
9
1
zo-
s io-
0
0
12
24
Time Post Admiss&
36
48
/hrsl
Figure 1. Methemoglobin levels followlng dapsono IngestIon as a function of time since rdmlselon. Arrows represent methylene blue admlnlstratlon.
trate, nitrite, and sulfonamide. Nitrates, nitrites, and sulfonamides were not detected in either sample. Although there was not sufficient serum from admission to perform a dapsone level, the 24 hour dapsone level was 3.9 mcg/mL (therapeutic levels approximately 2 to 10 mcg/mL [7]).
COMMENT Until recently, the use of dapsone was limited to the treatment of leprosy and dermatitis herpetiformis. However, in recent years, the clinical applications of the drug have been greatly expanded, with a dramatic increase in its use in the United States. In the case described here, the child’s grandmother was being treated with dapsone for dermatologic manifestations of lupus erythematosus. Although the grandmother had noticed no medication missing and the child was not witnessed to have ingested any medication, her serum was positive for dapsone. After an oral dose, gastrointestinal absorption of dapsone is slow but nearly complete, with peak serum concentrations of the drug occurring from 2 to 8 hours post ingestion. Its elimination half-life varies widely, ranging from 10 to 50 hours, with a mean of 30 hours. In serious overdose, the half-life of the drug may be markedly prolonged (6), perhaps secondary to enterohepatic recycling of the drug (8). The predominant toxic effect of dapsone is oxidation of the ferrous iron in heme to ferric iron, with the resultant production of methemoglobin. A large variety of chemicals and medications have been shown to be capable of producing methemoglobinemia through their oxidizing effects. Cyanosis generally occurs when methemoglobin levels exceed 15 % , although patients usually remain asymptomatic until the level of methemoglobin approaches 30% (9). In addition to methemoglobinemia, dapsone overdose may also produce sulfhemoglobinemia and red blood cell hemolysis (10,ll). This hemolysis may be exaggerated in G6PD deficient individuals. Other symptoms of dapsone ingestion in children have included impaired consciousness (1,4), tremors or movement disorders (4,5), agitation (1,3-5), and seizures (1,4). Death due to dapsone ingestion may be delayed for 2 or more days (7,12), and has occurred following overdoses of 1450 mg to 5 g (7). The only death reported in a child from a dapsone poisoning involved a dapsone-containing agricultural product (12). In only two reported pediatric overdose cases has the amount of dapsone ingested been known (3,6). Stanfield (3) described a 2-year-old who was believed to have ingested one or two 100 mg tablets of dap-
Dapsone Intoxication
in a Child
sone. In that child, cyanosis persisted for 8 days with the peak methemoglobin level reported as 18%. Her peak serum dapsone concentration was 73 mcg/mL. Reigart et al. (6) reported an l&month-old who ingested a single 100 mg tablet of dapsone with a peak methemoglobin level of 27 % . Serum dapsone concentrations were not obtained. In our case, the serum dapsone concentration at 24 hours postpresentation was 3.9 mcg/mL; the simultaneous methemoglobin level was still elevated, at 9%. Given the wide variation in dapsone’s elimination half-life, the child’s peak level of dapsone 24 hours previously could have been 6 to 17 mcg/mL. Interestingly, the peak dapsone concentration reported by Stanfield (3) and others reported in adults (7,13) were significantly higher than the one estimated here (3,6), yet were associated with similar or lower methemoglobin levels. Since our patient had no evidence of an enzyme defect or abnormal hemoglobin, it seems possible that methemoglobin levels correlate poorly with serum dapsone concentrations. A perplexing issue in our case was the 10% discordance between the oxygen saturation from the arterial blood gas on admission and the oxygen saturation by pulse oximetry. In our hospital, as in most, arterial blood gas results are reported with a calculated (not measured) oxygen saturation. This calculated O2 saturation is based on the measured p0, of the blood gas specimen. Since p0, is a function of the amount of oxygen dissolved in the plasma, it is relatively unaffected by the presence of dysfunctional hemoglobins such as methemoglobin. Thus, even when significant amounts of methemoglobin are present, the calculated 0, saturation may appear deceptively normal. Similarly, the usefulness of oximetry in directly measuring oxygen saturation is a function of the way the oximeter interprets the various types of hemoglobin that may be present. Hemoglobin may be bound to oxygen, it may be unbound to oxygen but capable of binding oxygen molecules (deoxyhemoglobin), or it may be functionally inert, that is, incapable of binding oxygen. Examples of the latter species include carboxyhemoglobin, methemoglobin and sulfhemoglobin. Some co-oximeters (e.g., the Instrumentation Laboratory 282 Co-oximeter) report oxygen saturation as the ratio of oxyhemoglobin to total hemoglobin. In such oximeters, the total hemoglobin measured includes oxyhemoglobin, deoxyhemoglobin, methemoglobin, and carboxyhemoglobin. This ratio of oxyhemoglobin to total hemoglobin is commonly referred to as the fractional oxygen saturation. Thus when methemoglobin or carboxyhemoglobin are present in significant quantities, the fractional oxygen saturation will, appropriately, be low. When the
479
oximeter being used measures fractional oxygen saturation, it is possible to calculate the so-called oxygen saturation gap (0, sat gap=calculated 0, saturation from arterial blood gas minus fractional 0, saturation from oximetry). When a dysfunctional hemoglobin such as carboxyhemoglobin or methemoglobin is suspected, the 0, saturation gap should approximate the percentage of abnormal hemoglobin present. The oximeter in our emergency department (Nellcor N100) and the oximeters most commonly used in clinical settings, on the other hand, report functional 0, saturation. Functional saturation is the ratio of oxyhemoglobin to the total hemoglobin that is bound to oxygen or available for binding oxygen (i.e., the sum of oxyhemoglobin and deoxyhemoglobin [14]). Carboxyhemoglobin and methemoglobin are therefore not measured with the Nellcor oximeter since they are not available for transporting oxygen. Even when methemoglobin or carboxyhemoglobin are present, 0, saturation as measured by the Nellcor oximeter is based only on oxyhemoglobin and deoxyhemoglobin. Thus, when functional O2 saturation is reported, as with the Nellcor instrument, it is not possible to detect an 0, saturation gap, since the 0, saturation calculated from an arterial blood gas and the functional saturation are usually equally misleading. It is not clear why there was a 10% difference in the oxygen saturation calculated from the arterial blood gas in our case and the oxygen saturation by oximetry. It seems likely that this difference is, in part, the result of an alteration in the color characteristics of blood produced by the large amount of methemoglobin present. Since the oximeter operates by sensing color changes in hemoglobin at two specific wavelengths, the presence of large amounts of dysfunctional hemoglobin may potentially alter blood color in a manner that is not accurately measured by the preset wavelengths. In fact, the oximeter’s manufacturer cautions that the accuracy of the instrument is affected by significant levels of dysfunctional hemoglobin (15). Treatment of dapsone intoxication includes gastrointestinal decontamination with ipecac or lavage, followed by the administration of activated charcoal. Repetitive dosing of activated charcoal appears to interrupt the enterohepatic circulation of dapsone thus significantly reducing its half-life (6,7). Although repetitive activated charcoal would have been appropriate in the present case, it was not used because dapsone was not positively identified as the offending agent until several days after the child’s admission. Both dialysis and hemoperfusion are of unproven value in the treatment of severe dapsone intoxications. Methylene blue is the specific therapy for symp-
480
J. G. Linakis, M. Shannon, A. Woolf, C. Sax
to methemoglobinemia and is given as a 1% solution in a dose of 1 to 2 mg/kg IV over 5 to 10 minutes. The indications for treatment with methylene blue are a methemoglobin level over 30% or methemoglobinemia in the presence of symptomatic evidence of hypoxia (e.g., shortness of breath, tachypnea, altered mental status, etc.). Treatment should be considered at lower methemoglobin levels in patients with anemia or pulmonary disease because of their increased susceptibility to tissue hypoxia. It should be noted that cyanosis alone is not an indication for treatment with methylene blue (9,16). The second dose of methylene blue was administered in the present case because our patient continued to be symptomatic (with agitation) in the presence of methemoglobin levels of approximately 30%. Further doses were not given, however, because at lower methemoglobin levels (10% to 20%) the child displayed no evidence of hypoxia although she was mildly cyanotic. Although toxicity from treatment with methylene blue is relatively uncommon, high doses have been reported to produce chest pain, tremor, anxiety, and dyspnea (16). Dysuria and bluish skin discoloration (9) have also been noted, as have methemoglobinemia at doses exceeding 7 mg/kg (17). Methylene blue is ineffective in the treatment of sulfhemoglobin and may fail to reduce methemoglobin in G6PD deficiency and NADPH methemoglobin reductase deficiency.
tomatic
cyanosis secondary
Ascorbic acid has also been used to treat methemoglobinemia. It appears to act by directly reducing oxidant compounds within the erythrocyte. Although ascorbic acid may have a role in the treatment of congenital methemoglobinemia, its usefulness in dapsone toxicity and other acquired methemoglobinemias has not been demonstrated.
CONCLUSION Dapsone is no longer used exclusively for the treatment of tropical diseases. As its use in clinical dermatology increases, so also does the potential for its accidental ingestion. Children would appear to be at high risk for adverse effects from the drug since methemoglobinemia seems to result from relatively small doses. Furthermore, in contrast to the methemoglobinemia produced by many other drugs, methemoglobinemia caused by dapsone appears to be prolonged or recurrent. In the case reported here, two treatments with methylene blue and supportive care were adequate to ameliorate the child’s symptoms. Nevertheless, her cyanosis was not entirely resolved until approximately five days from the time of presentation. In instances where larger doses are ingested or severe symptoms persist, multiple doses of activated charcoal and continuous or repeated infusions of methylene blue may be required.
REFERENCES 1. Nair PM, Philip E. Accidental dapsone poisoning in children. Ann Trop Paediatr. 1984;4:241-2. 2. Rees RS, Altenbern P, Lynch JB, King LE. Brown recluse spider bites: A comparison of early surgical excision versus dapsone and delayed surgical excision. Ann Surg. 1985;202: 659-63. 3. Stanfield JP. A case of acute poisoning with dapsone. J Trop Med Hyg. 1963;66:292-5. 4. Schvartsman S, Marcondes E. Accidental poisoning by sulphones in childhood: presentation of 12 cases. Trop Dis Bull. 1974;61:162-3. 5. Khan MA, Singh SD, Agarwal AK. Acute sulphone poisoning. Indian Pediatr. 1981;18:199-200. 6. Reigart JR, Trammel HL, Lindsey JM. Repetitive doses of activated charcoal in dapsone poisoning in a child. J Toxic01 Clin Toxicol. 1982/1983;19:1061-6. 7. Elonen E, Neuvonen PJ, Halmekoski J, Mattila MJ. Acute dapsone intoxication: a case with prolonged symptoms. Clin Toxicol. 1979;14:79-85. 8. Berlin G, Brodin B, Hilden J-O, Martensson J. Acute dapsone intoxication. A case treated with continuous infusion of methylene blue, forced diuresis and plasma exchange. Clin Toxicol. 1984/1985;22:537-48.
9. Lovejoy FH Jr. Methemoglobinemia. Clin Toxic01 Rev. 1984; 6(5):1-2. 10. Lambert M, Sonnett J, Mahieu P, Hassoun A. Delayed sulfhemoglobinemia after acute dapsone intoxication. J Toxic01 Clin Toxicol. 1982;19:45-50. 11. Rasbridge MR, Scott GL. The hemolytic action of dapsone: changes in the red cell membrane. Br J Haematol. 1973;24: 183-93. 12. Davies R. Fatal poisoning with Udolac. Lancet. 1950;1:905-6. 13. Woodhouse KW, Henderson DB, Charlton B, Peaston RT, Rawlins MD. Acute dapsone poisoning: clinical features and pharmacokinetic studies. Human Toxicol. 1983;3:507-10. 14. Yelderman M, New W Jr. Evaluation of pulse oximetry. Anesthesiology. 1983;59:349-52. 15. Nellcor Incorporated. User’s manual for the Nellcor pulse oximeter model N-1OOC. Hayward, California: Nellcor Incorporated; 1984; p. 29. 16. Curry S. Methemoglobinemia. Ann Emerg Med. 1982;11:21421. 17. Smith RP, Thron CD. Hemoglobin, methylene blue and oxygen interactions in human red cells. J Pharmacol Exp Ther. 1972;183:549-58.
RECURRENT
Prlnted in the USA
1989
Copyright 0 1989 Pergamon Press plc
??
METHEMOGLOBINEMIA AFTER ACUTE DAPSONE INTOXICATION IN A CHILD
James G. Linakis, PhD, MD,*Vt+$ Michael Shannon, MD, MPH,*st+§ Alan Woolf, MD, MPH,*+§ CarOlyn Sax, MD* *Program in Clinical Toxicology, tDivision of Emergency Medicine, *Department of Medicine, The Children’s Hospital, Harvard Medical School and the §Massachusetts Poison Control System, Boston, Massachusetts Reprint address: James G. Linakis, PhD, MD, Massachusetts Poison Control System, 300 Longwood Avenue, Boston, MA 02115
0 Abstract - Dapsone is a synthetic sulfone increasingly used in the treatment of a wide variety of dermatologic disorders. The case of a child with dapsone-induced recurrent methemoglobinemia is presented with a discussion of dapsone toxicity and its treatment. In addftion, the diagnostic value of pulse oximetry in the presence of dysfunctional hemoglobins is discussed.
PATIENT REPORT
A 3l/2-year-old white female presented to her pediatrician’s office after the acute onset of acral cyanosis that had progressed over 1l/2 hours to include central cyanosis. She had one episode of vomiting, but was otherwise asymptomatic. In her pediatrician’s office she was markedly cyanotic, but in no respiratory distress; her cardiac history and physical examination were within normal limits. She was referred to the Children’s Hospital Emergency Department for further evaluation and treatment. There was no known drug or toxic exposure, although the child had a history of a previous (nontoxic) drug ingestion. She had not been left unattended except for during a brief period approximately 7 hours prior to presentation. Medications in the household included sulfonamides, oral contraceptives and dapsone. Of note, her parents indicated that the child had an episode of acral cyanosis three weeks previously that had resolved spontaneously within 6 to 7 hours. Upon arrival in the emergency department, the child was noted to be severely cyanotic and moderately agitated. Her respiratory rate was 30, with a pulse of 135 and a blood pressure of 110/60. She had clear and symmetrical breath sounds and a normal cardiac exam. Her peripheral extremities were cyanotic, but warm and well perfused. Electrolytes, complete blood count, and a glucose-
0 Keywords- dapsone; methemoglobinemia; child; methylene blue
INTRODUCTION
Dapsone is a synthetic sulfone that is structurally similar to the sulfonamides. It is considered the drug of choice for the treatment of leprosy, and is being used increasingly for the treatment of various dermatologic diseases. These include dermatitis herpetiformis, pyoderma gangrenosum, pustular psoriasis, lichen planus, pemphigus, subcorneal pustular dermatosis, and brown recluse spider bites (1,2). To date, reports of dapsone toxicity in children have been largely limited to the tropical medicine literature (1,35). However, as dapsone becomes more widely used, accidental ingestions may become more prevalent in the pediatric population (6). We report a case of dapsone-induced, prolonged methemoglobinemia in a 3’12 year old child who required repeated treatment with methylene blue.
Toxicology-one of the most critical and challenging areas confronting the emergency department staff -is coordinated by Kenneth Ku&, MD, of the Rocky Mountain Poison Center. RECEIVED: 21 November 1988; FINALSUBMISSION RECEIVED:14 February 1989; ACCEPTED:9 March 1989
477
0736-4679189 $3.00 + .OO
478
J. G. Linakis, M. Shannon, A. Woolf, C. Sax
6-phosphate dehydrogenase (G6PD) screen were all normal. An arterial blood gas revealed a pH of 7.39, a pC0, of 24 torr, a p0, of 72 torr, and a calculated O2 saturation of 95 A. Pulse oximetry (Nellcor, model N-100, Nellcor Incorporated, Hayward, CA) at the time the blood gas was obtained revealed an O2 saturation of 85%. A toxicology screen of serum and urine was negative. The child’s blood was noted to have a chocolate-brown color that did not change when oxygen was bubbled through. An initial methemoglobin level was reported as 44.7 % . Activated charcoal was given in a dose of 1 g/kg and methylene blue was then administered in a dose of 1 mg/kg IV over 5 minutes. This resulted in rapid, but incomplete, resolution of the cyanosis. The child was subsequently admitted for observation and over the next 24 hours again became increasingly cyanotic. Methemoglobin levels were repeated at 14, 22, 25, 40, and 48 hours post admission (Figure 1). Ascorbic acid, 250 mg po per day, was begun and a second dose of methylene blue was administered (1 mg/kg IV) 22 hours after admission. After administration of the second dose of methylene blue, the child’s cyanosis showed nearly complete resolution except for mild circumoral cyanosis while crying. Over the next 24 hours, she again experienced a mild increase in the degree of cyanosis coinciding with a gradual increase in the methemoglobin level; however, no further methylene blue was given. The child was discharged 66 hours after admission with residual mild cyanosis that resolved over the next 2 to 3 days. A methemoglobin level performed 3l/2 weeks after discharge was 0.2%. Methemoglobin levels obtained from each of the child’s parents were reported as 0.4% in each. Serum from the time of admission and from 24 hours after admission was assayed for dapsone, ni-
40Methykne Blue gi, $
p
9
1
zo-
s io-
0
0
12
24
Time Post Admiss&
36
48
/hrsl
Figure 1. Methemoglobin levels followlng dapsono IngestIon as a function of time since rdmlselon. Arrows represent methylene blue admlnlstratlon.
trate, nitrite, and sulfonamide. Nitrates, nitrites, and sulfonamides were not detected in either sample. Although there was not sufficient serum from admission to perform a dapsone level, the 24 hour dapsone level was 3.9 mcg/mL (therapeutic levels approximately 2 to 10 mcg/mL [7]).
COMMENT Until recently, the use of dapsone was limited to the treatment of leprosy and dermatitis herpetiformis. However, in recent years, the clinical applications of the drug have been greatly expanded, with a dramatic increase in its use in the United States. In the case described here, the child’s grandmother was being treated with dapsone for dermatologic manifestations of lupus erythematosus. Although the grandmother had noticed no medication missing and the child was not witnessed to have ingested any medication, her serum was positive for dapsone. After an oral dose, gastrointestinal absorption of dapsone is slow but nearly complete, with peak serum concentrations of the drug occurring from 2 to 8 hours post ingestion. Its elimination half-life varies widely, ranging from 10 to 50 hours, with a mean of 30 hours. In serious overdose, the half-life of the drug may be markedly prolonged (6), perhaps secondary to enterohepatic recycling of the drug (8). The predominant toxic effect of dapsone is oxidation of the ferrous iron in heme to ferric iron, with the resultant production of methemoglobin. A large variety of chemicals and medications have been shown to be capable of producing methemoglobinemia through their oxidizing effects. Cyanosis generally occurs when methemoglobin levels exceed 15 % , although patients usually remain asymptomatic until the level of methemoglobin approaches 30% (9). In addition to methemoglobinemia, dapsone overdose may also produce sulfhemoglobinemia and red blood cell hemolysis (10,ll). This hemolysis may be exaggerated in G6PD deficient individuals. Other symptoms of dapsone ingestion in children have included impaired consciousness (1,4), tremors or movement disorders (4,5), agitation (1,3-5), and seizures (1,4). Death due to dapsone ingestion may be delayed for 2 or more days (7,12), and has occurred following overdoses of 1450 mg to 5 g (7). The only death reported in a child from a dapsone poisoning involved a dapsone-containing agricultural product (12). In only two reported pediatric overdose cases has the amount of dapsone ingested been known (3,6). Stanfield (3) described a 2-year-old who was believed to have ingested one or two 100 mg tablets of dap-
Dapsone Intoxication
in a Child
sone. In that child, cyanosis persisted for 8 days with the peak methemoglobin level reported as 18%. Her peak serum dapsone concentration was 73 mcg/mL. Reigart et al. (6) reported an l&month-old who ingested a single 100 mg tablet of dapsone with a peak methemoglobin level of 27 % . Serum dapsone concentrations were not obtained. In our case, the serum dapsone concentration at 24 hours postpresentation was 3.9 mcg/mL; the simultaneous methemoglobin level was still elevated, at 9%. Given the wide variation in dapsone’s elimination half-life, the child’s peak level of dapsone 24 hours previously could have been 6 to 17 mcg/mL. Interestingly, the peak dapsone concentration reported by Stanfield (3) and others reported in adults (7,13) were significantly higher than the one estimated here (3,6), yet were associated with similar or lower methemoglobin levels. Since our patient had no evidence of an enzyme defect or abnormal hemoglobin, it seems possible that methemoglobin levels correlate poorly with serum dapsone concentrations. A perplexing issue in our case was the 10% discordance between the oxygen saturation from the arterial blood gas on admission and the oxygen saturation by pulse oximetry. In our hospital, as in most, arterial blood gas results are reported with a calculated (not measured) oxygen saturation. This calculated O2 saturation is based on the measured p0, of the blood gas specimen. Since p0, is a function of the amount of oxygen dissolved in the plasma, it is relatively unaffected by the presence of dysfunctional hemoglobins such as methemoglobin. Thus, even when significant amounts of methemoglobin are present, the calculated 0, saturation may appear deceptively normal. Similarly, the usefulness of oximetry in directly measuring oxygen saturation is a function of the way the oximeter interprets the various types of hemoglobin that may be present. Hemoglobin may be bound to oxygen, it may be unbound to oxygen but capable of binding oxygen molecules (deoxyhemoglobin), or it may be functionally inert, that is, incapable of binding oxygen. Examples of the latter species include carboxyhemoglobin, methemoglobin and sulfhemoglobin. Some co-oximeters (e.g., the Instrumentation Laboratory 282 Co-oximeter) report oxygen saturation as the ratio of oxyhemoglobin to total hemoglobin. In such oximeters, the total hemoglobin measured includes oxyhemoglobin, deoxyhemoglobin, methemoglobin, and carboxyhemoglobin. This ratio of oxyhemoglobin to total hemoglobin is commonly referred to as the fractional oxygen saturation. Thus when methemoglobin or carboxyhemoglobin are present in significant quantities, the fractional oxygen saturation will, appropriately, be low. When the
479
oximeter being used measures fractional oxygen saturation, it is possible to calculate the so-called oxygen saturation gap (0, sat gap=calculated 0, saturation from arterial blood gas minus fractional 0, saturation from oximetry). When a dysfunctional hemoglobin such as carboxyhemoglobin or methemoglobin is suspected, the 0, saturation gap should approximate the percentage of abnormal hemoglobin present. The oximeter in our emergency department (Nellcor N100) and the oximeters most commonly used in clinical settings, on the other hand, report functional 0, saturation. Functional saturation is the ratio of oxyhemoglobin to the total hemoglobin that is bound to oxygen or available for binding oxygen (i.e., the sum of oxyhemoglobin and deoxyhemoglobin [14]). Carboxyhemoglobin and methemoglobin are therefore not measured with the Nellcor oximeter since they are not available for transporting oxygen. Even when methemoglobin or carboxyhemoglobin are present, 0, saturation as measured by the Nellcor oximeter is based only on oxyhemoglobin and deoxyhemoglobin. Thus, when functional O2 saturation is reported, as with the Nellcor instrument, it is not possible to detect an 0, saturation gap, since the 0, saturation calculated from an arterial blood gas and the functional saturation are usually equally misleading. It is not clear why there was a 10% difference in the oxygen saturation calculated from the arterial blood gas in our case and the oxygen saturation by oximetry. It seems likely that this difference is, in part, the result of an alteration in the color characteristics of blood produced by the large amount of methemoglobin present. Since the oximeter operates by sensing color changes in hemoglobin at two specific wavelengths, the presence of large amounts of dysfunctional hemoglobin may potentially alter blood color in a manner that is not accurately measured by the preset wavelengths. In fact, the oximeter’s manufacturer cautions that the accuracy of the instrument is affected by significant levels of dysfunctional hemoglobin (15). Treatment of dapsone intoxication includes gastrointestinal decontamination with ipecac or lavage, followed by the administration of activated charcoal. Repetitive dosing of activated charcoal appears to interrupt the enterohepatic circulation of dapsone thus significantly reducing its half-life (6,7). Although repetitive activated charcoal would have been appropriate in the present case, it was not used because dapsone was not positively identified as the offending agent until several days after the child’s admission. Both dialysis and hemoperfusion are of unproven value in the treatment of severe dapsone intoxications. Methylene blue is the specific therapy for symp-
480
J. G. Linakis, M. Shannon, A. Woolf, C. Sax
to methemoglobinemia and is given as a 1% solution in a dose of 1 to 2 mg/kg IV over 5 to 10 minutes. The indications for treatment with methylene blue are a methemoglobin level over 30% or methemoglobinemia in the presence of symptomatic evidence of hypoxia (e.g., shortness of breath, tachypnea, altered mental status, etc.). Treatment should be considered at lower methemoglobin levels in patients with anemia or pulmonary disease because of their increased susceptibility to tissue hypoxia. It should be noted that cyanosis alone is not an indication for treatment with methylene blue (9,16). The second dose of methylene blue was administered in the present case because our patient continued to be symptomatic (with agitation) in the presence of methemoglobin levels of approximately 30%. Further doses were not given, however, because at lower methemoglobin levels (10% to 20%) the child displayed no evidence of hypoxia although she was mildly cyanotic. Although toxicity from treatment with methylene blue is relatively uncommon, high doses have been reported to produce chest pain, tremor, anxiety, and dyspnea (16). Dysuria and bluish skin discoloration (9) have also been noted, as have methemoglobinemia at doses exceeding 7 mg/kg (17). Methylene blue is ineffective in the treatment of sulfhemoglobin and may fail to reduce methemoglobin in G6PD deficiency and NADPH methemoglobin reductase deficiency.
tomatic
cyanosis secondary
Ascorbic acid has also been used to treat methemoglobinemia. It appears to act by directly reducing oxidant compounds within the erythrocyte. Although ascorbic acid may have a role in the treatment of congenital methemoglobinemia, its usefulness in dapsone toxicity and other acquired methemoglobinemias has not been demonstrated.
CONCLUSION Dapsone is no longer used exclusively for the treatment of tropical diseases. As its use in clinical dermatology increases, so also does the potential for its accidental ingestion. Children would appear to be at high risk for adverse effects from the drug since methemoglobinemia seems to result from relatively small doses. Furthermore, in contrast to the methemoglobinemia produced by many other drugs, methemoglobinemia caused by dapsone appears to be prolonged or recurrent. In the case reported here, two treatments with methylene blue and supportive care were adequate to ameliorate the child’s symptoms. Nevertheless, her cyanosis was not entirely resolved until approximately five days from the time of presentation. In instances where larger doses are ingested or severe symptoms persist, multiple doses of activated charcoal and continuous or repeated infusions of methylene blue may be required.
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