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Acute Methemoglobinemia Following Attempted Suicide by Dapson
Archives of Medical Research 37 (2006) 410–414
CASE REPORT
Acute Methemoglobinemia Following Attempted Suicide by Dapson Shahin Shadnia,a,b Mojgan Rahimi,a Mahsa Moeinsadat,a Ghazal Vesal,c Mohadeseh Donyavi,b and Mohammad Abdollahib a
Poison Control Center, Loghman-Hakim Hospital, Faculty of Medicine, Shaheed-Beheshti University of Medical Sciences, Tehran, Iran b Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, c Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Received for publication February 23, 2005; accepted June 7, 2005 (ARCMED-D-05-00075).
This report describes the case of an otherwise healthy young adult female, with oral ingestion of 40 unknown tablets. Her clinical course included progressive bluish discoloration of lips and limbs, hemolysis and jaundice. A high PaO2 in the presence of cyanosis and dark blood lead to suspicion of methemoglobinemia. Laboratory results showed methemoglobin level to be 3.8 g/dL (38%). The etiology was traced to dapsone according to patient history; after 3 days it became evident that she had ingested 2 g dapsone in suicidal intent. The therapeutic and diagnostic approach in such patients is discussed. In conclusion, acute methemoglobinemia is an uncommon but potentially treatable disorder. Ó 2006 IMSS. Published by Elsevier Inc. Key Words: Dapsone, Methemoglobinemia.
Introduction Acute methemoglobinemia is an uncommon but potentially treatable disorder in which patients can present with dramatic signs and symptoms. Usually there is a history of some precipitating factor such as accidental or intentional ingestion of a drug or inhalation of certain substances. It is also well known that administration of certain medications can precipitate methemoglobin formation in cases of overdose or even in normal doses if the patient is susceptible. We report the case of a young woman who presented with methemoglobinemia without any clear history.
Case Report An 18-year-old girl was referred to Loghman-Hakim Hospital poison center following a drug suicide attempt. Physical examination showed a lethargic girl with normal vital signs and normal size pupils that were reactive to light. The conjunctivae were not pale and the scleras were not Address reprint requests to: Prof. Mohammad Abdollahi, Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, PO Box 14155-6451, Tehran, Iran; E-mail: [email protected]
icteric. Except for these, general physical and neurologic examinations were not significant. History revealed suicidal poisoning by ingestion of 40 unknown tablets. There was no past history of other illness, deep vein thrombosis or pulmonary embolism and drug abuse. She was a non-smoker. In the emergency room the patient underwent gastric lavage with water. Activated charcoal (30 g) and sorbitol (100 mL of a 70% suspension) were administered by the lavage tube. An intravenous (IV) line was established and blood samples were sent to the laboratory to perform complete blood cell count, electrolytes, renal function tests and drug screening (Tables 1 and 4). Twenty-four h maintenance IV fluid therapy with D5W serum (1 L) and dextrose-saline serum (2 L) was administered together with sodium bicarbonate 7.5%. Serial-activated charcoal (30 g every 3 h) and sorbitol (100 mL of 70% suspension every 8 h) were also started. One hour after admission, bluish discoloration of the periphery and cyanosis of mucous membranes were noticed. At that time her blood pressure was 120/80 mmHg and her pulse rate and respiratory rate were 88/min and 35/min, respectively. The pupillary sizes were normal, symmetric and reactive. Cardiovascular, respiratory and abdominal examinations were all normal. An arterial blood gas was performed showing a respiratory alkalosis (Table 2). The patient was transferred to the intensive care unit because of peripheral and mucous
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2005.06.010
Methemoglobinemia Following Attempted Suicide
411
Table 1. Complete blood cell count of the patient during hospitalization Day after admission White blood cells (m3) Hemoglobin (g/dL) Hematocrit (%) MCV (mm3/cell) MCH (pg/RBC) MCH concentration (g/dL) Platelet count (m3) Anisocytosis Poikilocytosis Reticulocyte count (%)
0
1
2
2A
3
3A
5
5A
11
14.3 12.6 41.1 85.1 26.1 30.7 384 -
18.5 10.6 31.1 84.8 28.7 33.9 286 0.5
13.6 8.6 28.6 86.7 26.1 30.1 295 -
17.3 10.6 32.4 84.6 27.7 32.7 254 0.6
15.5 8.8 28 85.6 26.9 31.4 289 -
26.2 10.9 31.7 84.3 29 34.4 204 -
17.6 6.3 18.9 84.8 28.3 33.3 148 1 1 4
32.4 12.5 37.1 87.5 29.5 33.7 347 -
15.4 11.7 39.1 98 29.3 29.9 204 -
MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin. AIndicates that the complete blood cell count was performed after transfusion of cross-matched packed red blood cells.
membrane cyanosis. She was also mechanically ventilated. According to arterial blood gas (Table 2), the patient had normal PaO2 and O2 saturation but the peripheral and mucous membrane cyanosis was still evident. Hence, methemoglobinemia was suspected and determination of methemoglobin level was ordered (1) (Table 4), but not sulfhemoglobin because of inability of the laboratory to determine sulfhemoglobin. Chest radiography and electrocardiography were also normal. On day one of admission, according to metabolic acidosis (Table 2) and cyanosis, 88 mEq sodium bicarbonate 7.5% together with a single dose (1000 mg) ascorbic acid was administered IV. After inadvertent extubation, she was not intubated again because of her stable respiratory condition. Another dose of ascorbic acid (1000 mg) was administered IV and ranitidine (50 mg every 12 h) IV was added to her drug regimen. The cyanosis was reduced and the last arterial blood gas that was performed on this day showed a correction of acidosis (Table 2). On day 2 of admission the patient became icteric (Table 3) and febrile. Due to her high temperature, blood cultures, urinalysis and urine culture were ordered and ceftriaxone 1 g every 12 h was administered IV empirically. Ascorbic acid (1000 mg every 12 h) was continued IV. Hemoglobin and hematocrit levels were reduced significantly from 12.6 mg/dL and 41.1% on admission time to 8.6 mg/dL and 28.6%, respectively (Table 1). Therefore, cross-matched packed red blood cells were transfused and hemoglobin and hematocrit levels were determined every 6 h.
Table 2. Arterial blood gas analysis of patient during hospitalization Day after admission PH (7.35–7.45) PaCO2 (35–45 mmHg) HCO3 (22–26 mEq/L) PaO2 (80–105 mmHg) O2sat (90–100%)
0
1
2
3
4
5
6
7
8
7.53 20 16.6 134 99
7.34 37 17.6 128 98
7.48 36 26.1 61.2 93.2
7.48 35 25.7 233 99.6
7.39 33.4 19.6 72.6 93.1
7.45 26 17.3 85.5 98.3
7.38 33 19 87 96.5
7.33 41 21.4 82 97
7.40 32.9 19.8 129 98.6
On day 3 of admission, administration of activated charcoal and sorbitol solutions was stopped because of constipation. Based on impaired liver function tests (Table 3), syrup of lactulose (30 mL every 6 h) was started orally. It was only on this day that we learned that the patient had taken forty 50-mg tablets of dapsone (2 g). Therefore, methemoglobinemia secondary to dapsone intoxication was assumed and 1 mg/kg methylene blue diluted with 100 mL normal saline was given IV over 20 min. Due to low hemoglobin and hematocrit levels (8.8 mg/ dL, 28%, respectively), other units of cross-matched packed red blood cells were transfused and hemoglobin and hematocrit levels increased to 10.9 mg/dL and 31.7%, respectively (Table 1). On day 4 of admission, according to continuation of fever, clindamycin (900 mg every 8 h) was added to her IV antibiotic regimen. On day 5 of admission the patient had abdominal and flank pain with generalized tenderness and rebound tenderness. According to the hemoglobin and hematocrit levels (6.3 mg/dL and 18.9%, respectively), a total of six units of cross-matched packed red blood cells were Table 3. Liver function tests of patient during hospitalization Day after admission
0
1
2
3
5
6
8
9
Bilirubin total (0.3–1.1 mg/dL) Bilirubin direct (0.1–0.4 mg/dL) Aspartate aminotransferase (5–40 IU/L) Alanine aminotransferase (5–40 IU/L) Creatinine phosphokinase (20–200 U/L) Lactate dehydrogenase (225–500 U/L) Prothrombin time (13 sec) Partial prothrombin time (30–40 sec)
-
-
10.1
-
5.1
-
7.2
4.3
-
-
0.9
-
1.1
-
1.1
1
-
-
29
-
30
-
41
36
-
-
11
-
17
-
36
19
-
86
511
-
-
-
-
-
-
364
764
-
-
-
-
-
-
15 32
16 32
16 60
23 80
15 45
14 32
13 32
Shadnia et al./ Archives of Medical Research 37 (2006) 410–414
412
transfused and the hemoglobin and hematocrit levels increased to 12.5 mg/dL and 37.1%, respectively (Table 1). Chest and abdominal radiography were normal. Serum amylases, prothrombin time (PT), partial prothrombin time (PTT), reticulocyte count, peripheral blood smear, direct and indirect coombs tests were performed (Tables 1, 3, and 4). According to PT and PTT, fresh frozen plasma was transfused (Table 3). On day 8 of admission, with significant improvement of general condition, oral diet was begun for patient and serum intake was decreased to 1500 mL together with sodium bicarbonate 7.5% every 24 h. Cyanosis, methemoglobin level and jaundice decreased significantly and the patient was transferred from the intensive care unit to the poisoning ward. On day 11 of admission all clinical signs and symptoms subsided and laboratory tests returned to normal values and the patient was discharged. Discussion Methemoglobinemia is a condition in which an abnormal proportion of the iron in heme moiety of the hemoglobin is oxidized to the ferric state leading to impaired oxygen transport and anemic hypoxia (2,3). The initial presentation of methemoglobinemia may cause diagnostic confusion because of the false oxygen saturation (about 85%) on the pulse oximeter in favor of the cyanosis. This can lead to unnecessary investigations and administration of certain potentially hazardous drugs (3). In the present patient, normal oxygen saturation on the first arterial blood gas along with cyanosis and mild tachypnea diverted the attention to methemoglobinemia. Arterial blood gas analyzers that calculate oxygen saturation based on PaO2 give falsely elevated values (3), but machines that use coTable 4. Miscellaneous laboratory tests of patient during hospitalization Day after admission
1
2
5
8
Erythrocyte sedimentation rate (0–10 mm/1st h) Serum phenobarbital level Serum phenytoin level Serum carbamazepin level Serum acetaminophen level Serum salicylate level Serum amitriptyline level Serum imipramine level Urine culture Blood culture G6P-PD Methemoglobin level (0–0.5 g/dL) Direct coombs test Indirect coombs test Serum amylase (20–220 U/L)
11
-
-
-
Negative Negative Negative Negative Negative Negative Negative -
Negative Negative Normal 3.8 (38%)
-
2.0
-
-
Negative Negative 100
-
oximetry give an accurate reading. It is important for the clinician to know which type of machine is in use at his/her hospital. Clinical features of methemoglobinemia depend on the methemoglobin levels in blood. The discoloration of blood and appearance of cyanosis manifest when the methemoglobin levels reach 15–20%. Levels between 20 and 45% are associated with dyspnea, lethargy, dizziness and headaches. Methemoglobin levels O45% are usually associated with impaired consciousness and levels O55% can cause seizures, coma, and cardiac arrhythmias (2,3,4). Although severe poisonings with methemoglobinemia over 70% are usually fatal, survival has been reported with levels as high as 83% (2,4,5). Methemoglobinemia can be caused either by a genetic defect in red cell metabolism or hemoglobin structure, or acquired by a variety of drugs and toxins. About 40 substances have been implicated in causing this condition, the most prominent being dapsone, nitrates, prilocaine, antimalarials, sulfonamids, and dyes (6,7). Apart from the potential offending agents, a search should be made for other substances of abuse, which can be co-ingested (3). Domestic causes of acquired methemoglobinemia include ingestion of food and water high in nitrites and nitrates, inhalation of room odorizers containing butyl nitrate, and exposure to aniline dyes (6,7). Dapsone has been associated with a number of overdoses in children and adults in the U.S. and overseas (1), but acute poisoning from dapsone intake is uncommon in Europe and Iran (4,8,9). However, with the increasing use of dapsone for diseases other than leprosy and dermatitis herpetiformis, clinicians should be aware of its toxic potential. Dapsone poisoning in children is usually accidental and results in not only methemoglobinemia but also in hemolysis, hepatitis, coma, seizures and metabolic acidosis (10). This report describes a case of methemoglobinemia without clear drug history. The etiology turned out to be an intentional ingestion of dapsone. In dapsone poisoning, massive and varying clinical presentations such as severe cyanosis, restlessness, dyspnea, extensive hemolysis, anemia and/or serious central nervous system dysfunction are expected. In addition, nausea and vomiting, tachycardia and elevation of blood pressure have been reported (2,4,11,12). Methemoglobinemia resulting from the ingestion of dapsone has been described as cyanosis without respiratory distress (11). The cyanosis is unresponsive to oxygen administration and it may be subtle, being confined to the nails and buccal mucosa or may be more dramatic (11). Dapsone overdose is often dangerous and potentially lethal (11). Toxicity resulting from the ingestion of 20–25 mg/kg has been reported (13). The situation is further complicated by the fact that patients receiving vigorous interventions have died (14). The standard management is that any patient including those who are asymptomatic but cyanotic should be admitted to the hospital (11) because the
Methemoglobinemia Following Attempted Suicide
development of hemolytic anemia secondary to a dapsone overdose may take up to 9 days to develop (2,11). Methemoglobin level is useful to confirm the diagnosis, but it is not as important as the patient’s clinical status for determining early treatment (11). The relatively slow absorption of dapsone from the gastrointestinal tract increases the importance of gastric emptying procedures (2,11), and in our case we performed gastric lavage with water as soon as the patient was admitted to the emergency center. The drug is believed to undergo significant enterohepatic circulation (2,11,15,16), making activated charcoal one of the mainstays of treatment (2,4,11,14,17–19). In one study, four times a day dosing resulted in a 4- to 5-fold diminution of the plasma half-life of both dapsone and its principal metabolite MADDA (2,14). Activated charcoal should be administered for at least 3 days (2), but in our case, multidose activated charcoal treatment was given only for 2 days and then discontinued because of the patient’s constipation. The decrease of hemoglobin level may also be explained by dapsone poisoning. It is well known that dapsone is responsible for hemolysis (2,4,10,11,19–24). In this case, excessive dapsone may have lead to the corresponding decrease in hemoglobin levels. Packed red blood cells transfusion may be required for symptomatic treatment of hemolytic anemia (2), and in our case we administered about ten units of cross-matched packed red blood cells to control the patient’s anemia. The hemoglobin that is released by hemolysis is metabolized in the liver. Correspondingly, bilirubin levels rise as we observed in this patient. Methylene blue is the drug of choice in the treatment of methemoglobinemia. Methylene blue (methylthioninium chloride) when given IV is rapidly reduced to leukomethylene blue by the enzyme NADPH-met-Hb reductase, which reduces the met-Hb back to Hb by a cyclic reaction so early administration of the antidote methylene blue usually leads to rapid improvement of the cyanosis (2,4,10,11). An effective dose initially is 1–2 mg/kg given IV over a 5- to 10-min period. According to the long halflife of the toxicant, which may cause rebound methemoglobinemia, repeated administration of methylene blue may be necessary (2,25). In the present case, single-dose administration of the antidote was sufficient. Known or suspected G6PD deficiency is a contraindication to the use of methylene blue. In G6PD-deficient individuals, insufficient NADPH is generated to efficiently reduce methylene blue to leukomethylene blue, which is necessary for the activation of the NADPH-dependent methemoglobin reductase system. G6PD-deficient individuals are also prone to methylene blue-induced hemolysis (7). In an earlier study, ascorbic acid was found to reduce xenobioticinduced methemoglobinemia (26). This is probably due to the increase in methemoglobin reductase activity by ascorbic acid (23); therefore, it was administered to our patient IV with a dose of 1000 mg every 12 h.
413
The exchange transfusion has been reported to be very effective in the management of methemoglobinemia (27), especially in patients who cannot receive methylene blue, but was later found to be of minor benefit, probably due to large volume of distribution of dapsone (28).
Acknowledgments The authors wish to convey their full appreciation to Professor Tareg Bey, MD, FACEP, ABMT for his kind assistance in editing of this paper.
References 1. Harrison HJ, Jollow JD. Role of aniline metabolites in aniline-induced hemolytic anemia. J Pharmacol Exp Ther 1992;238:1045–1054. 2. Schonwald S. Medical Toxicology. A Synopsis and Study Guide. Philadelphia: Lippincott Williams and Wilkins;2001. pp. 117–120. 3. Falkenhahn M, Kannan S, O’Kane M. Unexplained acute severe methemoglobinemia in a young adult. Br J Anaesth 2001;86:278–280. 4. Kraemer T, Paul LD, Jochum Ch, Maurer HH. Acute poisoning with Dapsone, a case report. Toxichem Krimtech 2002;69:80–85. 5. Caudill L, Walbridge J, Kuhn G. Methaemoglobinemia as a cause for coma. Ann Emerg Med 1990;19:677–679. 6. Bucklin R, Myint MK. Fatal methemoglobinemia due to well water nitrates. Ann Intern Med 1960;52:703–705. 7. Delaney KA, Ling LJ, Erickson T, Ford MD. Clinical Toxicology. 1st ed. Philadelphia: W.B. Saunders;2001. 8. Abdollahi M, Jalali N, Sabzevari O, Hoseini R, Ghanea T. A retrospective study of poisoning in Tehran. J Toxicol Clin Toxicol 1997;35:387–393. 9. Jalali N, Pajoumand A, Abdollahi M, Shadnia SH. Epidemiological survey of poisoning mortality in Tehran during 1997–1998. Toxicol Lett 2000;116(Suppl 1):84. 10. Prasad R, Das BP, Singh R, Sharma KK. Dapsone induced methemoglobinemia, sulfhemoglobinemia and hemolytic anemia: a case report with note on treatment strategies. Ind J Pharm 2002;34:283–285. 11. Viccellio P. Emergency Toxicology. 2nd ed. Philadelphia: LippincottRaven Publishers;1998. pp. 595–598. 12. Woodhouse KW, Henderson DB, Charlton B, Peaston RT, Rawlins MD. Acute dapsone poisoning: clinical features and pharmacokinetic studies. Hum Toxicol 1983;2:507–510. 13. Elonen E, Neuvonen PJ, Halmekoski J, Mattila MJ. Acute dapsone intoxication: a case with prolonged symptoms. Clin Toxicol 1979;14: 79–85. 14. Reigart JR, Harold LT, Lindsey JM. Repetitive doses of activated charcoal in dapsone poisoning in a child. J Toxicol Clin Toxicol 1982; 19:1061–1066. 15. Ferguson AJ, Lavery GG. Deliberate self-poisoning with dapsone. A case report and summary of relevant pharmacology and treatment. Anaesthesia 1997;52:359–363. 16. Zuidema J, Hilbers-Modderman ES, Merkus FW. Clinical pharmacokinetics of dapsone. Clin Pharmacokinet 1986;11:299–315. 17. Anon. Position statement and practice guidelines on the use of multidose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centers and Clinical Toxicologists. J Toxicol Clin Toxicol 1999;37: 731–751. 18. Souhami RL, Moxham J. Text Book of Medicine. London: Churchill Livingstone;1990. 19. Klaassen CD. Casarett and Doull’s Toxicology: The Basic Science of Poisons. 6th ed. New York: McGraw-Hill;2001. 20. Olson KR. Poisoning and Drug Overdose. Norwalk, CT: Appleton & Lange;1999. pp. 152–154.
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21. Katzung BG. Basic and Clinical Pharmacology. 4th ed. Englewood Cliffs, NJ: Prentice-Hall;1989. pp. 583–585. 22. Malfara WR, Pereira CP, Dos Santos AC, Costa Queiroz RH. Effects of H2-receptors antagonists on dapsone-induced methemoglobinemia in rats. Pharmacol Res 2002;45:269–273. 23. Vage C, Saab N, Woster PM, Svensson CK. Dapsone-induced hematologic toxicity: comparison of the methemoglobin-forming ability of hydroxylamine metabolites of dapsone in rat and human blood. Toxicol Appl Pharmacol 1994;129:309–316. 24. Wilson JD, Braunwald E, Isselbacher KJ, Petersdorf RG, Martin JB, Fauci AS, Root RK. Harrison’s Principles of Internal Medicine. 12th ed. New York: McGraw-Hill;1991.
25. Dawson AH, Whyte IM. Management of dapsone poisoning complicated by methaemoglobinaemia. Med Toxicol Adverse Drug Exp 1989;4:387–392. 26. Bolyai JZ, Smith RP, Gray CT. Ascorbic acid and chemically induced methemoglobinemia. Toxicol Appl Pharmacol 1972;21:176–185. 27. Kumar A, Antony TJ, Kurein KM, Taneja LN, Mohan M, Anand NK. Exchange transfusion of dapsone poisoning. Indian Pediatr 1998;25: 798–800. 28. Berlin G, Brodin B, Hilden JO, Martensson J. Acute dapsone intoxication: a case treated with continuous infusion of methylene blue, forced diuresis and plasma exchange. J Toxicol Clin Toxicol 1984;22:537–548.
CASE REPORT
Acute Methemoglobinemia Following Attempted Suicide by Dapson Shahin Shadnia,a,b Mojgan Rahimi,a Mahsa Moeinsadat,a Ghazal Vesal,c Mohadeseh Donyavi,b and Mohammad Abdollahib a
Poison Control Center, Loghman-Hakim Hospital, Faculty of Medicine, Shaheed-Beheshti University of Medical Sciences, Tehran, Iran b Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, c Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Received for publication February 23, 2005; accepted June 7, 2005 (ARCMED-D-05-00075).
This report describes the case of an otherwise healthy young adult female, with oral ingestion of 40 unknown tablets. Her clinical course included progressive bluish discoloration of lips and limbs, hemolysis and jaundice. A high PaO2 in the presence of cyanosis and dark blood lead to suspicion of methemoglobinemia. Laboratory results showed methemoglobin level to be 3.8 g/dL (38%). The etiology was traced to dapsone according to patient history; after 3 days it became evident that she had ingested 2 g dapsone in suicidal intent. The therapeutic and diagnostic approach in such patients is discussed. In conclusion, acute methemoglobinemia is an uncommon but potentially treatable disorder. Ó 2006 IMSS. Published by Elsevier Inc. Key Words: Dapsone, Methemoglobinemia.
Introduction Acute methemoglobinemia is an uncommon but potentially treatable disorder in which patients can present with dramatic signs and symptoms. Usually there is a history of some precipitating factor such as accidental or intentional ingestion of a drug or inhalation of certain substances. It is also well known that administration of certain medications can precipitate methemoglobin formation in cases of overdose or even in normal doses if the patient is susceptible. We report the case of a young woman who presented with methemoglobinemia without any clear history.
Case Report An 18-year-old girl was referred to Loghman-Hakim Hospital poison center following a drug suicide attempt. Physical examination showed a lethargic girl with normal vital signs and normal size pupils that were reactive to light. The conjunctivae were not pale and the scleras were not Address reprint requests to: Prof. Mohammad Abdollahi, Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, PO Box 14155-6451, Tehran, Iran; E-mail: [email protected]
icteric. Except for these, general physical and neurologic examinations were not significant. History revealed suicidal poisoning by ingestion of 40 unknown tablets. There was no past history of other illness, deep vein thrombosis or pulmonary embolism and drug abuse. She was a non-smoker. In the emergency room the patient underwent gastric lavage with water. Activated charcoal (30 g) and sorbitol (100 mL of a 70% suspension) were administered by the lavage tube. An intravenous (IV) line was established and blood samples were sent to the laboratory to perform complete blood cell count, electrolytes, renal function tests and drug screening (Tables 1 and 4). Twenty-four h maintenance IV fluid therapy with D5W serum (1 L) and dextrose-saline serum (2 L) was administered together with sodium bicarbonate 7.5%. Serial-activated charcoal (30 g every 3 h) and sorbitol (100 mL of 70% suspension every 8 h) were also started. One hour after admission, bluish discoloration of the periphery and cyanosis of mucous membranes were noticed. At that time her blood pressure was 120/80 mmHg and her pulse rate and respiratory rate were 88/min and 35/min, respectively. The pupillary sizes were normal, symmetric and reactive. Cardiovascular, respiratory and abdominal examinations were all normal. An arterial blood gas was performed showing a respiratory alkalosis (Table 2). The patient was transferred to the intensive care unit because of peripheral and mucous
0188-4409/06 $–see front matter. Copyright Ó 2006 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2005.06.010
Methemoglobinemia Following Attempted Suicide
411
Table 1. Complete blood cell count of the patient during hospitalization Day after admission White blood cells (m3) Hemoglobin (g/dL) Hematocrit (%) MCV (mm3/cell) MCH (pg/RBC) MCH concentration (g/dL) Platelet count (m3) Anisocytosis Poikilocytosis Reticulocyte count (%)
0
1
2
2A
3
3A
5
5A
11
14.3 12.6 41.1 85.1 26.1 30.7 384 -
18.5 10.6 31.1 84.8 28.7 33.9 286 0.5
13.6 8.6 28.6 86.7 26.1 30.1 295 -
17.3 10.6 32.4 84.6 27.7 32.7 254 0.6
15.5 8.8 28 85.6 26.9 31.4 289 -
26.2 10.9 31.7 84.3 29 34.4 204 -
17.6 6.3 18.9 84.8 28.3 33.3 148 1 1 4
32.4 12.5 37.1 87.5 29.5 33.7 347 -
15.4 11.7 39.1 98 29.3 29.9 204 -
MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin. AIndicates that the complete blood cell count was performed after transfusion of cross-matched packed red blood cells.
membrane cyanosis. She was also mechanically ventilated. According to arterial blood gas (Table 2), the patient had normal PaO2 and O2 saturation but the peripheral and mucous membrane cyanosis was still evident. Hence, methemoglobinemia was suspected and determination of methemoglobin level was ordered (1) (Table 4), but not sulfhemoglobin because of inability of the laboratory to determine sulfhemoglobin. Chest radiography and electrocardiography were also normal. On day one of admission, according to metabolic acidosis (Table 2) and cyanosis, 88 mEq sodium bicarbonate 7.5% together with a single dose (1000 mg) ascorbic acid was administered IV. After inadvertent extubation, she was not intubated again because of her stable respiratory condition. Another dose of ascorbic acid (1000 mg) was administered IV and ranitidine (50 mg every 12 h) IV was added to her drug regimen. The cyanosis was reduced and the last arterial blood gas that was performed on this day showed a correction of acidosis (Table 2). On day 2 of admission the patient became icteric (Table 3) and febrile. Due to her high temperature, blood cultures, urinalysis and urine culture were ordered and ceftriaxone 1 g every 12 h was administered IV empirically. Ascorbic acid (1000 mg every 12 h) was continued IV. Hemoglobin and hematocrit levels were reduced significantly from 12.6 mg/dL and 41.1% on admission time to 8.6 mg/dL and 28.6%, respectively (Table 1). Therefore, cross-matched packed red blood cells were transfused and hemoglobin and hematocrit levels were determined every 6 h.
Table 2. Arterial blood gas analysis of patient during hospitalization Day after admission PH (7.35–7.45) PaCO2 (35–45 mmHg) HCO3 (22–26 mEq/L) PaO2 (80–105 mmHg) O2sat (90–100%)
0
1
2
3
4
5
6
7
8
7.53 20 16.6 134 99
7.34 37 17.6 128 98
7.48 36 26.1 61.2 93.2
7.48 35 25.7 233 99.6
7.39 33.4 19.6 72.6 93.1
7.45 26 17.3 85.5 98.3
7.38 33 19 87 96.5
7.33 41 21.4 82 97
7.40 32.9 19.8 129 98.6
On day 3 of admission, administration of activated charcoal and sorbitol solutions was stopped because of constipation. Based on impaired liver function tests (Table 3), syrup of lactulose (30 mL every 6 h) was started orally. It was only on this day that we learned that the patient had taken forty 50-mg tablets of dapsone (2 g). Therefore, methemoglobinemia secondary to dapsone intoxication was assumed and 1 mg/kg methylene blue diluted with 100 mL normal saline was given IV over 20 min. Due to low hemoglobin and hematocrit levels (8.8 mg/ dL, 28%, respectively), other units of cross-matched packed red blood cells were transfused and hemoglobin and hematocrit levels increased to 10.9 mg/dL and 31.7%, respectively (Table 1). On day 4 of admission, according to continuation of fever, clindamycin (900 mg every 8 h) was added to her IV antibiotic regimen. On day 5 of admission the patient had abdominal and flank pain with generalized tenderness and rebound tenderness. According to the hemoglobin and hematocrit levels (6.3 mg/dL and 18.9%, respectively), a total of six units of cross-matched packed red blood cells were Table 3. Liver function tests of patient during hospitalization Day after admission
0
1
2
3
5
6
8
9
Bilirubin total (0.3–1.1 mg/dL) Bilirubin direct (0.1–0.4 mg/dL) Aspartate aminotransferase (5–40 IU/L) Alanine aminotransferase (5–40 IU/L) Creatinine phosphokinase (20–200 U/L) Lactate dehydrogenase (225–500 U/L) Prothrombin time (13 sec) Partial prothrombin time (30–40 sec)
-
-
10.1
-
5.1
-
7.2
4.3
-
-
0.9
-
1.1
-
1.1
1
-
-
29
-
30
-
41
36
-
-
11
-
17
-
36
19
-
86
511
-
-
-
-
-
-
364
764
-
-
-
-
-
-
15 32
16 32
16 60
23 80
15 45
14 32
13 32
Shadnia et al./ Archives of Medical Research 37 (2006) 410–414
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transfused and the hemoglobin and hematocrit levels increased to 12.5 mg/dL and 37.1%, respectively (Table 1). Chest and abdominal radiography were normal. Serum amylases, prothrombin time (PT), partial prothrombin time (PTT), reticulocyte count, peripheral blood smear, direct and indirect coombs tests were performed (Tables 1, 3, and 4). According to PT and PTT, fresh frozen plasma was transfused (Table 3). On day 8 of admission, with significant improvement of general condition, oral diet was begun for patient and serum intake was decreased to 1500 mL together with sodium bicarbonate 7.5% every 24 h. Cyanosis, methemoglobin level and jaundice decreased significantly and the patient was transferred from the intensive care unit to the poisoning ward. On day 11 of admission all clinical signs and symptoms subsided and laboratory tests returned to normal values and the patient was discharged. Discussion Methemoglobinemia is a condition in which an abnormal proportion of the iron in heme moiety of the hemoglobin is oxidized to the ferric state leading to impaired oxygen transport and anemic hypoxia (2,3). The initial presentation of methemoglobinemia may cause diagnostic confusion because of the false oxygen saturation (about 85%) on the pulse oximeter in favor of the cyanosis. This can lead to unnecessary investigations and administration of certain potentially hazardous drugs (3). In the present patient, normal oxygen saturation on the first arterial blood gas along with cyanosis and mild tachypnea diverted the attention to methemoglobinemia. Arterial blood gas analyzers that calculate oxygen saturation based on PaO2 give falsely elevated values (3), but machines that use coTable 4. Miscellaneous laboratory tests of patient during hospitalization Day after admission
1
2
5
8
Erythrocyte sedimentation rate (0–10 mm/1st h) Serum phenobarbital level Serum phenytoin level Serum carbamazepin level Serum acetaminophen level Serum salicylate level Serum amitriptyline level Serum imipramine level Urine culture Blood culture G6P-PD Methemoglobin level (0–0.5 g/dL) Direct coombs test Indirect coombs test Serum amylase (20–220 U/L)
11
-
-
-
Negative Negative Negative Negative Negative Negative Negative -
Negative Negative Normal 3.8 (38%)
-
2.0
-
-
Negative Negative 100
-
oximetry give an accurate reading. It is important for the clinician to know which type of machine is in use at his/her hospital. Clinical features of methemoglobinemia depend on the methemoglobin levels in blood. The discoloration of blood and appearance of cyanosis manifest when the methemoglobin levels reach 15–20%. Levels between 20 and 45% are associated with dyspnea, lethargy, dizziness and headaches. Methemoglobin levels O45% are usually associated with impaired consciousness and levels O55% can cause seizures, coma, and cardiac arrhythmias (2,3,4). Although severe poisonings with methemoglobinemia over 70% are usually fatal, survival has been reported with levels as high as 83% (2,4,5). Methemoglobinemia can be caused either by a genetic defect in red cell metabolism or hemoglobin structure, or acquired by a variety of drugs and toxins. About 40 substances have been implicated in causing this condition, the most prominent being dapsone, nitrates, prilocaine, antimalarials, sulfonamids, and dyes (6,7). Apart from the potential offending agents, a search should be made for other substances of abuse, which can be co-ingested (3). Domestic causes of acquired methemoglobinemia include ingestion of food and water high in nitrites and nitrates, inhalation of room odorizers containing butyl nitrate, and exposure to aniline dyes (6,7). Dapsone has been associated with a number of overdoses in children and adults in the U.S. and overseas (1), but acute poisoning from dapsone intake is uncommon in Europe and Iran (4,8,9). However, with the increasing use of dapsone for diseases other than leprosy and dermatitis herpetiformis, clinicians should be aware of its toxic potential. Dapsone poisoning in children is usually accidental and results in not only methemoglobinemia but also in hemolysis, hepatitis, coma, seizures and metabolic acidosis (10). This report describes a case of methemoglobinemia without clear drug history. The etiology turned out to be an intentional ingestion of dapsone. In dapsone poisoning, massive and varying clinical presentations such as severe cyanosis, restlessness, dyspnea, extensive hemolysis, anemia and/or serious central nervous system dysfunction are expected. In addition, nausea and vomiting, tachycardia and elevation of blood pressure have been reported (2,4,11,12). Methemoglobinemia resulting from the ingestion of dapsone has been described as cyanosis without respiratory distress (11). The cyanosis is unresponsive to oxygen administration and it may be subtle, being confined to the nails and buccal mucosa or may be more dramatic (11). Dapsone overdose is often dangerous and potentially lethal (11). Toxicity resulting from the ingestion of 20–25 mg/kg has been reported (13). The situation is further complicated by the fact that patients receiving vigorous interventions have died (14). The standard management is that any patient including those who are asymptomatic but cyanotic should be admitted to the hospital (11) because the
Methemoglobinemia Following Attempted Suicide
development of hemolytic anemia secondary to a dapsone overdose may take up to 9 days to develop (2,11). Methemoglobin level is useful to confirm the diagnosis, but it is not as important as the patient’s clinical status for determining early treatment (11). The relatively slow absorption of dapsone from the gastrointestinal tract increases the importance of gastric emptying procedures (2,11), and in our case we performed gastric lavage with water as soon as the patient was admitted to the emergency center. The drug is believed to undergo significant enterohepatic circulation (2,11,15,16), making activated charcoal one of the mainstays of treatment (2,4,11,14,17–19). In one study, four times a day dosing resulted in a 4- to 5-fold diminution of the plasma half-life of both dapsone and its principal metabolite MADDA (2,14). Activated charcoal should be administered for at least 3 days (2), but in our case, multidose activated charcoal treatment was given only for 2 days and then discontinued because of the patient’s constipation. The decrease of hemoglobin level may also be explained by dapsone poisoning. It is well known that dapsone is responsible for hemolysis (2,4,10,11,19–24). In this case, excessive dapsone may have lead to the corresponding decrease in hemoglobin levels. Packed red blood cells transfusion may be required for symptomatic treatment of hemolytic anemia (2), and in our case we administered about ten units of cross-matched packed red blood cells to control the patient’s anemia. The hemoglobin that is released by hemolysis is metabolized in the liver. Correspondingly, bilirubin levels rise as we observed in this patient. Methylene blue is the drug of choice in the treatment of methemoglobinemia. Methylene blue (methylthioninium chloride) when given IV is rapidly reduced to leukomethylene blue by the enzyme NADPH-met-Hb reductase, which reduces the met-Hb back to Hb by a cyclic reaction so early administration of the antidote methylene blue usually leads to rapid improvement of the cyanosis (2,4,10,11). An effective dose initially is 1–2 mg/kg given IV over a 5- to 10-min period. According to the long halflife of the toxicant, which may cause rebound methemoglobinemia, repeated administration of methylene blue may be necessary (2,25). In the present case, single-dose administration of the antidote was sufficient. Known or suspected G6PD deficiency is a contraindication to the use of methylene blue. In G6PD-deficient individuals, insufficient NADPH is generated to efficiently reduce methylene blue to leukomethylene blue, which is necessary for the activation of the NADPH-dependent methemoglobin reductase system. G6PD-deficient individuals are also prone to methylene blue-induced hemolysis (7). In an earlier study, ascorbic acid was found to reduce xenobioticinduced methemoglobinemia (26). This is probably due to the increase in methemoglobin reductase activity by ascorbic acid (23); therefore, it was administered to our patient IV with a dose of 1000 mg every 12 h.
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The exchange transfusion has been reported to be very effective in the management of methemoglobinemia (27), especially in patients who cannot receive methylene blue, but was later found to be of minor benefit, probably due to large volume of distribution of dapsone (28).
Acknowledgments The authors wish to convey their full appreciation to Professor Tareg Bey, MD, FACEP, ABMT for his kind assistance in editing of this paper.
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