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Acute dapsone overdose: the effects of continuous veno-venous haemofiltration on the elimination of dapsone.

Dapsone (diamino-diphenyl sulfone, DDS) is used clinically in humans to treat several dermatological conditions, specifically those related to inflammatory diseases, autoimmune dermatoses and illnesses that involve neutrophil infiltration of the skin such as dermatitis herpetiformis and Sweet syndrome. It is also used to treat infections caused by Plasmodium spp., Mycobacterium spp. and Pneumocystis jiroveci (1). Acute DDS poisoning is potentially lethal due to severe methaemoglobinaemia and haemolytic anaemia.

CASE HISTORY

A previously healthy 15-year-old female was brought to the emergency department with a history of intentional ingestion of DDS (7.2 g) and small quantities of azathioprine, methotrexate, methylprednisolone and prednisolone. The ingested medications had been prescribed to a family member. On presentation she was centrally cyanosed, confused and agitated. She had sinus tachycardia and was tachypnoeic, normotensive and afebrile. Oxygen saturation on pulse oximetry was 89% on 15 litres/minute oxygen via a non-rebreathing mask. Arterial blood gas analysis showed oxygen saturation of 98%, pH 7.36, [P.sub.a]C[O.sub.2] 26 mmHg, [P.sub.a][O.sub.2] 123 mmHg, bicarbonate 14 mmol/l, lactate 8.5 mmol/l and methaemoglobin level 46.8%. No sulfhaemoglobin was detected. Chest X-ray and electrocardiogram were normal.

As part of her emergency care, she was intubated, ventilated and given methylene blue 150 mg intravenously in three divided doses. She also received gastric lavage and activated charcoal before being transferred to the intensive care unit. Her initial treatment in the intensive care unit included multiple-dose activated charcoal (MDAC) 25 g administered six hourly, methylene blue intravenouslyby infusion at 0.1 mg/kg/hour and ascorbic acid 1.0 g intravenously six hourly. Intravenous folinic acid 15 mg daily was also given in view of the potential methotrexate overdose.

Methaemoglobin levels initially decreased to 9.9% with the above treatment, then increased to 18.7% at 10 hours after presentation to hospital. Taking into consideration the high methaemoglobin levels, lactic acidosis and the potential to clear some of the ingested drugs, a dialysis catheter was placed and continuous veno-venous haemofiltration (CVVH) was commenced with regional citrate anticoagulation. Serial arterial blood gas analyses are shown in Table 1. She remained haemodynamically stable throughout the admission and was mechanically ventilated for five days. After commencement of CVVH the methaemoglobin concentration began to decline, as illustrated in Figure 1. The CVVH treatment period was 75 hours.

On day 2 the patient developed an ileus secondary to charcoal and MDAC had to be ceased. She developed anaem ia and reticulocytosis on day 4 consistent with haemolysis for which she received a unit of packed red blood cells. At 12 hours after admission, her blood methotrexate and 6-mercaptopurine concentrations were 0.01 [micro]mol/l and <22.1 pmol/8x[10.sup.8] red blood cells respectively. Both of these were in the non-toxic range and she did not develop features of toxicity from these two drugs. There was no demonstrable neurological deficit once the patient was extubated and she was discharged home from the intensive care unit on day 11. No residual morbidity was associated with the admission.

During the admission period, 14 blood samples were collected and allowed to clot. Serum samples were obtained by centrifugation (3000 g x 10 minutes) and samples stored at -80[degrees]C. Concentrations of DDS and its major metabolite monoacetyldapsone (MADDS) were measured by reversed-phase high-pressure liquid chromatography (2). The limit of quantification of DDS and MADDS was 10 ng/ml, using 0.5 ml of serum. The interday assay coefficients of variation (CV%) for the measurement of DDS at 10, 500 and 2000 ng/ml were 8.5%, 3.7% and 4.5% (n=9), respectively. Corresponding CV values for MADDS were 13.0%, 3.2% and 5.5%. The inaccuracy of the method at 10 ng/ml was 7.6% and 13.7% for DDS and MADDS (n=9). The mean tablet DDS content based on eight tablets of 100 mg DDS was 102.1 [+ or -] 9.6 mg.

Figure 2 shows the patient's serum DDS concentration versus time profile following comencement of CVVH. At admission the patient had serum DDS and MADDS concentrations of 59.816 [micro]g/ml and 16.041 [micro]g/ml respectively. At 73.5 hours after commencement of CVVH treatment her concentrations had declined to 0.469 [micro]g/ml for DDS and 0.121 [micro]g/ml for MADDS. At 147.5 hours post CVVH the corresponding DDS and MADDS concentrations were 0.040 [micro]g/ml and 0.020 [micro]g/ml.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Two elimination profiles of DDS were observed; elimination half-lives of 12.7 hours during CVVH and 40.9 hours during the post CVVH period. Corresponding elimination half-lives of MADDS were 12.6 hours and 48.6 hours. The elimination rate constant and elimination half-lives of DDS and MADDS were calculated using PK Solutions 2.0 (Summit Research Services, Montrose, CO, USA).

DISCUSSION

The development of methaemoglobinaemia and haemolytic anaemia are recognised adverse effects associated with DDS use. DDS is an oxidising agent which overrides the body's innate protective mechanisms and causes an abnormal proportion of iron in the haem moiety of haemoglobin to be oxidised to the ferric state ([Fe.sup.3+]). This oxidised ferric iron is unable to transport oxygen leading to reduced tissue oxygenation (3).

Dapsone is a lipid-soluble compound that penetrates well into both cells and tissues. It is well-absorbed from the gastrointestinal tract with a significant enterohepatic circulation. The elimination half-life of DDS averages between 24 and 30 hours, with significant variability ranging between 14 and 83 hours (4). Between 70% and 90% of DDS is bound to plasma protein, with a high apparent volume of distribution. DDS has been noted to remain in the circulation for as long as 35 days (4). Renal excretion of unchanged DDS is limited to approximately 20% of the administered dose (5). As a result of the prolonged absorption time and enterohepatic recirculation of DDS, methaemoglobinaemia may persist for several days following DDS ingestion. DDS possesses a very narrow therapeutic index. The therapeutic range is generally taken to be between 1.0 and 3.5 [micro]g/ml, with toxicity reported at plasma DDS concentrations above 3.5 [micro]g/ml (6,7). Some cases of sulfhaemoglobinaemia have also been described (8); this was not a feature of our patient's course.

Mainstays of treatment of DDS overdose are the provision of supplemental oxygen, administration of methylene blue, dermal decontamination, gastric lavage, MDAC and ascorbic acid which acts as an antioxidant (3). Elonen et al showed that MDAC reduces the mean elimination half-life of DDS in patients with acute DDS toxicity from 77 hours to 12.7 hours (9). Endre et al reported the successful use of charcoal haemoperfusion and sequential dialysis in a case of acute DDS overdose which controlled the progression of haemolysis and methaemoglobinaemia (10). A few studies have also suggested haemodialysis for the management of methaemoglobinaemia associated with acute dapsone poisoning. Thunga et al described the benefit of haemodialysis in a patient with acute DDS poisoning (5). Haemodialysis was used in conjunction with gastric lavage, activated charcoal, methylene blue and other supportive therapy. A case series of three patients with acute DDS intoxication demonstrated that intermittent haemodialysis corrected the resultant methaemoglobinaemia rapidly, however a subsequent rebound increase was observed. During intervening periods the mean elimination half-life of DDS increased considerably (6). Although the potential exists for 10 to 30% of unbound DDS to be dialysed, DDS is moderately distributed to tissues (2), which could limit the efficacy of intermittent dialysis. The use of continuous renal replacement therapy for the treatment of acute DDS overdose has not been reported.

In the present study, we used a combination of supplemental oxygen, administration of methylene blue, dermal decontamination, gastric lavage, MDAC and ascorbic acid as well as CVVH. MDAC was given in view of the long elimination half-life and enterohepatic circulation of DDS. However, MDAC could not be continued beyond 24 hours because the patient developed ileus. In our patient, we were concerned that haemolysis due to DDS in the presence of bone marrow depression caused by the antimetabolites (the levels of which were unavailable at the time), could be catastrophic. In a series of three patients with DDS toxicity reported by Neuvonen et al, the mean elimination half-life of DDS was 10.4 hours while the patients were on dialysis (6). Hence, we continued CVVH for 75 hours in our patient, which was well over five times the reported half-life of DDS by Neuvonen et al (6).

After CVVH was commenced, the rate of clearance of DDS was increased 3.2-fold, thus shortening its elimination half-life from 40.9 to 12.7 hours. A similar reduction in half-life was seen for MADDS (48.6 to 12.6 hours). Without CVVH, however, the overall predicted time for clearance of DDS to safe concentrations of about 1.0 [micro]g/ml would have been 225 hours after starting treatment. This was significantly shortened to 72 hours using CVVH. Treatment times for the other toxic effects of DDS were similarly reduced, particularly the time required for treatment of the resulting methaemoglobinaemia with intravenous methylene blue.

Few studies have looked at outcome following dapsone intoxication. Two cases with peak serum DDS levels of 80 [micro]g/ml and 120 [micro]g/ml have been reported with good outcomes (7,11). The first patient was treated with MDAC and plasma exchange and the second received haemodialysis and exchange transfusion. A retrospective observational study of patients presenting to a tertiary hospital in South Korea showed that late presentation to medical care and an altered mental status were predictive of death. Methaemoglobin levels tended to be higher on day 9 in non-survivors compared to survivors (94.8 [+ or -] 85.8 vs 36.4 [+ or -] 39.1 g/l) (12). Dapsone levels were however, not measured in this study. Although our patient presented early, she had altered mental status and a high methaemoglobin level 46.8% (58.5 g/l) on presentation. The methaemoglobin level reduced to 1.5% (1.17 g/l) on day nine. This reduction can be explained by the clearance of dapsone by CVVH and to a lesser extent MDAC, which could not be administered beyond 24 hours in our patient due to ileus.

Permanent retinal necrosis has been reported following massive dapsone overdose (13). Our patient recovered without any residual morbidity.

In summary, in patients with acute DDS overdose when methaemoglobinemia does not respond to initial management, CVVH provides a safe alternative management option by increasing the elimination of DDS and its principal metabolite. We suggest that CVVH can be useful in the management of acute dapsone poisoning.

ACKNOWLEDGMENTS

The authors are most grateful to Mr Bruce Arbuckle, Ms Lise Henriksen, Ms Melissa Newman and Dr Jason Roberts and for their support of the study, and to Mr Thomas Travers for his excellent technical expertise in assaying DDS and MADDS concentrations. The opinions expressed are those of the authors and do not necessarily reflect those of Australian Defence Joint Health Command or any extant Australian Defence Force policy.

REFERENCES

(1.) Barr J. A short history of dapsone or an alternative model of drug development. J Hist Med Allied Sci 2010; Epub ahead of print.

(2.) Edstein MD, Rieckmann KH, Veenendaal JR. Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man. Br J Clin Pharmacol 1990; 30:259-265.

(3.) Ferguson AJ, Lavery GG. Deliberate self-poisoning with dapsone. A case report and summary of relevant pharmacology and treatment. Anaesthesia 1997; 52:359-363.

(4.) Sago J, Hall RP. Dapsone. Dermatologic Therapy 2002; 15:340-351.

(5.) Thunga G, Sam KG, Patel D, Khera K, Sheshadhri S, Bahuleyan S et al. Effectiveness of hemodialysis in acute dapsone overdose--a case report. Am J Emerg Med 2008; 26:1070.

(6.) Neuvonen PJ, Elonen E, Haapanen EJ. Acute dapsone intoxication: clinical findings and effects of oral charcoal and haemodialysis on dapsone elimination. Acta Med Scand 1983; 214:215-220.

(7.) 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.

(8.) Whyte IM. Dapsone. In: Dart RC, ed. Medical Toxicology, 3rd ed. Lippincott: Williams & Wilkins 2004. p. 475-478.

(9.) Elonen E, Neuvonen PJ, Halmekoski J, Mattila MJ. Acute dapsone intoxication: a case with prolonged symptoms. Clin Toxicol 1979; 14:79-85.

(10.) Endre ZH, Charlesworth JA, Macdonald GJ, Woodbridge L. Successful treatment of acute dapsone intoxication using charcoal haemoperfusion. Aust N Z J Med 1983; 13:509-512.

(11.) Szajewski JM, Dorywalski T, Tomecka Z, Sabiniewicz M. Case of severe poisoning with diamino-diphenylsulfone (DDS)--an antileprotic drug. Pol Arch Med Wewn 1972; 49:181-186.

(12.) Park KH, Kim H, Lee CC, Cha KCl, Park SM, Ji HJ et al. Dapsone intoxication: clinical course and characteristics. Clin Toxicol (Phila) 2010; 48:516-521.

(13.) Kenner DJ, Holt K, Agnello R, Chester GH. Permanent retinal damage following massive dapsone overdose. Br J Ophthalmol 1980; 64:741-744.

V. A. MASURKAR *, M. D. EDSTEIN ([dagger]), C. J. GORTON ([double dagger]), C. M. ANSTEY ([section])

Department of Intensive Care Medicine, Nambour General Hospital, Nambour, Queensland, Australia

* M.B., B.S., M.D., D.N.B., F.N.B., F.C.I.C.M., Staff Specialist.

([dagger]) Ph.D., Head, Drug Evaluation, Australian Army Malaria Institute, Brisbane.

([double dagger]) M.B., B.S., Registrar.

([section]) M.B., B.S., B.Sc., M.Sc., F.A.N.Z.C.A., F.C.I.C.M., Director.

Address for correspondence: Dr V. Masurkar, Staff Specialist, Department of Intensive Care Medicine, Nambour General Hospital, PO Box 547, Nambour, Qld 4556. Email: vikram_masurkar@health.qld.gov.au

Accepted for publication on June 19, 2011.
Table 1
Arterial blood gas analyses during the admission

Hours after 0.5 0.75 1.5 3.25 7.5 10
presentation to
hospital

Blood pH 7.37 7.36 7.19 7.28 7.27 7.27
[P.sub.a]C[O.sub.2], 25 26 53 38 38 39
mmHg
[P.sub.a][O.sub.2], 111 123 339 560 469 511
mmHg
Base excess, mmol/l -10 -9.2 -8.8 -8.0 -9.1 -8.7
Serum lactate, mmol/l 7.9 8.5 4.0 4.7 5.7 8.9
Serum methaemoglobin, 46.8 3.5 12.2 15.7 18.7
%

Hours after 11 13.5 19 20 21
presentation to
hospital

Blood pH 7.27 7.29 7.30 7.31 7.32
[P.sub.a]C[O.sub.2], 37 36 33 34 34
mmHg
[P.sub.a][O.sub.2], 410 415 507 485 519
mmHg
Base excess, mmol/l -9.2 -8.6 -9.2 -8.6 -7.9
Serum lactate, mmol/l 8.7 7.9 7.9 7.2 6.9
Serum methaemoglobin, 15.5 12.5 8.2 7.3 6.7
%

Hours after 23.5 48 72 96 216
presentation to
hospital

Blood pH 7.29 7.35 7.45 7.43 7.45
[P.sub.a]C[O.sub.2], 36 49 39 38 38
mmHg
[P.sub.a][O.sub.2], 501 165 145 170 147
mmHg
Base excess, mmol/l -8.3 0.8 3.1 1.1 2.9
Serum lactate, mmol/l 6.7 1.8 0.9 0.6 0.9
Serum methaemoglobin, 5.3 7.1 6.3 5.0 1.5
%
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Author:Masurkar, V.A.; Edstein, M.D.; Gorton, C.J.; Anstey, C.M.
Publication:Anaesthesia and Intensive Care
Article Type:Case study
Date:Nov 1, 2011
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