- Email: [email protected]
Fatal complication of desmopressin
ulcerative mucosal lesions. Histological examination of the bronchii showed epithelial detachment, and culture yielded Streptococcus pneumoniae (10’ U/mL). Serological tests for Herpes simplex, Mycoplasma pneumoniae, and HIV were negative. Lamotrigine was withdrawn on day 26. Pulmonary deterioration required both intensive care and antibiotics. The patient recovered completely on day 42. Our patient presented with typical SJS 21 days after lamotrigine was started. Clinical features can include specific visceral involvement such as bronchial or gastrointestinal erosive detachment, as previously described in SJS and toxic epidermal necrolysis.1,2 Lamotrigine is a chemically novel antiepileptic drug acting by inhibiting glutamate release. The mean elimination half time is about 24 h and increases to 60-70 h when it is jointly administered with sodium valproate.’ It is licensed as add-on therapy for refractory epilepsy. Skin reactions are the most frequent adverse effect, affecting 5-10% of patients and could become more common by concomitant administration of sodium valproate. The frequency of such reactions could be diminished by starting with low doses. Despite these precautions, the risk of SJS does exist, although the exact frequency is unknown. Moreover, severe adverse drug skin reactions to lamotrigine-ie, in SJS, toxic epidermal
necrolysis, or hypersensitivity syndrome-seem unexpectedly frequent in series, even without sodium valproate association.’ Indeed, caution is always warranted, since lifethreatening cutaneous toxicity might arise in larger series.2 We thank Dr C Guelaud who provides bronchic fibroscopy and Dr J F Finet and Dr E Marinho for histological procedures.
Xavier Duval, *Olivier Chosidow, Franck Semah, Dan Lipsker, Camille Francès, Serge Herson Departments of *Internal Medicine and Neurology, Groupe Hospitalier PitiéSalpétrière, 75013 Paris, France 1
2 3 4
Chosidow O, Delchier J-C, Chaumette MT, et al. Intestinal involvement in drug-induced toxic epidermal necrolysis. Lancet 1991; 337: 928. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331: 1272-85. Brodie MJ. Lamotngine. Lancet 1992; 339: 1397-400. Anon. Lamotrigine. Drug Safety 1993; 19: 3.
SIR-Lamotrigine might be as effective as carbamazepine in maintaining epileptic patients free of seizures and it is well tolerated by most users, as Brodie and colleagues claim, but in predisposed patients a serious side-effect might arise. In May, 1994, a 32-year-old mentally disabled, epileptic man was admitted because of progressive weakness and loss of appetite. He presented with tachycardia and microcytic anaemia (Hb 2-8 g/dL; mean cell volume 64 fL), 0% reticulocytes, and normal leucocyte and thrombocyte counts. Gastrointestinal bleeding was excluded. Serum iron (266 fJLg/dL) and ferritine (1100 ng/mL) concentrations were substantially increased although iron treatment had not been given. We had diagnosed heterozygous (3-thalassaemia in the patient’s mother 2 years earlier. We found out that the patient’s laboratory values had shown microcytic anaemia with haemoglobin values around 11 g/dL, which were stable between, 1987, and February, 1994. Between February and May, 1994, severe anaemia had developed. A bone-marrow aspirate showed that erythropoiesis had virtually vanished, with erythropoietic cells accounting for less than 0-5% of all haemopoietic cells. Granulopoiesis and thrombopoiesis were normal. Acquired pure red-cell aplasia (PRCA) was diagnosed. PRCA is known to occur in patients with haemolytic disorders such as haemoglobinopathies. It can also be triggered by several neoplasms, infectious agents, 1302
rheumatic disease, and pregnancy. In our patient we found no evidence of lymphoma, thymoma, or of systemic lupus erythematosis, and we ruled out viral disease, especially infection with parvovirus B19. Vitamins B6 and B12 and folic acid were within normal ranges. Serum erythropoietin was greatly increased (2300 mU/mL, normal
drugs,
10-37). The patient’s drug history showed that after a long phase without any change of drugs, lamotrigine had been substituted for sodium valproate in increasing doses up to 100 mg twice daily from Feb 10, 1994, onwards because of an increased frequency of seizures. Carbamazepine was continued. He received no other drugs. On May 9, 1994, we stopped lamotrigine, continued with carbamazepine, and added sodium valproate. Four units of packed red cells were transfused. On May 17, 1994, reticulocytes were detected for the first time (0-3%). No further transfusions were required. During follow-up, the patient recovered (June 29: Hb 11 -0 g/dL, reticulocytes 2-1%), and he remained seizurefree. Heterozygous j3-thalassaemia was confirmed. Lamotrigine is a weak inhibitor of dihydrofolatereductase, which catalyses the reduction of folate to dihydrofolate and of dihydrofolate to tetrahydrofolate.’ Only the latter molecule works as a coenzyme in purine synthesis. We conclude that lamotrigine completely inhibited erythropoiesis by interfering with folate metabolism in a patient whose haemopoiesis was permanently compromised by heterozygous &bgr;-thalassaemia. We therefore do not recommend the use of lamotrigine in patients with thalassaemia. Special care must be taken when any haemolytic disorder is present, even if it is well compensated under normal circumstances. *C Haedicke, B
Angrick,
C Hauswaldt
Medizinische Klinik, Stadtisches Klinikum, D-38114 Braunschweig,
1
Babior BM. In: Williams WJ. McGraw-Hill, 1990.
Fatal
Germany.
Hematology, 4th ed. New York:
complication of desmopressin
SIR-Desmopressin, a synthetic derivative of vasopressin, stimulates both coagulation and fibrinolysis, increasing plasma levels of factor VIII (FVIII), von Willebrand factor, and tissue plasminogen activator. This drug has become the of choice in von Willebrand’s disease type 1 and haemophilia A, and it has gained widespread use in the prevention and control of bleeding disorders due to platelet treatment
mild
dysfunction. Desmopressin is considered to be a harmless drug. Common side-effects are mild, including facial flush, headache of a migraine type, tachycardia, and slight hypotension, resulting from vasodilation and water retention. No special precautions are recommended. However, serious side-effects have been reported, notably thrombosis of coronary or cerebral arteries,I,2 and in our view the risks have not been adequately appreciated.3 In a 40-year-old man presenting with abnormal bleeding after a hip replacement for coxarthrosis, mild haemophilia A was detected (FVIII 20%, von Willebrand factor borderline low at 55%). The other major coagulation factors were normal; von Willebrand’s disease type Normandie was excluded. He had a history of abdominal surgery for a liver abscess (possibly amoebiasis) 20 years ago, apparently without bleeding complication.5 The patient was a smoker. He had no signs of cardiopulmonary disease but was physically disabled by his hip condition. We used desmopressin (Minirin, Ferring) prophylactically before the second planned surgical procedure. We used a
dose (0-4 µg/kg) followed by a total of 34-4 g in 80 mL saline 0’9% intravenously over 35 min. Blood pressure was 155/100 mm Hg; no hypertension had been reported previously. 20 min into the infusion the patient suddenly became restless and complained of malaise and dyspnoea. There were no definite signs of a cardiac complication. The infusion was stopped immediately. Within 5 min he lost consciousness in an epileptic seizure followed by apnoea and arrest. cardiac Cardiopulmonary resuscitation was unsuccessful. Necropsy revealed an acute myocardial infarction with a fresh platelet thrombus in the left coronary artery plus several atheromatous stenoses (with apparent recanalisation after complete occlusion of the right coronary test
artery). Hardly
any thrombotic events after
of desmopressin have been reported. In this patient a causal relation is not proven but is probable. It seems that neither close clinical surveillance nor exclusion of patients at known risk provide sufficient safety. Desmopressin use should be restricted, primarily in the treatment of mild haemophilia A. Now that recombinant FVIII is available the benefits of desmopressin do not outweigh the risks. use
*Serena Hartmann, Walter Reinhart Haemophilia Centre, Medizinische Klinik, Kantonsspital, 7000 Chur, Switzerland
1 Mannucci PM, Lusher JM. Desmopressin and thrombosis. Lancet 2 3
1989; ii: 675. Dantzig JM, Düren DR, Ten Cate JW. Desmopressin and myocardial infarction. Lancet 1989; i: 664-65. Lusher JM. Myocardial infarction and stroke: is the risk increased by
van
Desmopressin? In:
Mariani G, ed. Desmopressin in bleeding disorders. New York: Plenum Press, 1993: 347-53.
Treatment of malnutrition SIR-Ashworth (March 25, p 787) claims that Khanum and colleagues (Dec 25/31, p 1728) were misreported in my letter (March 25, p 787), that I have misunderstood a figure, and that I err in terminology and references. The essence of my argument was that the children studied were an extreme group both in terms of anthropometry and recent morbidity, and that following them from 3 SDs below expected weightfor-height to 2 SDs below was insufficient to establish that the change was under the control of the treatments. At this
distance from the mean, well-attested artifactual regression effects are likely to be a potent influence. Ashworth says that Khanum and colleagues did not infer that the malnourished children had recovered when they reached 80% weight-for-height (approx 2 SDs below expected median), but merely took this as the point when treatment had ceased. But Khanum also links "speed of recovery" and "identification of the most cost-effective approach for nutritional rehabilitation" as being of importance to "decision makers in developing countries and to aid agencies". My fear was that readers could well be attracted by the cost-cutting without seeing the validity difficulty. Also, attention is drawn away from the valuable aspects of Khanum’s work. Not only at the Dhaka unit, but in many parts of the world the need is daunting, and resources are abysmally scarce and circumstances will vary greatly. There is thus a continuing need for studies that in various provide information for practitioners and for rather than circumstances, training, unsupportable claims of generalisability when the research context does not allow implementation of the necessary design requirements. Chopra and Wilkinson’s findings (March 25, p 788) foreshadow the type of reports that are needed. I clearly state that the recommended 100% weight-forheight criterion would be qualified by local circumstance
and the National Center for Health Statistics sample. Even so, my point was not about what should be done at the unit concerned, which is hardly for me to judge, but what was needed for valid research results. Nowhere in my letter do I refer to weight-for-age, but rather to weight-for-height, and my references are to this. For very young children weightfor-height is not independent of age, and there is an age discrepancy when one transfers from percentage units (used by Khanum) to the recommended SD units.’ For this reason I have referred to an expected value for age on the measure used by Khanum-percentage median weight-for-heightwhen equating it with the more meaningful SD units to evaluate the likelihood of a regression to mean effect. Finally I am aware that in Khanum’s figure 100% means that all three groups had reached 80%. It is the differences in changes of slope which suggest that the rate of improvement for the home-care group was approaching an asymptote (consistent with regression to mean), but not so for the hospital group. This finding suggests a pattern of velocity differences similar to those we reported,2,3 and that a successful treatment was changed in full flight for unavoidable reasons, as Ashworth has explained. One would then expect the children in all 3 groups to improve at similar rates during follow-up, and to move towards local expected values, and this is what Ashwell reports in her letter although not in the full report. This subsequent progression does not elucidate the early confounding of natural regression and treatment effects. Setting a higher criterion for recovery4 (in the study not in the unit at large) would have been but one possible ethical line of action because the balance of regression and treatment effect would move in the direction of the treatment effect as the groups became less extreme. Always, what can be done to aid validity and interpretation has to be judged in the context of the prevailing situation and circumstance, but the issues do need to be taken into account at design level if research findings in these difficult but important areas are to be taken seriously. W N Schofield Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, UK 1 2
3
Shann F. Nutritional indices: Z, centile, or percent median. Lancet 1993; 341: 526-27. Heikens GT, Schofield WN, Dawson S. The Kingston ProJect II. The effects of high energy supplement and metronidazole on malnourished children rehabilitated in the community: anthropometry. Eur J Clin Nutr 1992; 47: 160-73. Heikens GT, Schofield WN, Dawson SM, Waterlow JC. Long-stay versus short-stay hospital treatment of children suffering from severe protein-energy malnutrition. Eur J Clin Nutr 1994; 48: 873-82.
Co-trimoxazole for cyclospora infection and colleagues’ report (March 18, p 691) and Soave and Johnson’s commentary (p 667) on cyclospora show that this parasite, which can cause longlasting diarrhoea, is eminently treatable with oral co-trimoxazole. Your commentators point out that cyclosporiasis was recognised in Nepal at a time when co-trimoxazole was being replaced by quinolones for the treatment of bacterial enteritis. They call for epidemiological studies, particularly in young people, to document the morbidity and mortality of this infection. Chronic diarrhoea accounts for two-thirds of diarrhoearelated deaths and a third of all deaths in Bangladeshi children under 5 years old. Another Nepali study’ done in the late 1980s corroborates the suggestion that cyclospora is an important pathogen in children. Pandey and colleagues2 showed that the community-based use of co-trimoxazole by village health workers, for treatment of pneumonia, could
SIR-Hoge
1303
necrolysis, or hypersensitivity syndrome-seem unexpectedly frequent in series, even without sodium valproate association.’ Indeed, caution is always warranted, since lifethreatening cutaneous toxicity might arise in larger series.2 We thank Dr C Guelaud who provides bronchic fibroscopy and Dr J F Finet and Dr E Marinho for histological procedures.
Xavier Duval, *Olivier Chosidow, Franck Semah, Dan Lipsker, Camille Francès, Serge Herson Departments of *Internal Medicine and Neurology, Groupe Hospitalier PitiéSalpétrière, 75013 Paris, France 1
2 3 4
Chosidow O, Delchier J-C, Chaumette MT, et al. Intestinal involvement in drug-induced toxic epidermal necrolysis. Lancet 1991; 337: 928. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331: 1272-85. Brodie MJ. Lamotngine. Lancet 1992; 339: 1397-400. Anon. Lamotrigine. Drug Safety 1993; 19: 3.
SIR-Lamotrigine might be as effective as carbamazepine in maintaining epileptic patients free of seizures and it is well tolerated by most users, as Brodie and colleagues claim, but in predisposed patients a serious side-effect might arise. In May, 1994, a 32-year-old mentally disabled, epileptic man was admitted because of progressive weakness and loss of appetite. He presented with tachycardia and microcytic anaemia (Hb 2-8 g/dL; mean cell volume 64 fL), 0% reticulocytes, and normal leucocyte and thrombocyte counts. Gastrointestinal bleeding was excluded. Serum iron (266 fJLg/dL) and ferritine (1100 ng/mL) concentrations were substantially increased although iron treatment had not been given. We had diagnosed heterozygous (3-thalassaemia in the patient’s mother 2 years earlier. We found out that the patient’s laboratory values had shown microcytic anaemia with haemoglobin values around 11 g/dL, which were stable between, 1987, and February, 1994. Between February and May, 1994, severe anaemia had developed. A bone-marrow aspirate showed that erythropoiesis had virtually vanished, with erythropoietic cells accounting for less than 0-5% of all haemopoietic cells. Granulopoiesis and thrombopoiesis were normal. Acquired pure red-cell aplasia (PRCA) was diagnosed. PRCA is known to occur in patients with haemolytic disorders such as haemoglobinopathies. It can also be triggered by several neoplasms, infectious agents, 1302
rheumatic disease, and pregnancy. In our patient we found no evidence of lymphoma, thymoma, or of systemic lupus erythematosis, and we ruled out viral disease, especially infection with parvovirus B19. Vitamins B6 and B12 and folic acid were within normal ranges. Serum erythropoietin was greatly increased (2300 mU/mL, normal
drugs,
10-37). The patient’s drug history showed that after a long phase without any change of drugs, lamotrigine had been substituted for sodium valproate in increasing doses up to 100 mg twice daily from Feb 10, 1994, onwards because of an increased frequency of seizures. Carbamazepine was continued. He received no other drugs. On May 9, 1994, we stopped lamotrigine, continued with carbamazepine, and added sodium valproate. Four units of packed red cells were transfused. On May 17, 1994, reticulocytes were detected for the first time (0-3%). No further transfusions were required. During follow-up, the patient recovered (June 29: Hb 11 -0 g/dL, reticulocytes 2-1%), and he remained seizurefree. Heterozygous j3-thalassaemia was confirmed. Lamotrigine is a weak inhibitor of dihydrofolatereductase, which catalyses the reduction of folate to dihydrofolate and of dihydrofolate to tetrahydrofolate.’ Only the latter molecule works as a coenzyme in purine synthesis. We conclude that lamotrigine completely inhibited erythropoiesis by interfering with folate metabolism in a patient whose haemopoiesis was permanently compromised by heterozygous &bgr;-thalassaemia. We therefore do not recommend the use of lamotrigine in patients with thalassaemia. Special care must be taken when any haemolytic disorder is present, even if it is well compensated under normal circumstances. *C Haedicke, B
Angrick,
C Hauswaldt
Medizinische Klinik, Stadtisches Klinikum, D-38114 Braunschweig,
1
Babior BM. In: Williams WJ. McGraw-Hill, 1990.
Fatal
Germany.
Hematology, 4th ed. New York:
complication of desmopressin
SIR-Desmopressin, a synthetic derivative of vasopressin, stimulates both coagulation and fibrinolysis, increasing plasma levels of factor VIII (FVIII), von Willebrand factor, and tissue plasminogen activator. This drug has become the of choice in von Willebrand’s disease type 1 and haemophilia A, and it has gained widespread use in the prevention and control of bleeding disorders due to platelet treatment
mild
dysfunction. Desmopressin is considered to be a harmless drug. Common side-effects are mild, including facial flush, headache of a migraine type, tachycardia, and slight hypotension, resulting from vasodilation and water retention. No special precautions are recommended. However, serious side-effects have been reported, notably thrombosis of coronary or cerebral arteries,I,2 and in our view the risks have not been adequately appreciated.3 In a 40-year-old man presenting with abnormal bleeding after a hip replacement for coxarthrosis, mild haemophilia A was detected (FVIII 20%, von Willebrand factor borderline low at 55%). The other major coagulation factors were normal; von Willebrand’s disease type Normandie was excluded. He had a history of abdominal surgery for a liver abscess (possibly amoebiasis) 20 years ago, apparently without bleeding complication.5 The patient was a smoker. He had no signs of cardiopulmonary disease but was physically disabled by his hip condition. We used desmopressin (Minirin, Ferring) prophylactically before the second planned surgical procedure. We used a
dose (0-4 µg/kg) followed by a total of 34-4 g in 80 mL saline 0’9% intravenously over 35 min. Blood pressure was 155/100 mm Hg; no hypertension had been reported previously. 20 min into the infusion the patient suddenly became restless and complained of malaise and dyspnoea. There were no definite signs of a cardiac complication. The infusion was stopped immediately. Within 5 min he lost consciousness in an epileptic seizure followed by apnoea and arrest. cardiac Cardiopulmonary resuscitation was unsuccessful. Necropsy revealed an acute myocardial infarction with a fresh platelet thrombus in the left coronary artery plus several atheromatous stenoses (with apparent recanalisation after complete occlusion of the right coronary test
artery). Hardly
any thrombotic events after
of desmopressin have been reported. In this patient a causal relation is not proven but is probable. It seems that neither close clinical surveillance nor exclusion of patients at known risk provide sufficient safety. Desmopressin use should be restricted, primarily in the treatment of mild haemophilia A. Now that recombinant FVIII is available the benefits of desmopressin do not outweigh the risks. use
*Serena Hartmann, Walter Reinhart Haemophilia Centre, Medizinische Klinik, Kantonsspital, 7000 Chur, Switzerland
1 Mannucci PM, Lusher JM. Desmopressin and thrombosis. Lancet 2 3
1989; ii: 675. Dantzig JM, Düren DR, Ten Cate JW. Desmopressin and myocardial infarction. Lancet 1989; i: 664-65. Lusher JM. Myocardial infarction and stroke: is the risk increased by
van
Desmopressin? In:
Mariani G, ed. Desmopressin in bleeding disorders. New York: Plenum Press, 1993: 347-53.
Treatment of malnutrition SIR-Ashworth (March 25, p 787) claims that Khanum and colleagues (Dec 25/31, p 1728) were misreported in my letter (March 25, p 787), that I have misunderstood a figure, and that I err in terminology and references. The essence of my argument was that the children studied were an extreme group both in terms of anthropometry and recent morbidity, and that following them from 3 SDs below expected weightfor-height to 2 SDs below was insufficient to establish that the change was under the control of the treatments. At this
distance from the mean, well-attested artifactual regression effects are likely to be a potent influence. Ashworth says that Khanum and colleagues did not infer that the malnourished children had recovered when they reached 80% weight-for-height (approx 2 SDs below expected median), but merely took this as the point when treatment had ceased. But Khanum also links "speed of recovery" and "identification of the most cost-effective approach for nutritional rehabilitation" as being of importance to "decision makers in developing countries and to aid agencies". My fear was that readers could well be attracted by the cost-cutting without seeing the validity difficulty. Also, attention is drawn away from the valuable aspects of Khanum’s work. Not only at the Dhaka unit, but in many parts of the world the need is daunting, and resources are abysmally scarce and circumstances will vary greatly. There is thus a continuing need for studies that in various provide information for practitioners and for rather than circumstances, training, unsupportable claims of generalisability when the research context does not allow implementation of the necessary design requirements. Chopra and Wilkinson’s findings (March 25, p 788) foreshadow the type of reports that are needed. I clearly state that the recommended 100% weight-forheight criterion would be qualified by local circumstance
and the National Center for Health Statistics sample. Even so, my point was not about what should be done at the unit concerned, which is hardly for me to judge, but what was needed for valid research results. Nowhere in my letter do I refer to weight-for-age, but rather to weight-for-height, and my references are to this. For very young children weightfor-height is not independent of age, and there is an age discrepancy when one transfers from percentage units (used by Khanum) to the recommended SD units.’ For this reason I have referred to an expected value for age on the measure used by Khanum-percentage median weight-for-heightwhen equating it with the more meaningful SD units to evaluate the likelihood of a regression to mean effect. Finally I am aware that in Khanum’s figure 100% means that all three groups had reached 80%. It is the differences in changes of slope which suggest that the rate of improvement for the home-care group was approaching an asymptote (consistent with regression to mean), but not so for the hospital group. This finding suggests a pattern of velocity differences similar to those we reported,2,3 and that a successful treatment was changed in full flight for unavoidable reasons, as Ashworth has explained. One would then expect the children in all 3 groups to improve at similar rates during follow-up, and to move towards local expected values, and this is what Ashwell reports in her letter although not in the full report. This subsequent progression does not elucidate the early confounding of natural regression and treatment effects. Setting a higher criterion for recovery4 (in the study not in the unit at large) would have been but one possible ethical line of action because the balance of regression and treatment effect would move in the direction of the treatment effect as the groups became less extreme. Always, what can be done to aid validity and interpretation has to be judged in the context of the prevailing situation and circumstance, but the issues do need to be taken into account at design level if research findings in these difficult but important areas are to be taken seriously. W N Schofield Department of Experimental Psychology, University of Cambridge, Cambridge CB2 3EB, UK 1 2
3
Shann F. Nutritional indices: Z, centile, or percent median. Lancet 1993; 341: 526-27. Heikens GT, Schofield WN, Dawson S. The Kingston ProJect II. The effects of high energy supplement and metronidazole on malnourished children rehabilitated in the community: anthropometry. Eur J Clin Nutr 1992; 47: 160-73. Heikens GT, Schofield WN, Dawson SM, Waterlow JC. Long-stay versus short-stay hospital treatment of children suffering from severe protein-energy malnutrition. Eur J Clin Nutr 1994; 48: 873-82.
Co-trimoxazole for cyclospora infection and colleagues’ report (March 18, p 691) and Soave and Johnson’s commentary (p 667) on cyclospora show that this parasite, which can cause longlasting diarrhoea, is eminently treatable with oral co-trimoxazole. Your commentators point out that cyclosporiasis was recognised in Nepal at a time when co-trimoxazole was being replaced by quinolones for the treatment of bacterial enteritis. They call for epidemiological studies, particularly in young people, to document the morbidity and mortality of this infection. Chronic diarrhoea accounts for two-thirds of diarrhoearelated deaths and a third of all deaths in Bangladeshi children under 5 years old. Another Nepali study’ done in the late 1980s corroborates the suggestion that cyclospora is an important pathogen in children. Pandey and colleagues2 showed that the community-based use of co-trimoxazole by village health workers, for treatment of pneumonia, could
SIR-Hoge
1303