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Chronic salicylate poisoning and severe malaria
Chronic Michael
salicylate poisoning and
English,
Victoria Marsh, Evans
Background Salicylates continue to be marketed and to be used in developing countries as over-the-counter (OTC) antipyretics in children, whereas in developed countries they are no longer used in children because of safety concerns. The presenting signs of salicylate poisoning, especially chronic (repeated administration of therapeutic or excessive doses for longer than 12 h), can include metabolic acidosis, hypoglycaemia, lethargy, and coma and fits. These signs are also common in severe malaria in African children. Admission of two probable cases of chronic salicylate poisoning prompted us to look for other cases among children presenting to our hospital in Kenya, apparently with severe malaria. Methods All children admitted to Kilifi District Hospital between July and September, 1994, who had a positive blood film for Plasmodium falciparum, and one or more of coma, prostration, or respiratory distress were eligible. As well as routine tests for malaria and routine biochemistry, salicylate concentrations were measured. Management of children (aged 6 months to 10 years) in the community was assessed by a cross-sectional survey of 463 households and by interviews with mothers 2 days after they had bought OTC drugs for a child with fever.
Findings Data were available for 143 of 154 children with initial primary diagnoses of severe malaria. 129 (90%) had detectable (>1 mg/dL) salicylate. Six of these had concentrations of 20 mg/dL or higher. All six had salicylate neurological impairment and metabolic acidosis and four were, or became, hypoglycaemic. OTC drugs were the firstline treatment in 188 (74%) of 254 fever episodes during the 2 weeks before the cross-sectional survey. Of 250 mothers who bought drugs for a febrile child, 236 (94%) bought a preparation containing salicylates and 50 (21%) gave a dose higher than the manufacturer’s recommended
maximum.
Interpretation These cases suggest that in some children salicylate poisoning may cause or contribute to the development of metabolic acidosis and hypoglycaemia, complications of severe malaria associated with high mortality.
Clinical Research Centre, Kenya Medical Research Institute, Kilifi Unit, Kilifi, Kenya (M English MRCP, V Marsh MRCGP, E Amukoye MMed, B Lowe BSc, S Murphy MRCP, K Marsh MRCP), and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK (M English, B Lowe, S Murphy, K Marsh)
Correspondence to: Dr Michael English, Molecular Parasitology Group, Institute of Molecular Medicine, John Radcliffe Hospital,
1736
malaria
Amukoye, Brett Lowe, Steven Murphy, Kevin Marsh
Summary
Oxford OX3 9DU, UK
severe
Introduction
Coma, respiratory distress, and hypoglycaemia are the most serious presenting signs of severe malaria in African children.’ Respiratory distress is closely associated with the presence of acidosis, an important indicator of poor prognosis.2 Metabolic acidosis, hypoglycaemia, lethargy, and fits in
cases, are also all features of children.3 Chronic salicylate salicylate poisoning poisoning (the repeated administration of therapeutic or excessive doses of salicylates for a period longer than 12 h4) is associated with more severe symptoms than acute intoxication, particularly the development of acidosis and disturbances of the central nervous system.4 However, plasma salicylate concentrations, useful in acute intoxication, are of limited clinical value after repeated salicylate administration, since the area under the concentration/time curve cannot be estimated from a single blood concentration. The diagnosis therefore relies largely on the presence of characteristic clinical features with accompanying biochemical evidence of ingestion.3,5 The admission of two probable cases of chronic salicylate poisoning prompted us to look in more detail for evidence of this disorder in Kenyan children with severe malaria.
and
coma
severe
in
Patients and methods Case reports Index case 1 A 19-month-old girl presented with a 3-day history of fever, vomiting, and dyspnoea. Although she was fully conscious, the initial diagnosis was severe malaria because of clinical respiratory distress. Auscultation of the chest was normal but the child was mildly dehydrated. Admission salicylate concentration was 48 mg/dL. The acidosis resolved over 16 h with administration of intravenous fluids and the child was discharged well. 2 An 11-month-old boy presented with a fever and cough days’ duration and vomiting of 1 day’s duration. He had respiratory distress and was comatose. Plasma salicylate concentration rose from 27 mg/dL on admission to 42 mg/dL at 24 h. Alkali infusion was started and the child regained consciousness 24 h later; he was discharged well after 5 days.
Index
case
of 3
Methods All children admitted to Kilifi District Hospital between July and September, 1994, who had a positive blood film for Plasmodium falciparum and who had one or more of coma, prostration, or respiratory distress’ were eligible for the study. A full clinical history was taken and details of examination recorded, and blood was taken for thick and thin blood films for malaria parasites, blood culture, and measurement of haemoglobin, electrolytes, urea, creatinine, venous blood gases, and glucose. Salicylate concentrations were measured by a spectrophometric assay based on the reaction between salicylates and ferric chloride/mercuric chlorideb with commercial controls (CIBA-Corning, UK). Lumbar puncture was done on all children admitted in coma and was normal in all cases. All were treated with intravenous quinine or intramuscular artemether and given supportive treatment.’ The management of febrile children (6 months to 10 years) in the community was assessed during two community surveys in the Chonyi location of Kilifi District during January, 1996-a
tSubsequently developed recurrent hypoglycaemia and died after developing widespread chest crackles with hypoxaemia. Table: Admission clinical and laboratory data for index cases and probable cases of chronic salicylate *Index
cases.
cross-sectional survey of 463 households, and interviews with mothers 2 days after they had purchased over-the-counter (OTC) drugs from local shops for a child with fever.
Results Data were available for 143 (93%) of 154 children admitted with an initial primary diagnosis of severe malaria. 129 (90%) children had detectable salicylate in plasma (>1 I mg/dL). Of these, six had salicylate concentrations of 20 mg/dL or higher; this value, in the presence of characteristic clinical features, has been used as an indication of intoxication in American children receiving aspirin for a range of acute, febrile illnesses.4 Clinical details and admission laboratory data for these children and the index cases are summarised in the table. In all cases deep breathing (Kussmaul’s respiration) was present on admission. All but one child (case 4) had a definite history of therapeutic aspirin use. Hypoglycaemia was present in three children on admission and developed subsequently in a fourth child. All six children had metabolic acidosis. OTC drugs were the first-line treatment in 188 (74%) of 254 fever episodes during the 2 weeks before the crosssectional survey. Such treatment was continued at home for a mean of 2-5 days (range 0-12 days) in children subsequently taken to a health centre (24%). Of the 250 mothers who bought drugs for a febrile child 236 (94%) purchased an OTC drug containing a salicylate preparation and 50 (21%) administered a dose exceeding the maximum recommended dose daily by manufacturers. 67 (27%) of children were given more than one salicylate preparation; of these children, 35 (52%) received a dose higher than the recommended maximum.
poisoning
that
salicylate poisoning contributed to her death. The also highlights the difficulties of accurately finding out the dose ingested by a child in a rural African population. All the evidence, however, suggests that salicylates are used on a massive scale. In Malawi, nearly 70% of parents treat their children with an antipyretic, usually aspirin based, at the first sign of fever.8 In the Kilifi District of Kenya, home treatment of a febrile child resulted in salicylate administration in 94% of cases. In 21% the dose was inappropriately high, often as a result of treatment with several salicylate-containing preparations or the use of adult preparations. The measurement of salicylate concentrations is rarely possible in African hospitals, but the mainstays of supportive treatment are the same as those for severe malaria-administration of glucose for hypoglycaemia and adequate fluid resuscitation in acidotic children. Further, case
detailed studies are needed to elucidate the true of salicylate poisoning in African children with and without malaria. Given the massive scale of aspirin use, even rare complications could be important causes of preventable morbidity and mortality. The possibilities that salicylate intoxication is more likely in children with malaria and that it serves as a co-factor in the pathogenesis of hypoglycaemia deserve particular attention. As has been shown in developed countries, the use of salicylates as antipyretics in children may expose them to unnecessary risk. more
extent
This study is published with the permission of the Director of the Kenya Medical Research Institute (KEMRI) and was supported by KEMRI and the Wellcome Trust (040313). We thank Peter Winstanley for help and advice. VM is supported by grants from Overseas Development Agency, UK, and Tropical Diseases Research, WHO, and KM is a Wellcome Trust senior research fellow in clinical science (031342).
Discussion
References
All of the children with high salicylate concentrations presented with well-described complications of severe malaria 1,2 but also met clinical criteria for moderate or severe chronic salicylate intoxication. 3,4 How much salicylate is required, over what period, to cause chronic salicylate poisoning is not known. Although daily doses as low as 32 mg/kg have been associated with this complicationTemple estimated that a daily dose of 100 mg/kg for at least 2 days is needed. The parents of the child who died (case 7, table) reported giving, among other medications, at least four adult aspirin tablets over the previous 2 days (a total minimum dose of 50-100 mg/kg). This child died after developing clinical pulmonary oedema, which is known to be a complication of aspirin intoxication9 but is rare in African children with severe malaria.’ This complication increases the likelihood
Marsh K, Forster D, Waruiru C, et al. Life threatening malaria in African children: clinical spectrum and simplified prognostic criteria. N Engl J Med 1995; 332: 1399-404. 2 Taylor T, Borgstein A, Molyneux M. Acid base status in paediatric Plasmodium falciparum malaria. Q J Med 1993; 86: 99-109. 3 Snodgrass W. Salicylate toxicity. Pediatr Clin N Am 1986; 33: 381-91. 4 Gaudreault P, Temple A, Lovejoy F. The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison. Pediatrics 1982; 70: 566-69. 5 Temple A. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981; 141: 364-69. 6 Trinder P. Rapid determination of salicylate in biological fluids. Biochem J 1954; 57: 301-03. 7 English M, Waruiru C, Lightowler C, et al. Hyponatraemia and dehydration in severe malaria. Arch Dis Child 1996; 74: 201-05. 8 Slutsker L, Chitsulo L, Macheso A, Steketee R. Treatment of malaria fever episodes among children in Malawi: results of a KAP survey. Trop Med Parasitol 1994; 45: 61-64. 9 Fisher C, Albertson T, Foulke G. Salicylate-induced pulmonary edema. Am J Emerg Med 1985; 3: 33-37. 1
1737
salicylate poisoning and
English,
Victoria Marsh, Evans
Background Salicylates continue to be marketed and to be used in developing countries as over-the-counter (OTC) antipyretics in children, whereas in developed countries they are no longer used in children because of safety concerns. The presenting signs of salicylate poisoning, especially chronic (repeated administration of therapeutic or excessive doses for longer than 12 h), can include metabolic acidosis, hypoglycaemia, lethargy, and coma and fits. These signs are also common in severe malaria in African children. Admission of two probable cases of chronic salicylate poisoning prompted us to look for other cases among children presenting to our hospital in Kenya, apparently with severe malaria. Methods All children admitted to Kilifi District Hospital between July and September, 1994, who had a positive blood film for Plasmodium falciparum, and one or more of coma, prostration, or respiratory distress were eligible. As well as routine tests for malaria and routine biochemistry, salicylate concentrations were measured. Management of children (aged 6 months to 10 years) in the community was assessed by a cross-sectional survey of 463 households and by interviews with mothers 2 days after they had bought OTC drugs for a child with fever.
Findings Data were available for 143 of 154 children with initial primary diagnoses of severe malaria. 129 (90%) had detectable (>1 mg/dL) salicylate. Six of these had concentrations of 20 mg/dL or higher. All six had salicylate neurological impairment and metabolic acidosis and four were, or became, hypoglycaemic. OTC drugs were the firstline treatment in 188 (74%) of 254 fever episodes during the 2 weeks before the cross-sectional survey. Of 250 mothers who bought drugs for a febrile child, 236 (94%) bought a preparation containing salicylates and 50 (21%) gave a dose higher than the manufacturer’s recommended
maximum.
Interpretation These cases suggest that in some children salicylate poisoning may cause or contribute to the development of metabolic acidosis and hypoglycaemia, complications of severe malaria associated with high mortality.
Clinical Research Centre, Kenya Medical Research Institute, Kilifi Unit, Kilifi, Kenya (M English MRCP, V Marsh MRCGP, E Amukoye MMed, B Lowe BSc, S Murphy MRCP, K Marsh MRCP), and Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK (M English, B Lowe, S Murphy, K Marsh)
Correspondence to: Dr Michael English, Molecular Parasitology Group, Institute of Molecular Medicine, John Radcliffe Hospital,
1736
malaria
Amukoye, Brett Lowe, Steven Murphy, Kevin Marsh
Summary
Oxford OX3 9DU, UK
severe
Introduction
Coma, respiratory distress, and hypoglycaemia are the most serious presenting signs of severe malaria in African children.’ Respiratory distress is closely associated with the presence of acidosis, an important indicator of poor prognosis.2 Metabolic acidosis, hypoglycaemia, lethargy, and fits in
cases, are also all features of children.3 Chronic salicylate salicylate poisoning poisoning (the repeated administration of therapeutic or excessive doses of salicylates for a period longer than 12 h4) is associated with more severe symptoms than acute intoxication, particularly the development of acidosis and disturbances of the central nervous system.4 However, plasma salicylate concentrations, useful in acute intoxication, are of limited clinical value after repeated salicylate administration, since the area under the concentration/time curve cannot be estimated from a single blood concentration. The diagnosis therefore relies largely on the presence of characteristic clinical features with accompanying biochemical evidence of ingestion.3,5 The admission of two probable cases of chronic salicylate poisoning prompted us to look in more detail for evidence of this disorder in Kenyan children with severe malaria.
and
coma
severe
in
Patients and methods Case reports Index case 1 A 19-month-old girl presented with a 3-day history of fever, vomiting, and dyspnoea. Although she was fully conscious, the initial diagnosis was severe malaria because of clinical respiratory distress. Auscultation of the chest was normal but the child was mildly dehydrated. Admission salicylate concentration was 48 mg/dL. The acidosis resolved over 16 h with administration of intravenous fluids and the child was discharged well. 2 An 11-month-old boy presented with a fever and cough days’ duration and vomiting of 1 day’s duration. He had respiratory distress and was comatose. Plasma salicylate concentration rose from 27 mg/dL on admission to 42 mg/dL at 24 h. Alkali infusion was started and the child regained consciousness 24 h later; he was discharged well after 5 days.
Index
case
of 3
Methods All children admitted to Kilifi District Hospital between July and September, 1994, who had a positive blood film for Plasmodium falciparum and who had one or more of coma, prostration, or respiratory distress’ were eligible for the study. A full clinical history was taken and details of examination recorded, and blood was taken for thick and thin blood films for malaria parasites, blood culture, and measurement of haemoglobin, electrolytes, urea, creatinine, venous blood gases, and glucose. Salicylate concentrations were measured by a spectrophometric assay based on the reaction between salicylates and ferric chloride/mercuric chlorideb with commercial controls (CIBA-Corning, UK). Lumbar puncture was done on all children admitted in coma and was normal in all cases. All were treated with intravenous quinine or intramuscular artemether and given supportive treatment.’ The management of febrile children (6 months to 10 years) in the community was assessed during two community surveys in the Chonyi location of Kilifi District during January, 1996-a
tSubsequently developed recurrent hypoglycaemia and died after developing widespread chest crackles with hypoxaemia. Table: Admission clinical and laboratory data for index cases and probable cases of chronic salicylate *Index
cases.
cross-sectional survey of 463 households, and interviews with mothers 2 days after they had purchased over-the-counter (OTC) drugs from local shops for a child with fever.
Results Data were available for 143 (93%) of 154 children admitted with an initial primary diagnosis of severe malaria. 129 (90%) children had detectable salicylate in plasma (>1 I mg/dL). Of these, six had salicylate concentrations of 20 mg/dL or higher; this value, in the presence of characteristic clinical features, has been used as an indication of intoxication in American children receiving aspirin for a range of acute, febrile illnesses.4 Clinical details and admission laboratory data for these children and the index cases are summarised in the table. In all cases deep breathing (Kussmaul’s respiration) was present on admission. All but one child (case 4) had a definite history of therapeutic aspirin use. Hypoglycaemia was present in three children on admission and developed subsequently in a fourth child. All six children had metabolic acidosis. OTC drugs were the first-line treatment in 188 (74%) of 254 fever episodes during the 2 weeks before the crosssectional survey. Such treatment was continued at home for a mean of 2-5 days (range 0-12 days) in children subsequently taken to a health centre (24%). Of the 250 mothers who bought drugs for a febrile child 236 (94%) purchased an OTC drug containing a salicylate preparation and 50 (21%) administered a dose exceeding the maximum recommended dose daily by manufacturers. 67 (27%) of children were given more than one salicylate preparation; of these children, 35 (52%) received a dose higher than the recommended maximum.
poisoning
that
salicylate poisoning contributed to her death. The also highlights the difficulties of accurately finding out the dose ingested by a child in a rural African population. All the evidence, however, suggests that salicylates are used on a massive scale. In Malawi, nearly 70% of parents treat their children with an antipyretic, usually aspirin based, at the first sign of fever.8 In the Kilifi District of Kenya, home treatment of a febrile child resulted in salicylate administration in 94% of cases. In 21% the dose was inappropriately high, often as a result of treatment with several salicylate-containing preparations or the use of adult preparations. The measurement of salicylate concentrations is rarely possible in African hospitals, but the mainstays of supportive treatment are the same as those for severe malaria-administration of glucose for hypoglycaemia and adequate fluid resuscitation in acidotic children. Further, case
detailed studies are needed to elucidate the true of salicylate poisoning in African children with and without malaria. Given the massive scale of aspirin use, even rare complications could be important causes of preventable morbidity and mortality. The possibilities that salicylate intoxication is more likely in children with malaria and that it serves as a co-factor in the pathogenesis of hypoglycaemia deserve particular attention. As has been shown in developed countries, the use of salicylates as antipyretics in children may expose them to unnecessary risk. more
extent
This study is published with the permission of the Director of the Kenya Medical Research Institute (KEMRI) and was supported by KEMRI and the Wellcome Trust (040313). We thank Peter Winstanley for help and advice. VM is supported by grants from Overseas Development Agency, UK, and Tropical Diseases Research, WHO, and KM is a Wellcome Trust senior research fellow in clinical science (031342).
Discussion
References
All of the children with high salicylate concentrations presented with well-described complications of severe malaria 1,2 but also met clinical criteria for moderate or severe chronic salicylate intoxication. 3,4 How much salicylate is required, over what period, to cause chronic salicylate poisoning is not known. Although daily doses as low as 32 mg/kg have been associated with this complicationTemple estimated that a daily dose of 100 mg/kg for at least 2 days is needed. The parents of the child who died (case 7, table) reported giving, among other medications, at least four adult aspirin tablets over the previous 2 days (a total minimum dose of 50-100 mg/kg). This child died after developing clinical pulmonary oedema, which is known to be a complication of aspirin intoxication9 but is rare in African children with severe malaria.’ This complication increases the likelihood
Marsh K, Forster D, Waruiru C, et al. Life threatening malaria in African children: clinical spectrum and simplified prognostic criteria. N Engl J Med 1995; 332: 1399-404. 2 Taylor T, Borgstein A, Molyneux M. Acid base status in paediatric Plasmodium falciparum malaria. Q J Med 1993; 86: 99-109. 3 Snodgrass W. Salicylate toxicity. Pediatr Clin N Am 1986; 33: 381-91. 4 Gaudreault P, Temple A, Lovejoy F. The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison. Pediatrics 1982; 70: 566-69. 5 Temple A. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981; 141: 364-69. 6 Trinder P. Rapid determination of salicylate in biological fluids. Biochem J 1954; 57: 301-03. 7 English M, Waruiru C, Lightowler C, et al. Hyponatraemia and dehydration in severe malaria. Arch Dis Child 1996; 74: 201-05. 8 Slutsker L, Chitsulo L, Macheso A, Steketee R. Treatment of malaria fever episodes among children in Malawi: results of a KAP survey. Trop Med Parasitol 1994; 45: 61-64. 9 Fisher C, Albertson T, Foulke G. Salicylate-induced pulmonary edema. Am J Emerg Med 1985; 3: 33-37. 1
1737