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SYMPOSIUM: ACCIDENTS AND POISONING In the US, the FDA reports that there are about 112,000 The management of poisoning calls, 56,000 emergency department (ED) visits, 26,000 hospitalisations and over 450 deaths annually associated paracetamol poisoning with paracetamol poisoning. FDA statistics also show that children aged 16 years or younger account for about 33% of ED Khairun Nain Bin Nor Aripin visits, 24% of hospitalisations but only between 1e3% of Imti Choonara mortality related to paracetamol overdose. Paracetamol toxicity primarily manifests in the liver, and paracetamol overdose is the most common apparent cause of acute liver failure in the UK and Western countries. Abstract Paracetamol poisoning in the paediatric age group can be Paracetamol poisoning is a common presentation in paediatrics. Toxicity divided into three major groups with differing demographic and may cause hepatocellular injury, in certain cases progressing to fulminant clinical characteristics. These are intentional self-poisoning, liver failure. Young children appear less at risk of hepatotoxicity due to an accidental paediatric ingestion and poisoning due to repeated increased metabolic capacity for paracetamol. A single dose of 150 mg/kg supratherapeutic dosings of paracetamol. can cause hepatocellular damage. Children who ingest multiple supra- Rumack and Matthew’s landmark review in 1975 brought therapeutic doses can accumulate significant concentrations and may attention to paracetamol poisoning in children. In 1984, Rumack suffer worse outcomes. Older children who intentionally overdose may described a cohort of 417 children, aged 5 years or younger, who also suffer worse outcomes, especially those who present late. The risk had ingested potentially toxic amounts of paracetamol. Only of hepatotoxicity after a single overdose can be predicted using a widely three children had altered liver enzymes and all recovered with used nomogram, although it was derived from adult data. The corner- treatment with no fatalities in the cohort. Thus, it was accepted stone of management is administering the antidote N-acetylcysteine that in general, young children with accidental single exposures when hepatotoxicity is likely to occur. The National Poisons Information to paracetamol overdoses were less at risk of developing toxic Service is available to be consulted at all hours. When severe poisoning reactions and subsequent morbidity and mortality than adoles- is suspected, the child may require referral to a liver unit in view of cents or adults. possible liver transplantation. A study of 140 children admitted to a hospital in Scotland reported only one case (a 13 year old girl) of hepatotoxicity. The Keywords children; drug metabolism; paracetamol; toxicity majority of the children were less than 5 years old (Table 1). Following early case reports, there has been growing concern regarding children developing toxicity after receiving repeated supratherapeutic doses of paracetamol. A Californian case series Introduction of 73 overdoses included 63 cases of intentional poisoning. The The analgesic and antipyretic properties of paracetamol were first remaining 10 cases where the overdoses were unintentional were described in 1893. It was shown to be an effective antipyretic in in children under 10 years of age who had been given multiple children in 1956 and since the 1960s, it has been widely available supratherapeutic doses. Eight out of the 10 developed hepato- as a non-prescription drug, with a therapeutic profile that reflects toxicity and encephalopathy resulting in one death and three widespread safety and efficacy. Following the discovery of an liver transplants. association between aspirin and Reye’s syndrome in the 1980s, Another American study of children under the age of 10 years paracetamol became the most widely used analgesic and anti- described 24 deaths occurring in a cohort of 47 young children. pyretic in children. It is the most frequently used over-the- The vast majority of these children experienced repeated para- counter medicine in young children and is nearly universally cetamol overdoses and these findings are in contrast to the used in infants. The drug is used by millions of children every cohort originally described by Rumack in the same country. day. In an Australian review of 18 children with fulminant hepatic failure, unintentional recurrent overdose was presumed to have Epidemiology caused the liver failure in 11 children, aged below 11 years of age. Alander et al. reviewed all presentations of paracetamol On the other hand, paracetamol is one of the most common poisoning to two regional children’s hospitals in the US over causes of poisoning in the developed world. Paracetamol a 10 year period. They found that out of 322 paediatric para- poisoning is the leading subject of inquiries to poison centres in cetamol overdoses, intentional and unintentional overdoses the US, UK and Australasia. It is the single most commonly taken occurred with a similar frequency. Intentional overdoses occurred drug in overdose in the UK, accounting for half of all admissions in older children and adolescents ranging between 11 to 17 years for poisoning and an estimated 100e200 deaths per year. old (median age, 14 years), while unintentional overdoses occurred in children with a median age of 2 years old. Only one out of the 172 young children who unintentionally ingested an Khairun Nain Bin Nor Aripin MBChB MSc is Postgraduate Student at overdose of paracetamol developed hepatotoxicity. 10 children University of Nottingham, Derbyshire Children’s Hospital, Derby, UK. presented after ingesting repeated supratherapeutic doses and one of the 10 developed hepatotoxicity. In this case series, all Imti Choonara MBChB MD is Professor of Child Health at University of four cases of liver failure and one death occurred in older Nottingham, Derbyshire Children’s Hospital, Derby, UK. children who intentionally overdosed on paracetamol. PAEDIATRICS AND CHILD HEALTH 19:11 492 Ó 2009 Elsevier Ltd. All rights reserved. SYMPOSIUM: ACCIDENTS AND POISONING Studies describing children with paracetamol poisoning First author, year Age and number of Setting Type of overdose Outcome children described Rumack 1984 <5 years, N ¼ 417 Poison center, Acute, short term 3 developed hepatotoxicity Denver, USA ingestion (all less than 5 years old) No deaths Kumar 1990 1e4 years, N ¼ 108 Children’s hospital, 130 accidental 1 developed hepatic failure 5 years, N ¼ 32 Glasgow, Scotland 10 intentional (>10 years) (13 year old) Full recovery with supportive treatment Rivera-Penera 10 years, N ¼ 14 California, USA 10 multiple overdoses In multiple group, 8/10 had hepatoxicity, 1997 >10 years, N ¼ 59 (10 years group) 3/10 had transplant, 1/10 died. (All less than 10 years old) In the other group, 3/63 had transplant, 1/63 died. (age not described) Heubi 1998 5 years, N ¼ 35 USA Multiple overdoses 5 had transplant (ages 7 months, 6e10 years, N ¼ 12 3,6,6,8 years) 24 died (ages 1 month to 10 years) Miles 1999 0.5e11 years, N ¼ 11 Liver transplant Multiple overdoses 6 recovered with supportive treatment, centre, Australia 1 brain damage (age 31 months) 4 died (ages 5,6,10,11 years) Alander 2000 0e17 years, N ¼ 322 2 regional children’s 140 intentional 4 had liver failure and 1 died, hospitals, USA 172 unintentional all from intentional group 10 multiple overdoses (all 11 years or older) James 2002 1.5e17 years, N ¼ 41 Children’s hospital, Acute single overdoses 16/41 had hepatotoxicity Arkansas, USA 1 had transplant (age not described) No deaths Ranganathan N ¼ 25 Children’s hospital, All 25 had multiple 3 died 2006 Colombo, Sri Lanka supratherapeutic doses Mahadevan 0.8e16 years, N ¼ 51 National liver unit, 6 multiple overdoses 3/6 In multiple group died 2006 United Kingdom (<7 years) (all under 7 years old) 45 single overdose 6/45 in single group died (age not described) Table 1 James et al. described 95 children who were admitted to administered supratherapeutic doses of paracetamol (mean Arkansas Children’s Hospital in the US with paracetamol 145 mg/kg/day). Cases had higher mean paracetamol plasma poisoning between 1991 and 2001. 41 had taken a single acute concentrations and longer durations of dosing. All the children overdose of paracetamol. 16 of these children between 8 to had acute viral infections with a fever. 17 years old developed hepatotoxicity; five had severe hepatotox- In summary, younger children who accidentally ingest icity and one required a liver transplant. There were six children a single dose of paracetamol are less at risk of hepatotoxicity and who had taken multiple overdoses but they were not described other serious complications of paracetamol poisoning. On the further in the study. other hand, older children who self-harm with paracetamol Mahadevan et al. recently reviewed 51 children admitted to the overdoses and young children who ingest repeated overdosings national liver unit in Birmingham (UK) with significant hepato- of paracetamol may suffer severe morbidity and mortality. toxicity induced by paracetamol overdose between 1992 and 2002. There were six children less than 7 years old who developed Pathophysiology toxicity following multiple dosing. All six were listed for trans- plantation, two died after transplantation while one died awaiting Paracetamol is rapidly absorbed from the small intestine and has transplant. The other 45 children were adolescents, 43 were a high bioavailability of around 80% after first-pass metabolism. female. All had taken

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