Fatal and Severe Pharmaceutical Poisoning in Young ...



Severe and Fatal Pharmaceutical Poisoning in Young Children in the United KingdomCorresponding author:Dr Mark AndersonGreat North Children’s HospitalRoyal Victoria InfirmaryQueen Victoria RoadNewcastle upon TyneNE1 4LPEmail:mark.anderson7@nuth.nhs.ukTel:0191 2823849Authors:Mark Anderson1,2, Leonard Hawkins2, Michael Eddleston3,4, John P Thompson5, J Allister Vale6, Simon HL Thomas2,71. Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne, UK2. National Poisons Information Service, Newcastle Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Wolfson Unit, Newcastle upon Tyne, UK3 National Poisons Information Service, Edinburgh Unit, Royal Infirmary of Edinburgh, Edinburgh, UK4 Pharmacology, Toxicology and Therapeutics, University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK5 National Poisons Information Service, Cardiff Unit, University Hospital Llandough, Penarth, Vale of Glamorgan, UK6 National Poisons Information Service, Birmingham Unit, City Hospital, Birmingham, UK7 Institute of Cellular Medicine, Medical Toxicology Centre, Wolfson Building, Newcastle University, Newcastle upon Tyne, UKKeywords: Toxicology, EpidemiologyWord count 2296AbstractObjective: Accidental poisoning in young children is common, but severe or fatal events are rare. This study was performed to identify the number of such events occurring in the UK and the medications that were most commonly responsibleDesign: Analysis of national datasets containing information relating to severe and fatal poisoning in children in the UKData sources: Office of National Statistics (ONS) mortality data for fatal poisoning; Paediatric Intensive Care Audit Network (PICANet) admissions database and the National Poisons Information Service (NPIS) for severe non-fatal poisoning; Hospital Episode Statistics (HES) for admission data for implicated agentsResults: Between 2001 and 2013 there were 28 children aged 4 years and under with a death registered as due to accidental poisoning by a pharmaceutical product in England and Wales. Methadone was the responsible drug in 16 (57%) cases. In the UK 201 children aged 4 years and under were admitted to paediatric intensive care with pharmaceutical poisoning between 2002 and 2012. The agent(s) responsible was identified in 115 cases, most commonly benzodiazepines (22/115, 19%) and methadone (20/115, 17%).Conclusions: Methadone is the most common pharmaceutical causing fatal poisoning and a common cause of ICU admissions in young children in the UK. IntroductionExploratory ingestion of medicines by pre-school children is a common reason for seeking urgent medical advice or assessment. During the 2013/14 reporting year, the National Poisons Information Service (NPIS) in the United Kingdom received over 14,000 telephone enquiries from healthcare professionals about children with suspected toxic exposures, many of which relate to accidental pharmaceutical ingestions (1). In the United States, it was estimated that there are more than 70,000 emergency department visits annually for unintentional paediatric poisoning, the majority unsupervised pharmaceutical ingestions in children under 6 years of age (2). Fortunately, the vast majority of these episodes do not lead to significant harm, with many children remaining at home and most of the remainder requiring a short observation period only. The low toxicity associated with most accidental childhood ingestions reflects the relative safety in overdose of many commonly used medicines and the modest doses usually ingested. However, some medications are considered high risk, where ingestion of 1 or 2 adult doses could theoretically be fatal for a 10Kg toddler. These include tricyclic antidepressants, antipsychotics, quinine, calcium channel blockers, opioids and oral hypoglycaemic agents (3). These medications are estimated to account for approximately 40% of fatalities due to poisoning in children aged less than 2 years in North America (4).There are limited epidemiological data relating to severe and fatal poisoning of young children in the UK as information is not collected in a systematic fashion. In order to characterise this important paediatric public health issue for the UK, relevant national clinical databases were analysed to identify the medications most frequently associated with significant harm to young children. Recognition of these may provide a focus for future surveillance, as well as targets for preventative work.MethodsSummary data recorded from death certificates in England and Wales from 2001 to 2013 were obtained from the Office of National Statistics (ONS). The cause of death is classified using the International Classification of Diseases, Tenth Revision (ICD-10) with the relevant codes being T36-T50 (Poisoning by drugs, medicaments and biological substances). Data for children aged 4 years and under were extracted to identify the pharmaceutical substances, or classes of substances, associated with death in young children.The Paediatric Intensive Care Network (PICANet) database records demographic and clinical data on all admissions to paediatric intensive care units (PICU) in the UK since 2002. This database was searched for the period November 2002 to November 2012 to identify admissions associated with a Read code or free text relating to drug poisoning. Data were extracted relating to admissions of children aged 4 years and under to identify causative substances.The UK National Poisons Information Service (NPIS) provides toxicology advice to healthcare professionals in the UK via a web-based database (TOXBASE?) and by telephone (1). All telephone enquiries to the four units of the NPIS have been recorded on a single central national database, the UK Poisons Information Database (UKPID), since 2008. The severity of each episode of poisoning is recorded using the IPCS/EAPCCT Poisoning Severity Score (PSS), a validated grading system of five categories based on severity, with 0 indicating no signs or symptoms related to toxicity, 1 mild, 2 moderate, 3 severe or life threatening and 4 fatal toxicity (5). The UKPID database was analysed for calls received between 2008 and 2014 (inclusive) where a PSS of 3 was recorded for a child aged four years and under. Demographic and clinical data were extracted for these severe cases. Note that clinical advice would not be sought from NPIS for cases where death has already occurred (PSS 4).The Hospital Episode Statistics (HES) database contains details of all admissions to NHS hospitals in England. Inpatient data are available from the financial year 1998/99, broken down by ICD-10 code and broad age band. To characterize further the burden of poisoning in children, the HES database was analysed to identify the number of finished consultant episodes (FCEs) for children (age < 14 years) admitted to hospital for each of the ICD-10 codes relating to poisoning with those pharmaceutical substances found to be associated with death or PICU admission. ResultsONS dataPharmaceutical substances were registered as causing death in 28 children aged 4 years and under from 2001 to 2013 (Table 1). Of these, 16 (57%, 95% CI 37-74%) were due to methadone (ICD-10 code T40.3). Only two other classes of drug were responsible for more than one death, tricyclic antidepressants (T43.0) accounting for three deaths (11%, 95% CI 3-29%), and heroin (T40.1) accounting for two deaths (7%, 95% CI 1-25%). Iron and its compounds (T45.4), other opioids (T40.2 – mostly morphine and codeine), hydantoin derivatives (T42.0), other synthetic narcotics (T40.4), skeletal muscle relaxants (T48.1), inhaled anaesthetics (T41.0) and other and unspecified hormones (T38.8) were each associated with one death. Because deaths due to skeletal muscle relaxants, inhaled anaesthetics and other/unspecified hormones are usually due to in-hospital error or idiosyncratic reaction, these cases were excluded from further analysis. PICANet dataDuring the 11 year period 2002 to 2012, 201 children aged less than five years were admitted to a PICU as a result of poisoning presumed to be pharmaceutical. Unfortunately, in 86 (43%) cases, the agent resulting in poisoning was not identified or recorded in the PICANet dataset. In the remaining cases, the most common causative agents were benzodiazepines and methadone (Table 1). The recorded data did not allow for differentiation between admissions due adverse drug effects (e.g. respiratory depression following therapeutic use of benzodiazepines), iatrogenic overdose, and accidental poisoning due to exploratory ingestion. NPIS DataIn the seven years between 2008 and 2014, the NPIS recorded 69 telephone enquiries relating to confirmed or suspected severe or life threatening poisoning by a pharmaceutical in a child aged 4 years and under (Table 1). Of these, 19 (28%,) related to iatrogenic overdoses, 3 (4%) resulted from therapeutic excess administered by parents/carers and the remaining 47 (68%) resulted from accidental poisoning due to exploratory ingestions. Iron containing compounds, anticonvulsants, methadone and tricyclic antidepressants accounted for nearly two thirds of the enquiries (Table 1).HES DataData were not available for children aged 4 years and under. However, the annual number of admissions for poisoning of all severities in children under the age of 14 has fallen for most of the drugs most commonly implicated in severe or fatal poisoning since the 1998/99 reporting year, with the exception of ‘other opioids’ (Figure 1). Admissions due to methadone poisoning were relatively infrequent when compared with the other medications DiscussionExploratory ingestion by toddlers is a common reason to seek medical attention; in previous work this accounted for 2% of attendances by this age group at a UK emergency department (6). Recent analysis of admission data for England demonstrated a 23% reduction in hospitalization of preschool children due to unintentional poisoning between 2000 and 2011 (7). The reasons for this are multifactorial but are likely to include a greater public awareness of the need to store medicines safely, as well as the wider availability of more reliable toxicological information on the relative risks associated with ingestion of pharmaceutical products in this age group, such as that provided by the NPIS on-line database TOXBASE, which has been available on the internet since 1999. This may have resulted in fewer admissions for observation of children poisoned by less toxic medicines. Despite these trends, episodes of severe and fatal poisoning still occur in preschool children (8) and this is the first UK study that attempts to identify which pharmaceutical products are implicated. This is important because it allows more explicit counselling of parents and carers regarding safe use and storage of these products and informs the consideration of targeted public health measures, such as more effective child resistant packaging. At present, there is no systematic recording of deaths or serious harm due to accidental poisoning in children in the UK and existing databases have limitations. Information about fatal and non-fatal cases depends on the accuracy of diagnosis, which may be imperfect, as has been demonstrated for hospital episode statistics for recreational drug poisoning (9). It is not possible to differentiate reliably between episodes caused by accidental poisoning and those resulting from adverse drug reactions and iatrogenic medication error. This is salient for tricyclic antidepressants, iron preparations and anticonvulsants, as these may be used therapeutically in children. However, because it has no therapeutic role in young children, all episodes of methadone toxicity relate to accidental poisoning or deliberate administration. In addition, we have been constricted by the age-bands used by the databases, with the HES data only providing information for children grouped as under 14 years of age. This broader age range captures some episodes of poisoning in the context of self-harm. ONS statistics on registered causes of death indicate that fatal childhood pharmaceutical poisoning in preschool children is fortunately a rare occurrence, affecting on average approximately two children aged under five years in England and Wales each year. A previous analysis of death certificates from England and Wales of children aged under 10 years revealed a fall in fatalities due to poisoning in general of 80% between 1968 and 2000 (10). The number of deaths per year in the present study is consistent with those in other developed countries. For example in the US there were 52 deaths of children aged 4 years and under due to drug poisoning in 2012 where intent was classified as unintentional or undetermined.(11). The ONS data also show that methadone was by far the most common pharmaceutical causing death over this period, accounting for more than half the fatalities. It was also second only to benzodiazepines as a cause of poisoning requiring intensive care according to the PICAnet database and it should be recognised that that many of the cases of benzodiazepine poisoning requiring PICU admission were actually related to adverse effects during therapeutic use rather than accidental poisoning. As a cause of severe or life threatening poisoning referred to the NPIS, methadone was ranked third after iron and its compounds and anticonvulsants. Some of these comparisons, however, are limited by the small numbers involved, reflecting the rarity of severe pharmaceutical poisoning in this age group. These data demonstrate the substantial risk of harm to small children from methadone exposure, which is further emphasised by case reports detailing fatal childhood methadone intoxication (reviewed in 12,13). Methadone is an effective maintenance therapy for heroin dependence (14), and there is observational evidence that it may reduce mortality, human immunodeficiency virus risk behaviour and crime compared with no therapy (15). In England in 2013, in excess of 2 million prescriptions for methadone were issued to over 140,000 adults. Methadone use is not without risk; it is the second commonest cause of drug-related death in England and Wales, after heroin/morphine (16). In addition, those to whom methadone is prescribed, due to their underlying condition, are potentially least able to guarantee it will not be accessible to young children. Current recommendations from the UK Royal College of General Practitioners (RCGP) advise discussion of secure storage of methadone with “…all patients particularly parents, and patients who have children regularly visiting their homes…” (17). A number of addiction services provide drug safes for use in the home, but use is dependent upon the individual patients. The risk to children posed by methadone in the UK has recently been highlighted in an analysis of 20 serious case reviews involving young children exposed to opioid substitution therapy medications (18). Previous UK surveys have demonstrated that many patients receiving methadone were not aware of its dangers to children, do not recall being given safe storage advice or do not keep their methadone in a safe locked location (19,20), although somewhat better results were obtained in an Australian study (21). It is therefore vital that prescribers ask patients repeatedly about the presence of children in their homes and adapt advice and/or practice accordingly. In some cases it may be appropriate to return to supervised administration. The use of buprenorphine as an alternative medication may also be considered. This may be safer because of a ceiling effect to respiratory depression, although a recent case report has questioned this advantage in children (22) and the drug may not be as effective as methadone in some circumstances (14). There is increasing evidence that provision of naloxone to those who abuse opioids for “lay administration” may reduce unintentional drug overdose deaths (23). Unfortunately due to the limitations of the data source used, no information is available in the present study relating to administration of naloxone to children who died as a result of methadone intoxication, either by caregivers or healthcare professionals. Provision and training in the administration of naloxone to children for methadone users might, however, have a role in preventing future deaths.All cases of accidental poisoning are potentially avoidable. There is a need for robust and systematic recording of the medication involved and circumstances around all exploratory ingestions that result in significant harm to young children. This requires regular review to inform targeted public health interventions to avoid these tragedies. It is also vital that, before and during the prescribing of methadone, extensive efforts are made to ensure the safety of children who might be at risk of exposure.What is already knownHospitalisation due to accidental poisoning due to pharmaceutical products in preschool children in the UK is reducingCertain medications can be fatal if 1 or 2 adult doses are ingested by a small childWhat this study addsMethadone ingestion accounts for over 50% of deaths due to accidental pharmaceutical poisoning of young children in the UKMethadone ingestion accounts for a significant proportion of PICU admissions due to accidental pharmaceutical poisoning in the UKThere is a need for systematic reporting of deaths and severe harm due to accidental poisoning to identify targets for poisoning prevention campaignsContributorship statement:MA conceived the project, collated, analysed and interpreted the data and drafted and revised the paper. He is the guarantor. LH collated the data and revised the draft paper. ME, JT and AV interpreted the data and revised the draft paper. ST conceived the project, interpreted the data and revised the draft paperReferencesNational Poisons information Service. Report 2013/14. (accessed 4th June 2015). Schillie SF, Shehab N, Thomas KE, Budnitz DS. Medication overdoses leading to emergency department visits among children. Am J Prev Med. 2009;37:181-7. Braitberg G, Oakley E. Small dose…big poison. Aust Fam Phys 2010;39:826-833Bar-Oz B, Levichek Z, Koren G. Medications that can kill a toddler with one tablet or a teaspoonful – a 2004 update. Paediatr Drugs 2004;6:123-6Persson HE , Sj?berg GK, Haines JA , De Garbino JP . Poisoning severity score . Grading of acute poisoning. J Toxicol Clin Toxicol 1998 ; 36 : 205 – 213 .Anderson M, Baker C. Ingestions and poisonings in children presenting to a UK emergency department: changes over 30 years. Clin Toxicol 2012;50:297-8.Mbeledogu CNA, Cecil EV, Millett C, Saxena S. Hospital admissions for unintentional poisoning in preschool children in England; 2000–2011. Arch Dis Child 2015;100:180-182BBC (2013) Derbyshire toddler ‘drank fatal beaker of methadone’ [online], available: [accessed 20th June 2015]Shah AD, Wood DM, Dargan PI. Survey of ICD-10 coding of hospital admissions in the UK due to recreational drug toxicity. QJM 2011; 104: 779-84Flanagan RJ, Rooney C, Griffiths C. Fatal Poisoning in Childhood, England & Wales 1968-2000. For Sci Int 2005;148:121-129WISQARS Fatal Injury Query on 2 July 2015 L, Levine B, Smialek JE. Fatal methadone poisoning in children: Maryland 1992-1996. Subst Use Misuse. 2000;35:1141-8.Palmiere C, Staub C, La Harpe R, Mangin P.Parental substance abuse and accidental death in children. J Forensic Sci. 2010;55:819-21Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD002207. DOI: 10.1002/14651858.CD002207.pub4National Institute for Health and Care Excellence. Methadone and buprenorphine for the management of opioid dependence. Technology appraisal guidance 114. January 2007. (accessed 4th June 2015)Office of National Statistics. Deaths Related to Drug Poisoning in England and Wales, 2013. September 2014. (accessed 21st January 2016)Ford C, Halliday K, Lawson E, and Browne E. Guidance for the use of substitute prescribing in the treatment of opioid dependence in primary care. Available at .uk and .uk. (accessed 4th June 2015)Adfam. Medications in drug treatment: tackling the risks to children. April 2014. (accessed 20th June 2015)Bloor RN, McAuley R, Smalldridge N. Safe storage of methadone in the home - an audit of the effectiveness of safety information giving. Harm Reduction Journal 2005, 2: 9Mullin A, McAuley RJ, Watts DJ, Crome IB, Bloor RN. Awareness of the need for safe storage of methadone at home is not improved by the use of protocols on recording information giving. Harm Reduct J. 2008 30;5:15.Winstock AR, Lea T. Safe storage of methadone takeaway doses - a survey of patient practice. Aust N Z J Public Health. 2007;31:526-8.Kim HK, Smiddy M, Hoffman RS, Nelson LS. Buprenorphine may not be as safe as you think: a pediatric fatality from unintentional exposure. Pediatrics 2012;130:e1700-3.Centers for Disease Control and Prevention (CDC). Community-based opioid overdose prevention programs providing naloxone—United States, 2010. Morb Mortal Wkly Rep 2012;61:101-5.The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ and co-owners or contracting owning societies (where published by the BMJ on their behalf), and its Licensees to permit this article (if accepted) to be published in Archives of Disease in Childhood and any other BMJ products and to exploit all subsidiary rights, as set out in our licence.Figure 1. Hospital admissions (FCEs) of children aged <14 years due to medications that have resulted in death (table 1) in England 1998 - 2014Competing interests: none declaredThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.Table 1. Medications resulting in death or severe symptoms of poisoning in childrenDataDeathsn (%) PICU admissionsn (% of identified substances) Hospital admissions n ‘Severe’ NPIS enquiries n (%)RegionEngland and WalesUnited KingdomEnglandUnited KingdomStudy period2001-20132002-20121998/99-2013/142008-2014Age range< 5 y< 5 y<14 y< 5 ySourceONSPICAnetHESUKPIDBenzodiazepines022 (19%)31560Methadone16 (57%)20 (17%)5366 (9%)Other opioids1 (4%)19 (17%)32651 (1%)Tricyclic and tetracyclic antidepressants3 (11%)13 (11%)33763 (4%)Iron and its compounds1(4%)13 (11%)201313 (19%)Anticonvulsants (except benzodiazepines)1(4%)6 (5%)39848 (12%)Heroin2 (7%)-960Others/unspecified4 (14%)108 -38 (55%)TOTAL28201-69 ................
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