Download SeverePoisoningChildren_vADC_revision2210316

Severe and Fatal Pharmaceutical Poisoning in Young
Children in the United Kingdom
Corresponding author:
Dr Mark Anderson
Great North Children’s Hospital
Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne
NE1 4LP
Email:
[email protected]
Tel:
0191 2823849
Authors:
Mark Anderson1,2, Leonard Hawkins2, Michael Eddleston3,4, John P Thompson5, J
Allister Vale6, Simon HL Thomas2,7
1. Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS
Foundation Trust, Queen Victoria Road, Newcastle upon Tyne, UK
2. National Poisons Information Service, Newcastle Unit, Newcastle upon Tyne
Hospitals NHS Foundation Trust, Wolfson Unit, Newcastle upon Tyne, UK
3 National Poisons Information Service, Edinburgh Unit, Royal Infirmary of
Edinburgh, Edinburgh, UK
4 Pharmacology, Toxicology and Therapeutics, University/BHF Centre for
Cardiovascular Science, University of Edinburgh, Edinburgh, UK
5 National Poisons Information Service, Cardiff Unit, University Hospital
Llandough, Penarth, Vale of Glamorgan, UK
6 National Poisons Information Service, Birmingham Unit, City Hospital,
Birmingham, UK
7 Institute of Cellular Medicine, Medical Toxicology Centre, Wolfson Building,
Newcastle University, Newcastle upon Tyne, UK
Keywords: Toxicology, Epidemiology
Word count 2296
1
Abstract
Objective: 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 responsible
Design: Analysis of national datasets containing information relating to severe
and fatal poisoning in children in the UK
Data 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 nonfatal poisoning; Hospital Episode Statistics (HES) for admission data for
implicated agents
Results: 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.
2
Introduction
Exploratory 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.
3
Methods
Summary 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
4
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.
5
Results
ONS data
Pharmaceutical 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 3774%) 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 inhospital error or idiosyncratic reaction, these cases were excluded from further
analysis.
PICANet data
During 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 Data
In 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
6
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 Data
Data 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
7
Discussion
Exploratory 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 online 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
8
providing information for children grouped as under 14 years of age. This
broader age range captures some episodes of poisoning in the context of selfharm.
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
9
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
10
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.
11
What is already known

Hospitalisation due to accidental poisoning due to pharmaceutical
products in preschool children in the UK is reducing

Certain medications can be fatal if 1 or 2 adult doses are ingested by a
small child
What this study adds

Methadone ingestion accounts for over 50% of deaths due to accidental
pharmaceutical poisoning of young children in the UK

Methadone ingestion accounts for a significant proportion of PICU
admissions due to accidental pharmaceutical poisoning in the UK

There is a need for systematic reporting of deaths and severe harm due to
accidental poisoning to identify targets for poisoning prevention
campaigns
Contributorship 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 paper
12
References
1.
National Poisons information Service. Report 2013/14.
http://www.npis.org/NPISAnnualReport2013-14.pdf (accessed 4th
June 2015).
2.
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.
3.
Braitberg G, Oakley E. Small dose…big poison. Aust Fam Phys
2010;39:826-833
4.
Bar-Oz B, Levichek Z, Koren G. Medications that can kill a toddler with
one tablet or a teaspoonful – a 2004 update. Paediatr Drugs
2004;6:123-6
5.
Persson HE , Sjöberg GK, Haines JA , De Garbino JP . Poisoning severity
score . Grading of acute poisoning. J Toxicol Clin Toxicol 1998 ; 36 :
205 – 213 .
6.
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.
7.
Mbeledogu CNA, Cecil EV, Millett C, Saxena S. Hospital admissions for
unintentional poisoning in preschool children in England; 2000–2011.
Arch Dis Child 2015;100:180-182
8.
BBC (2013) Derbyshire toddler ‘drank fatal beaker of methadone’
[online], available: http://www.bbc.co.uk/news/uk-englandderbyshire-20939055 [accessed 20th June 2015]
9.
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:
779-84
10.
Flanagan RJ, Rooney C, Griffiths C. Fatal Poisoning in Childhood,
England & Wales 1968-2000. For Sci Int 2005;148:121-129
11.
WISQARS Fatal Injury Query on 2 July 2015
http://webappa.cdc.gov/sasweb/ncipc/mortrate10_us.html
13
12.
Li L, Levine B, Smialek JE. Fatal methadone poisoning in children:
Maryland 1992-1996. Subst Use Misuse. 2000;35:1141-8.
13.
Palmiere C, Staub C, La Harpe R, Mangin P.Parental substance abuse
and accidental death in children. J Forensic Sci. 2010;55:819-21
14.
Mattick 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.pub4
15.
National Institute for Health and Care Excellence. Methadone and
buprenorphine for the management of opioid dependence.
Technology appraisal guidance 114. January 2007.
http://www.nice.org.uk/guidance/ta114 (accessed 4th June 2015)
16.
Office of National Statistics. Deaths Related to Drug Poisoning in
England and Wales, 2013. September 2014.
http://www.ons.gov.uk/ons/dcp171778_375498.pdf (accessed 21st
January 2016)
17.
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 www.rcgp.org.uk and www.smmgp.org.uk.
(accessed 4th June 2015)
18.
Adfam. Medications in drug treatment: tackling the risks to children.
April 2014. http://www.adfam.org.uk (accessed 20th June 2015)
19.
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: 9
20.
Mullin 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.
21.
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.
14
22.
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.
23.
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 - 2014
Competing interests: none declared
This research received no specific grant from any funding agency in the public,
commercial or not-for-profit sectors.
15
Table 1. Medications resulting in death or severe symptoms of poisoning in children
Data
Deaths
PICU admissions
Hospital admissions
‘Severe’ NPIS enquiries
n (%)
n (% of identified substances)
n
n (%)
England and Wales
United Kingdom
England
United Kingdom
2001-2013
2002-2012
1998/99-2013/14
2008-2014
Age range
<5y
<5y
<14 y
<5y
Source
ONS
PICAnet
HES
UKPID
0
22 (19%)
3156
0
16 (57%)
20 (17%)
536
6 (9%)
Other opioids
1 (4%)
19 (17%)
3265
1 (1%)
Tricyclic and tetracyclic
3 (11%)
13 (11%)
3376
3 (4%)
Iron and its compounds
1(4%)
13 (11%)
2013
13 (19%)
Anticonvulsants (except
1(4%)
6 (5%)
3984
8 (12%)
Heroin
2 (7%)
-
96
0
Others/unspecified
4 (14%)
108
-
38 (55%)
28
201
-
69
Region
Study period
Benzodiazepines
Methadone
antidepressants
benzodiazepines)
TOTAL
16