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: mark.anderson7@nuth.nhs.uk

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 non-

fatal 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 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 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 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

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 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

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

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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

n (%)

PICU admissions

n (% of identified substances)

Hospital admissions

n

‘Severe’ NPIS enquiries

n (%)

Region England and Wales United Kingdom England United Kingdom

Study period 2001-2013 2002-2012 1998/99-2013/14 2008-2014

Age range < 5 y < 5 y <14 y < 5 y

Source ONS PICAnet HES UKPID

Benzodiazepines 0 22 (19%) 3156 0

Methadone 16 (57%) 20 (17%) 536 6 (9%)

Other opioids 1 (4%) 19 (17%) 3265 1 (1%)

Tricyclic and tetracyclic

antidepressants

3 (11%) 13 (11%) 3376 3 (4%)

Iron and its compounds 1(4%) 13 (11%) 2013 13 (19%)

Anticonvulsants (except

benzodiazepines)

1(4%) 6 (5%) 3984 8 (12%)

Heroin 2 (7%) - 96 0

Others/unspecified 4 (14%) 108 - 38 (55%)

TOTAL 28 201 - 69

16