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com
Original article
1
Department of Paediatric
Endocrinology, University
Hospital Southampton,
Southampton, UK
2
Department of Paediatric
Diabetes, Oxford Children’s
Hospital, Oxford, UK
Correspondence to
Dr Justin H Davies, Department
of Paediatric Endocrinology,
University Hospital
Southampton, Tremona Road,
Southampton, SO16 6YD, UK;
Justin.Davies@uhs.nhs.uk
Received 20 July 2013
Revised 12 December 2013
Accepted 13 December 2013
Published Online First
6 January 2014
To cite: Lokulo-Sodipe K,
Moon RJ, Edge JA, et al.
Arch Dis Child
2014;99:438–442.
438
Identifying targets to reduce the incidence of
diabetic ketoacidosis at diagnosis of type 1 diabetes
in the UK
K Lokulo-Sodipe,1 R J Moon,1 J A Edge,2 J H Davies1
ABSTRACT
Background Diabetic ketoacidosis (DKA) is the leading
cause of mortality in childhood diabetes, and at
diagnosis might represent delayed presentation. The
extent and reasons for delays are unclear, but identifying
and targeting factors associated with DKA could reduce
this incidence.
Objective To compare the patient pathway before
diagnosis of type 1 diabetes mellitus (T1DM) in children
presenting with DKA and non-acidotic hyperglycaemia.
Design, setting and patients Over a 3-month
period, children newly diagnosed with T1DM were
identified on admission to UK hospitals. Parents and
medical teams completed a questionnaire about events
before diagnosis.
Results Data were available for 261 children (54%
male), median age 10.3y (range 0.8–16.6 y). 25%
presented with DKA, but more commonly in children
<2y (80% vs 23%, p<0.001). Fewer children with DKA
reported polyuria (76% vs 86%) or polydipsia (86% vs
94%) (both p<0.05), but more reported fatigue (74% vs
52%) and weight loss (75% vs 54%) (both p<0.01).
24% of children had multiple healthcare professional
(HCP) contacts, and these children had lower pH on
admission. 46% of children with a delayed presentation
to secondary care had non-urgent investigations. 64% of
parents had considered a diagnosis of diabetes, and
these children were less likely to present with DKA
(13% vs 47%, p<0.001).
Conclusions Multiple HCP contacts increased risk of
presentation in DKA, whereas, parental awareness of
diabetes was protective. Improved public and health
professional education targeting non-classical symptoms,
awareness of diabetes in under 2 y, and point-of-care
testing could reduce DKA at diagnosis of diabetes.
INTRODUCTION
Approximately 26 per 100 000 children are diag-
nosed with type 1 diabetes mellitus (T1DM) each
year, although this figure continues to rise by
approximately 4% per year.1 2 Despite improve-
ments in diabetes care leading to an increasing life
expectancy, the mortality rate for children with
T1DM remains higher than the general population,
and the leading cause of death is diabetic ketoaci-
dosis (DKA).3 In the UK, approximately 25–30%
of children will present with DKA.4–7 However,
globally, there is a large variation in the incidence
of DKA at presentation, ranging from 13% to
80%.8 Children presenting with DKA are at higher
risk of life-threatening complications including
Lokulo-Sodipe K, et al. Arch Dis Child 2014;99:438–442. doi:10.1136/archdischild-2013-304818
What is already known on this topic
▸ The incidence of DKA at diagnosis of T1DM in
the UK is 25% and is relatively unchanged
from reports over the past 20 years.
▸ Risk factors for presentation at diagnosis with
DKA include younger age, ethnic minority
background, delayed diagnosis, diagnostic error
and delayed treatment.
▸ Protective factors against DKA may include
higher caregiver education level, family history
of T1DM, higher background incidence of
T1DM and higher gross domestic product.
What this study adds
▸ Multiple healthcare professional contacts prior
to diagnosis, lead to delayed referral, lower pH
on admission and increased need for
intravenous insulin.
▸ Fewer children present with DKA when parents
consider the diagnosis of diabetes, and this is
more likely when polydipsia and/or polyuria are
present.
▸ Parents report symptoms of fatigue and weight
loss more frequently in children presenting with
DKA compared with hyperglycaemia alone.
cerebral oedema, cerebral ischaemia and hypoxic
brain injury.9 They are more likely to require
admission to an intensive care unit and contribute
to greater healthcare spending.10
A recent systematic review including data from
more than 30 countries demonstrated an increased
risk of DKA at presentation of T1DM in younger
children, ethnic minority groups, and those without
private healthcare insurance.11 Furthermore, a coun-
try’s gross domestic product and background inci-
dence of T1DM are inversely associated with the
percentage of children that present with DKA8 12
suggesting that healthcare accessibility and diabetes
awareness are key contributing factors. This is also
supported by a lower incidence of DKA at presenta-
tion in children who have a first-degree relative with
T1DM.11
It is not clear whether DKA at diagnosis repre-
sents a delay in presentation or a more aggressive
course of the disease,13 but the National Institute
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Original article

of Health and Care Excellence guidance published in 2004 As the audit was entirely anonymous, advice was taken from
recommended that children with suspected diabetes should be Caldicott guardian that consent was not required and was impli-
referred on the same day to the local paediatric diabetes team.14 cit by the completion of the voluntary questionnaire.
Despite this, the incidence of DKA at diagnosis in the UK has
remained virtually unchanged for 20 years,4–6 and is nearly Definitions
twice as high as that observed in Sweden.8 It is possible that dif- DKA was defined as a blood glucose >11 mmol/L, ketonuria or
ferences in healthcare provision prevent the UK achieving these ketonaemia, and venous pH <7.3 or bicarbonate <15 mmol/L.15
lower rates. We undertook this study to obtain a contemporary A delayed diagnosis was defined as >24 h from presentation to
estimate of DKA incidence at diagnosis of T1DM, and to primary or secondary services to referral to the diabetes multidis-
develop a greater understanding of demographic and healthcare ciplinary team.14 16
factors that are associated with a longer duration of symptoms Deprivation index scores were calculated using the partici-
and/or DKA at diagnosis in the UK. It is hoped that this infor- pant’s postcode and the English 2010 Index of Multiple
mation could contribute to the development of future interven- Deprivation from the UK Office of National Statistics, which has
tions to improve the patient pathway to diagnosis of T1DM. been demonstrated to serve as a surrogate measure of poverty
within a geographical area.17 For participants from Wales and
Northern Ireland, postcodes were converted to deprivation
METHODS indices using the Welsh Index of Multiple Deprivation 201118
A national survey was carried out through the Regional and the Northern Ireland Multiple Deprivation Measure
Paediatric Diabetes Networks with the support of NHS 2010,19 respectively, and converted to UK-equivalent values.
Diabetes, the Association of Children’s Diabetes Clinicians
(ACDC), and the British Society for Paediatric Endocrinology Statistical analysis
and Diabetes (BSPED). Children presenting with T1DM in Data was checked for normality of distribution, and where pos-
England, Wales and Northern Ireland between December 2011 sible, non-normally distributed data was log transformed.
and February 2012 were included. Data was collected by local Continuous outcomes were compared using independent
paediatric diabetes teams at the time of diagnosis. samples t test or Mann–Whitney U test for normal and non-
normally distributed variables, respectively. One-way analysis of
variance with posthoc Bonferroni correction was used to deter-
mine differences in outcome when three or more groups were
Questionnaire compared. Correlations were examined using Pearson’s correl-
Following initial stabilisation, a questionnaire was completed by ation coefficient or Spearman’s rank correlation coefficient.
the child’s primary caregiver during the hospital admission. Categorical outcomes were analysed using χ2 test. Results are
Questions included their child’s gender, date of birth, postcode, presented as mean±SD, unless otherwise stated. All analyses
ethnic background, family history of diabetes, number of family were performed using SPSS V.19. P<0.05 was considered statis-
members and caregiver education level. Information was also tically significant.
collected regarding the duration of non-specific parental con-
cerns about their child, specific symptom duration, healthcare RESULTS
professional (HCP) contacts, advice given and investigations per- Characteristics of study participants
formed before referral to hospital. Questionnaires were returned for 261 children treated at 75
Local paediatric diabetes teams completed the second part of hospitals (hospital name provided in 233 questionnaires)
the questionnaire, recording the investigations prior to referral, (median 3 children per hospital (range 1–11)): 140 (54%) chil-
method of referral, and biochemical results on admission. dren were male, and the median age at diagnosis of T1DM was
Questionnaires were sent without identifying data to the 10.3 years (range 0.8–16.6 years). Of the 252 children for
researchers for analysis. whom biochemical data was available, 63 (25%) presented in
DKA.
The median age of children presenting with DKA was similar
Table 1 Characteristics of the children included in the survey, to those presenting with non-acidotic hyperglycaemia (HG),
separated by presentation with either diabetic ketoacidosis (DKA) or although for children under the age of 2 years, significantly
non-acidotic hyperglycaemia (HG) more presented with DKA (table 1); in this age group, 80% pre-
Characteristic DKA HG p Value sented with DKA, compared with 23% of children older than
2 years.
n (% male) 63 (54.0) 189 (53.4) 0.90 Children who presented with DKA were of similar sex, ethni-
Median age, years (range) 9.9 (0.8–16.6) 10.6 (1.7–16.3) 0.21 city and family structure, and to children who presented with
≤2 years, % (n) 80.0 (8) 20.0 (2) <0.001 HG (table 1). Social deprivation scores did not differ between
>2 years, % (n) 22.7 (55) 77.3 (242) the two groups ( p>0.05 for all).
Ethnicity, % (n)
White caucasian 23.1 (51) 76.9 (170) 0.11 Symptom duration
Other 35.7 (10) 64.2 (18) Polyuria and/or polydipsia were reported for at least 1 day prior
Family structure, % (n) to diagnosis in 93% patients. In children with polyuria and/or
Single-parent household 17.3 (9) 82.7 (43) 0.16 polydipsia, the median durations of these symptoms were
Two-parent household 26.8 (51) 73.2 (139) 14 days (range 1–182 days) and 14 days (1–152 days), respect-
First-degree relative with diabetes, % (n) ively. Overall, fewer children reported enuresis (32%), fatigue
Yes 15.9 (7) 84.1 (37) 0.13 (55%), and weight loss (57%). No associations were identified
No 26.8 (56) 73.2 (153) between duration of symptoms and social deprivation score,
caregiver education level or the number of parents living in the

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Original article

Table 2 Frequency and duration of symptoms at presentation of type 1 diabetes mellitus in children presenting with diabetic ketoacidosis in
comparison to non-acidotic hyperglycaemia
All children Children age > 2 years at diagnosis

Mode of presentation Diabetic ketoacidosis Non-acidotic hyperglycaemia Diabetic ketoacidosis Non-acidotic hyperglycaemia

n 63 189 55 187
Polyuria % children reporting symptom 75.8 87.5* 77.8 87.9
Duration if present (days) 7 (7–23) 14 (7–21) 9 (7–25) 14 (7–21)
Polydipsia % children reporting symptom 85.5 94.1* 88.9 94.6
Duration if present (days) 14 (7–28) 14 (7–21) 14 (7–30) 14 (7–21)
Fatigue % children reporting symptom 74.2 51.7** 77.8 51.7***
Duration if present (days) 7 (3–18) 14 (7–30)* 7 (3–18) 14 (7–30)*
Weight loss % children reporting symptom 75.4 54.4** 81.1 54.5***
Duration if present (days) 7 (4–21) 14 (7–30)* 7 (5–21) 14 (7–30)
Enuresis % children reporting symptom 32.8 33.5 34.0 33.3
Duration if present (days) 14 (5–30) 14 (7–29) 7 (3–18) 14 (7–30)*
Parental Concerns Duration (days) 14 (4–25) 14 (7–30)* 14 (5–28) 14 (7–30)
Results displayed as % and median (IQR). *p<0.05, **p<0.01, ***p<0.001 in comparison with children with DKA.

household ( p>0.05 for all). However, symptom duration was
significantly shorter in children who had four or more siblings
compared with those with no siblings ( polydipsia 6±3 vs 18
±3 days, p<0.01 and polyuria 7±3 vs 20±3 days, p<0.05).
Overall, children who presented in DKA were less likely to
report polyuria and/or polydipsia, however, when only children
older than 2 years were included, the number of children
reporting these symptoms was similar (table 2). Parents of chil-
dren presenting with DKA were more likely to report weight
loss ( p=0.004) and fatigue ( p=0.002) than those with children
who presented with HG (table 2). In all children, the duration
of fatigue and weight loss, and the total length of parental
concern were shorter in those presenting with DKA (table 2),
despite a similar HbA1c at present (109±21 mmol/mmol (12.9±
4.1%) vs 104±27 mmol/L (11.7±4.6%), p=0.32). HbA1c at
diagnosis was moderately positively correlated with reported dur-
ation of polyuria, polydipsia, weight loss and parental concern in
children who presented with HG, but displayed no significant
correlations with reported symptom duration in those who pre-
sented with DKA (table 3).
Health professional contacts
Totally, 248 (95%) parents responded to the question detailing
the number of HCP encounters related to their concerns, prior
to hospital admission. Of these, 188 (76%) were admitted fol-
lowing the first HCP contact. Where there was delayed
Table 3 Correlation coefficients for symptom duration with HbA1c
in children with newly diagnosed T1DM, and according to mode of
presentation with either diabetic ketoacidosis (DKA) or non-acidotic
hyperglycaemia (HG)
All children DKA
Polyuria 0.214** −0.068
Polydipsia 0.367*** 0.173
Fatigue 0.131 0.195
Weight loss 0.464*** 0.302
Enuresis −0.033 0.165
Parental concerns 0.338*** 0.099
*p<0.05, **p<0.01, ***p<0.001.
admission, the median delay was 5 days (range 1–152 days).
Explanations for this included being given an alternative diagno-
sis (n=19; 33%), receiving advice to have blood or urine inves-
tigations (n=26; 46%) and referral to another HCP (n=2; 4%).
Children aged below 2 years were more likely to have mul-
tiple HCP contacts prior to admission than older children (69%
vs 23%, p=0.007). All children under 2 years who had been
seen on more than one occasion were initially given an alterna-
tive diagnosis, which was most commonly an infection. There
were no differences identified in ethnicity, social deprivation
score, or caregiver educational level between children who had
single and multiple HCP contacts (data not shown), however,
children from single-parent families were more likely to be
admitted following first HCP contact (88% vs 73%, p=0.04).
There were 33% of children who presented in DKA and had
been seen by multiple HCPs prior to admission, compared with
21% of those with HG, which was of borderline statistical sig-
nificance ( p=0.058). However, children who had multiple HCP
contacts had a lower pH on admission (median 7.32 (IQR
7.15–7.43) vs median 7.36 (IQR 7.29–7.39), p=0.03) and a
higher percentage were treated with intravenous insulin (39% vs
24%, p=0.04).
No child who presented with DKA had been advised to have
routine investigations, whereas, 25% of those with HG did.
Parental consideration of T1DM as a possible diagnosis
Overall, 64% of parents reported having considered diabetes as
the cause for their child’s symptoms, and 80% of those parents
raised their concerns with a HCP. If polyuria and/or polydipsia
were present, more parents considered the diagnosis (68% vs
20%, p<0.001).
Parents of children who have a first-degree relative with dia-
betes were more likely to consider T1DM as a possible diagnosis
HG
(80% vs 62%, p=0.021), and although fewer presented with
0.314** DKA, this did not reach statistical significance (16% vs 27%,
0.440*** p=0.13).
0.104 Of the children whose parents considered diabetes as a diag-
0.499*** nosis in their child, fewer presented with DKA than those where
−0.071 the diagnosis was not considered (13% vs 47%, p<0.001).
0.442*** However, the incidence of DKA at presentation was no different
whether or not the parent(s) discussed these concerns with a
HCP (13% vs 24%, p=0.24).

440 Lokulo-Sodipe K, et al. Arch Dis Child 2014;99:438–442. doi:10.1136/archdischild-2013-304818

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Of the 26 children referred by their GP for routine blood or
urine investigations, 21 (81%) of the parents had considered
diabetes as a possible diagnosis, and 18 (86%) had raised these
concerns with the HCP. None of these children presented with
DKA.
DISCUSSION
This survey provides contemporary information regarding the
patient journey prior to diagnosis of T1DM, and explored
potential factors for presentation with DKA. We have identified
a number of key findings: first, the incidence of DKA at presen-
tation of T1DM remains unchanged from previous UK studies
over the last 25 years,4–6 with one-quarter of children present-
ing in this way. Second, the majority of children do report clas-
sical symptoms of polyuria and/or polydipsia, although there is
marked variation in the duration of these symptoms. However,
fatigue, weight loss and enuresis are also common symptoms,
and more frequently, short histories of these symptoms were
reported in children who presented with DKA. Third, multiple
HCP contacts and delayed presentation to secondary care were
common and were associated with increased incidence of DKA
at presentation. Many children had undergone unnecessary
investigations prior to referral, and while none of these children
progressed to DKA in this cohort, these delays could lead to
greater morbidity and mortality. Finally, we identified a number
of factors which were associated with presentation with DKA.
Parental consideration of diabetes, and having a relative with
diabetes, were protective, and highlight the need for education
of the general public.
There are a number of limitations to this survey. We invited
all centres in England, Wales and Northern Ireland to take part
in the audit. Although this is the largest survey of its kind, only
42% of paediatric units contributed data to the survey.
Therefore, we cannot be certain that the DKA rate would have
been the same across the country, or that presentations may not
have varied between regions. However, the incidence of DKA
was remarkably similar (and alarmingly high) to that previously
reported, so it did not appear that there was any reporting bias.
Secondly, the data on duration of symptoms and HCP contacts
is subject to recall bias and parental perception. It is possible
that symptoms parents attributed to T1DM were caused by an
alternative diagnosis, and this is particularly likely in a small
number who reported symptoms for several months to years
prior to diagnosis. Similarly, we did not seek to confirm the
reported number of HCP contacts, or that the diagnosis of
T1DM was definitely missed. Furthermore, we relied on the
local diabetes team to provide accurate data on biochemical
findings and management at initial presentation rather than
obtaining copies of the case-notes. This approach was important
to enable collection of countrywide data. Importantly however,
as the data were collected prospectively over a three-month
period, the results should not be influenced by temporal
changes in healthcare-seeking behaviour, referral patterns or
changes in management.
The pattern of presenting symptoms differed in children with
DKA and HG, such that those with DKA were less likely to
report classical symptoms, but more frequently reported the less
specific symptoms of fatigue and weight loss. However, when
children aged below 2 years at diagnosis were excluded from the
analysis, the proportions of children in the two groups reporting
polyuria and polydipsia were similar. It is well recognised that
younger children are more likely to present with DKA,11 and
difficulty in recognising these symptoms in this age group might
contribute to greater morbidity at presentation. Reported
Lokulo-Sodipe K, et al. Arch Dis Child 2014;99:438–442. doi:10.1136/archdischild-2013-304818
Original article
symptom duration was shorter in children with DKA, consistent
with reports of some,20–22 but not all23 previous studies. This
could represent either a more aggressive disease process with
more rapid decline in pancreatic insulin production and/or
metabolic decompensation, or parental failure to recognise
symptoms. The concept of a more aggressive disease is sup-
ported by studies which have demonstrated a shorter honey-
moon period in children who present in DKA.24 However, in
this study, we identified a number of factors which would
support a theory of delayed parental recognition of symptoms.
First, HbA1c at presentation was similar in children with DKA
and HG, and while symptom duration displayed positive correl-
ation with HbA1c in children with HG, this was not evident in
those with DKA. Second, fewer parents of children with DKA
reported considering diabetes as a possible diagnosis, although
this could be due to a more rapid onset and less opportunity to
explore potential causes themselves (eg, searching the internet or
discussions with friends/family). Children who had four or more
siblings had shorter symptom duration, possibly suggesting that
experienced parents had greater ability to detect abnormal symp-
toms, although incidence of DKA at presentation did not differ.
Third, similar to previous studies,11 we found that fewer children
who have a first-degree relative with diabetes presented with
DKA. Together, these findings suggest that some knowledge or
experience of diabetes is protective and, therefore, highlight the
need for education of the general public with regards to symp-
toms, signs and need for early presentation in suspected diabetes.
Previous studies have shown diagnostic error to be associated
with increased risk of presentation with DKA25 26 and to occur
frequently in younger children.26 Our findings support this as
those who had multiple HCP contacts had lower blood pH on
admission and were more likely to present in DKA. It has previ-
ously been suggested that increased medical consultations27 and
delayed referral5 are associated with DKA, although this is not
supported by all studies.12 28 We particularly found that chil-
dren under 2 years of age were more likely to have multiple
HCP contacts. DKA rates are highest in this age group, there-
fore, it is important to highlight that opportunities to make an
earlier diagnosis might have been missed and could have pre-
vented progression to DKA. Nearly half of all children who had
a delay in admission of greater than 24 h had been advised to
undergo routine blood and/or urine investigations, yet nearly
70% of the parents of these children had discussed a possible
diagnosis of diabetes with the advising HCP. Although none of
these children progressed to DKA, point-of-care blood sugar
testing might have enabled an earlier diagnosis in these children.
Three intervention studies aiming to reduce the incidence of
DKA at diagnosis have had varying success.7 29 30 In Italy,
Vanelli et al identified that secondary enuresis and nocturia can
be early and frequent symptoms of T1DM and, therefore, used
this in a poster campaign targeted towards HCPs, teachers and
parents. Primary care paediatricians were also provided with
equipment for measuring capillary blood glucose and guidelines
for the diagnosis of T1DM.29 In comparison with a neighbour-
ing region, the incidence of DKA, duration of symptoms and
HbA1c at diagnosis decreased.29 In our study, only a third of
children reported enuresis compared with 89% in the Italian
study after the campaign. Therefore, specifically targeting this
symptom in the UK might prevent a large proportion of chil-
dren with symptoms being missed. A similar campaign in
Australia using HCP education sessions, posters, radio and news-
paper adverts and provision of blood glucose testing equipment to
HCPs also reported a significant decrease in DKA at diagnosis.30
By contrast, a Welsh campaign using posters in primary care
441
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Original article
surgeries and radio broadcasts, but without provision of equip-
ment or education, failed to reduce DKA incidence.7 It is pos-
sible that the differences in healthcare systems contributed to
the variable success of these campaigns; Italy has primary care
paediatricians, and in Australia, patients do not have a named
primary care practitioner. The results would also suggest that
increasing awareness in HCP by significant amounts of educa-
tion is important to the success of such campaigns.
In conclusion, this survey has identified a number of factors
which are related to having DKA at diagnosis of T1DM: older
age, a first-degree relative with diabetes, and parental consider-
ation of diabetes as a diagnosis were all protective, whereas,
lacking classical symptoms of polyuria and/or polydipsia, and
multiple HCP contacts increased the risk. These might represent
important targets to reduce the incidence of DKA at diagnosis
in the UK, and clearly, future campaigns should include general
public awareness and HCP education. In particular, educational
programmes for HCPs should highlight the importance of non-
specific symptoms (eg, weight loss and fatigue), in addition to
the classical symptoms. Awareness that T1DM does occur in
young children needs to be increased, as children under the age
of 2 years were likely to have multiple HCP contacts and
present in DKA. In this age group, polyuria and polydipsia are
less likely to be recognised and, therefore, consideration needs
to be given towards other symptoms. Furthermore, an emphasis
needs to be placed on point-of-care blood glucose testing, as
many children were referred for routine investigations, which
further contribute to diagnostic delays.
Acknowledgements The authors would like to thank NHS Diabetes, the
Association of Children’s Diabetes Clinicians, the British Society for Paediatric
Endocrinology and Diabetes, and participating local diabetes teams across the UK
for facilitating this study. All authors had full access to all the data (including
statistical reports and tables) in the study and can take responsibility for the integrity
of the data and the accuracy of the data analysis.
Contributors KLS performed the literature search, extracted the data, performed
data analysis, and wrote the first draft of the manuscript. RJM performed statistical
analysis, reviewed and edited the manuscript. JHD and JE developed and designed
the survey, reviewed and edited the manuscript. JHD and JE are the guarantors of
the work.
Funding RJM is supported by an NIHR academic clinical fellowship.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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 Downloaded from http://adc.bmj.com/ on September 18, 2016 - Published by group.bmj.com

Identifying targets to reduce the incidence of

diabetic ketoacidosis at diagnosis of type 1
diabetes in the UK
K Lokulo-Sodipe, R J Moon, J A Edge and J H Davies

Arch Dis Child 2014 99: 438-442 originally published online January 6,
2014
doi: 10.1136/archdischild-2013-304818

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Collections Child health (3897)
Diabetes (339)
Metabolic disorders (757)
Immunology (including allergy) (1999)
Epidemiologic studies (1796)
Urology (445)

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