Continuous Subcutaneous Glucose Monitoring Improved Metabolic
Control in Pediatric Patients With Type 1 Diabetes: A Controlled
Crossover Study
Johnny Ludvigsson, MD, PhD, and Ragnar Hanas, MD, PhD
ABSTRACT. Objective. To improve metabolic control and
prevent complications, both acute and late, we need to adjust
treatment on the basis of the blood glucose (BG) profile, as
not even the most active BG self-monitoring gives sufficient
information.
Design. We have used Continuous Glucose Monitor-ing
System (CGMS; Medtronic MiniMed, Northridge, CA) in a
controlled crossover study including 27 diabetic patients
aged 12.5 3.3 (mean; standard deviation; range: 5–19) years.
All patients were treated with intensive in-sulin therapy, 14
with multiple injections, and 13 with pumps. The patients
were randomized into an open or blind study arm. Both
arms wore the CGMS sensor for 3 days every 2 weeks.
CGMS profiles were used in the open study arm to adjust
insulin therapy at follow-up visits every 6 weeks. Both the
patients and the diabetes team were masked to the CGMS
profiles in the blinded arm, and insulin therapy adjustments
were based solely on 7-point BG profiles performed by the
patients. At 3 months the 2 study arms were crossed over.
Results. Despite initial problems with a device new to both
patients and the diabetes team, hemoglobin A 1C decreased
significantly in the open arm (from 7.70%– 7.31%) but not
in the blind arm (7.75%–7.65%). A total of 26/27 patients
experienced daytime low subcutaneous glucose (<3.0
mmol/L; .8 episodes/day; duration 58 29 minutes; 5.5% of
total time), and 27/27 patients had at least 1 nocturnal
episode of low subcutaneous glucose (.4 episodes/night;
duration 132 81 minutes; 10.1% of total time).
Conclusions. Use of CGMS facilitated an improved
treatment, and patients received new insight and in-creased
motivation. In this study, we found CGMS to be a useful tool
for education and improving metabolic control. Pediatrics
2003;111:933–938; type 1 diabetes, chil-dren, glucose sensing,
Continuous Glucose Monitoring System, metabolic control,
hypoglycemia, Dawn phenom-enon, Somogyi phenomenon,
rebound phenomenon.
ABBREVIATIONS. CGMS, Continuous Glucose Monitoring Sys-tem;
BG, blood glucose; MDI, multiple daily injection; HbA1C, hemoglobin
A1C; DCCT, Diabetes Control and Complications Trial.
From the Department of Pediatrics, University Hospital, Linko¨ping and Central
Hospital, Uddevalla, Sweden.
Received for publication Feb 26, 2002; accepted Jul 22, 2002.
Address correspondence to Johnny Ludvigsson, MD, PhD, Division of Pediatrics,
Faculty of Health Sciences, Department of Health and Environ-ment, S-581 85
Linko¨ping, Sweden. E-mail: johnny.ludvigsson@lio.se PEDIATRICS (ISSN 0031
4005). Copyright © 2003 by the American Acad-emy of Pediatrics.
Downloaded from www.aappublications.org/news by guest on August 29, 2018
I mproved metabolic control may prevent or at least postpone
late vascular complications.1 This is true not only in selected
and motivated study
groups but also in geographic populations without any
2– 4
selection of patients. However, despite very active
education and psychosocial support, it is quite difficult to
5,6
avoid hypoglycemia, and too many patients have poor
5,7–9
metabolic control. One impor-tant, yet missing,
element of metabolic control is the blood glucose (BG)
profile that guides the patient and diabetes team to adjust
insulin therapy to mimic normal pancreatic function. Even
the most active patient who self-monitors BG usually gets
only 4 to 8 snapshots of the BG profile during 24 hours,
giving only limited information about the real profile.
Glu-cose sensors (Continuous Glucose Monitoring Sys-
tem [CGMS]; Medtronic MiniMed, Northridge, CA) have
so far given promising results according to a few clinical
10 –13
studies. The incidence of hypoglyce-mic events has
decreased and metabolic control im-proved, as shown by
decreased hemoglobin A1C (HbA1C) in adults. In
10
pediatric studies, CGMS readings have been used for
11–13
short-time adjustments of insulin. Our patient
population is already used to quite active insulin treatment
6
and self-mon-itoring of BG. The aim of this study was to
see if we could further improve metabolic control with the
use of CGMS. The study was approved by the Research
Ethics Committees of the Medical Faculties of Go¨te-borg
and Linko¨ping Universities.
METHODS
The CGMS sensor monitors interstitial glucose levels (2.2–22
mmol/L) in subcutaneous tissue every 10 seconds and records an
average value every 5 minutes.14 The subcutaneous glucose oxi-dase
electrode is viable for up to 72 hours. Data are downloaded to a
computer providing a continuous tracing of BG values in the form of
daily BG profiles and a summary table of average glucose levels,
glucose ranges, and standard deviations. The lag time between CGMS
and BG after a meal has been found to be 4 minutes in rise and 9
minutes in fall.15 Local anesthetic EMLA Cream (Astra, So¨derta¨lje,
Sweden) was used before all insertions. Most used a special instrument
(Senserter) to minimize insertion pain.
Patients
Type 1 diabetic patients with an HbA 1C of 6.8% or above ( 8%
Diabetes Control and Complications Trial [DCCT]-level) were
consecutively asked to participate until we had reached 32 pa-tients that
agreed to participate after written information and informed consent
from their parents. Half of the patients were randomized into an open
study arm and the remaining patients into the blinded arm. Both arms
had 8 pump users and 8 patients with multiple daily injections (MDI).
Both study arms wore the
PEDIATRICS Vol. 111 No. 5 May 2003 933
CGMS for 3 days every 2 weeks and were instructed to complete at least
2 self-monitoring of BG measures at different times during the day and a
7-point SMGB once every week. During the blinded study arm, neither
the patient nor the diabetes team reviewed the results. After 3 months,
the open and blinded study arms crossed over. HbA 1C was determined
before and after each 3-month study period and the number of severe
hypoglycemic events were re-corded. HbA 1C was determined by DCA
2000 (Bayer, Gothen-burg, Sweden) and adjusted to the Swedish
national standard,16 which is 1.2% below the DCCT standard.17
One patient was excluded because of pregnancy, 1 had diffi-culty
managing the CGMS, and 3 found the protocol too demand-ing. The
remaining 27 patients were aged 12.5 3.3 (mean and standard deviation)
years (range: 5–19), with a type 1 diabetes duration of 7.0 3.9 (2–15)
years.
All patients were treated with intensive insulin therapy (usu-ally
rapid-acting insulin analogs before meals plus twice daily intermediate-
acting insulin, N 14) or insulin infusion pumps (N 13). Their baseline
HbA1C was 8.0% 1.1% (range 6.8%– 10.8%). According to our routine
instructions, meals were to be eaten at regular intervals, and a low-fat,
high-fiber diet with regular physical exercise was recommended.
Patients in both study arms were scheduled to visit the diabetes team
every 6 weeks during the study. Normally, clinic visits are scheduled
every 2 to 3 months or every month if HbA1C is 8% to 8.5%. Five
patients did not complete all 12 of the sensor evaluation periods;
however, their HbA1C results were included in the statistical analysis on
an intention-to-treat basis.
Statistics
Results from both partial and complete 24-hour CGMS profiles were
used in the statistical analysis. The 2-sided t test was used for statistical
analysis unless otherwise stated.
RESULTS
We registered 298 sensor profiles (both open and blind
arms included) with an average sensor life of 2.1 1.0 days.
This corresponded to 642 days of glucose measurements
(partial and complete days added to 24-hour periods). In
both the open and blinded study arms there was a
decrease in HbA1C during the first 3-month period. After
crossover, the now open arm had a further decrease in
HbA1C (caused mostly by a decrease in nocturnal high
sub-cutaneous glucose readings), whereas the now blind
arm increased again (Fig 1). Altogether there was a
Fig 1. HbA1C (Swedish calibration, 1.2%
below DCCT standard) values dur-ing the
study. After 12 weeks, the treat-ment arms
crossed over. Comparisons be-tween the start
and end of the 12-week periods are done with
the 2-sided t test. The P values above the
graph refer to the blinded sensors, below the
graph to the open sensors.
934 GLUCOSE SENSING IN DIABETIC CHILDREN
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significant decrease in HbA1C during the open arm when
there was access to the CGMS data from 7.70% to 7.31%
(P .013; Fig 2), whereas the decrease during the “blind”
arm was from 7.75% to 7.65% (P not significant). There
were on average 1.5 episodes/day of daytime high
subcutaneous glucose ( 15 mmol/L, duration 126 33
minutes, 19.4% of total time) and .6 episodes/night
(duration 177 83 minutes, 25.5% of total time). Low
glucose values were measured quite frequently, as
exemplified in Fig 3. Twenty-six of 27 patients
experienced daytime low subcutaneous glucose ( 3.0
mmol/L, .8 epi-sodes/day, duration 58 29 minutes, 5.5%
of total time) and all patients had at least 1 nighttime
episode of low subcutaneous glucose (Fig 3; .4 episodes/
night, duration 132 81 minutes, 10.1% of total time)
during the study. We found no difference in low
subcutaneous glucose frequency between the 2 treat-ment
arms, nor between MDI and continuous sub-cutaneous
insulin infusion users.
Fig 4 illustrates how individual patients registered
abnormal but quite systematic glucose profiles mea-sured
by the sensor, which led to recommendations of treatment
changes and improved glucose profiles as a consequence.
Examples of changes in treatment are both increased and
decreased bedtime insulin dose/nighttime basal rate,
change in premeal bolus dose and timing, changed type of
basal insulin in MDI, and change in the amount of extra
insulin used to correct high BG levels. Dawn phenomena,
defined as a nighttime subcutaneous glucose level of 3.5
mmol/L (absence of hypoglycemia), followed by a
spontaneous rise in subcutaneous glucose of 7 mmol/L in
the early morning hours (Fig 5), were found in 5.3% of
the total number of recorded days (in 10 patients).
Somogyi phenomena, defined as a similar spontaneous
rise of subcutaneous glucose during night but preceded by
a low subcutaneous glucose ( 3.5 mmol/L), occurred in
13.3% of the days (in 17 patients). Somogyi phenomena
were less

Fig 2. HbA1C values during the open and blind arm for all 27 patients.
The difference between baseline and 12 weeks was sig-nificant for the
open arm (7.70% vs 7.31%; P .013; 2-sided t test) but not for the blind.
The P values in the figure refer to the difference between the arms,
which was significant at 12 weeks (7.65% vs 7.31%; P .011; 2-sided t
test).
common in the pump patients (5/13 vs 12/14 pa-tients, P .
2 several possible ex-planations. Glucose in subcutaneous
018, x ). Daytime rebound phenomena (Fig 6) with a
rapid increase (within 3 hours) of subcutaenous glucose
from 3.5 mmol/L with 10 mmol/L were found in 25.7% of
the days (in 24 patients). Two patients experienced severe
hypogly-cemia during the study: 1 during the blind arm
and 1 during the open.
The glucose sensors gave important information, but
there were several practical problems. A total of 104 of
the 298 (34.9%) sensors diplayed a 3-day curve, whereas
154 of the 298 (51.7%) curves gave information during 1
to 2 days. In 25 of the 298 (8.4%) cases, no sensor curves
were generated. In some cases, the cable had to be
exchanged. A 7-year-old girl left the study after having
tried the sensor during the first 3-day period, as she
disliked wearing it.
DISCUSSION
Our results indicate that changes in intensive in-sulin
therapy based on CGMS profiles improved metabolic
control in pediatric patients with type 1 diabetes. As the
device was completely new for us, one could expect less
effect on HbA1C during the first period, when many
initial practical problems (such as forgetting to calibrate
the monitor or enter self-monitoring of BG readings in the
appropriate time frame) were encountered. We were
surprised and cautioned by the many low subcutaneous
glu-cose periods, not least during nighttime, which led to
decreased insulin doses in the open arm during the first 3-
month period. Our lack of experience of CGMS before
the study, leading to insufficient/inef-fective information
to the patients/parents, may ex-plain some of the practical
problems. This led to some difficulties with the
interpretation of the glu-cose sensor profiles, especially in
the beginning of
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the study. Despite such initial problems, we were able to
decrease HbA1C significantly during the open arm when
we received information about the glucose profiles,
without increasing the frequency of hypo-glycemia.
Improvements in HbA1C, even in patients initially
randomized to the blinded study arm, may be attributed to
a study effect related to more fre-quent visits to the
diabetes team and enthusiasm to see CGMS profiles in the
future open study arm. For most patients, the number of
7-point profiles taken during the study months did not
differ from their regular routines. It is remarkable that
HbA1C de-creased as the large number of periods with
very low subcutaneous glucose led to decreased insulin
doses in several patients, especially during the first 3-
month period. The return of HbA 1C to baseline levels in
the group that ended with the blind arm indicates a need
for repeated use of the sensor, espe-cially in this group of
patients including many teen-agers with unstable diabetes
control.
The number and duration of low subcutaneous glucose
readings is surprising and perhaps even scary. Other
authors have also found a surprisingly high frequency of
nighttime low subcutaneous glu-cose after only 2 to 3
11
days use of CGMS: 67.8% of patients aged 2 to 18 years
13
and 83% of patients aged 3 to 29 years. There are
tissue fluid has been said to be in rapid steady state with
BG, but we cannot be sure that this is the case during very
low glucose concentrations when glucose might be dis-
18
tributed to the organs with greatest need, eg, the brain.
If subcutaneous glucose does not reflect BG in the very
low range this would be a great pity, as a subcutaneous
sensor then cannot be used as an alarm preventing
hypoglycemia. Does sleeping on your belly affect
subcutaneous blood flow, thus lowering the registered
values? A third, interesting, possibility would be that our
present paradigm regarding BG concentrations is wrong.
Thus, perhaps BG concen-trations might go down to 2 to
3 mmol/L without causing neither counter regulation nor
harm? This would actually fit with our own observations
(J. Lud-vigsson, unpublished observations) that many
healthy school children may have BG values down to 2.7
mmol/L, without showing any symptoms of hy-
poglycemia. Interestingly, when we tried the glucose
sensor on the staff before the study, several nondia-betic
adults noticed readings below 2.2 mmol/L dur-ing the
night. More studies are needed, but so far we have to act
6,19
aiming at prevention of hypoglycemia.
Our study showed wide and rapid glucose fluctu-ations
in all patients. Whether spontaneous increase of BG in the
early morning should be defined as Dawn phenomena,
Somogyi phenomena, or are just consequences of
fluctuations of insulin concentra-tions cannot be answered
by our study. Elevations of glucose levels in the early
morning were found in 22% of pediatric patients after
13
using CGMS at 1 occasion. We can only notice that
such rapid fluc-tuations exist in children and adolescents.
Daytime so-called rebound phenomena are even more
com-mon, sometimes seemingly caused by hormonal
ARTICLES 935
Fig 3. All patients showed low ( 3 mmol/L) nocturnal subcutaneous glucose on 1 or more occasions, and all but 1 had at least 1 episode of low daytime
subcutaneous glucose. This chart is from an 11-year-old girl with HbA1C of 5.7%.

Fig 4. Modal day view from a 13-year-old boy with HbA1C of 7.3%. The variations over the day and night are sometimes very similar for the 3 testing
days. Glucose concentration in millimoles per liter.

counterregulation, but at other times probably caused by
eating too much extra food to cure hypo-glycemia. This
knowledge can lead to an insight which improves both
treatment routines and meta-bolic control.
Some patients did not want to try the device at all as it
meant new pricks, a subcutaneous catheter and an
instrument connected to the body, which may be
disturbing during sports, baths, and perhaps during sleep.
However, most patients accepted the device, and in most
cases we got very informative glucose profiles during 48
to 72 hours. Too many inter-ruptions of the glucose
curves, unexpected alarms, and nonfunctioning wires
certainly diminished the enthusiasm, but these practical
problems have de-creased with more practical experience
of the

936 GLUCOSE SENSING IN DIABETIC CHILDREN

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 Fig 5. Example of “Dawn phenomenon” in a 16-year-old girl with HbA1C of 7.4%.

Fig 6. A 9-year-old girl with HbA1C 7.0% showing 2 rebound phenomena (arrows). It is unlikely that the very rapid increase in BG is caused only by
eating as a girl of this weight (36.6 kg) would need 50 g of quick-acting sugars to accomplish a rise of close to 20 mmol/l in such a short time.

method, and could perhaps be overcome with im-
provements of the device.
CONCLUSIONS
Our experience of CGMS in diabetic children and
teenagers is mainly good and we expect this device
to be an important complement of our treatment choices
and a useful educational tool. The sensor gave valuable
information that we have never had before. We are now
turning this device into clinical practice. We recommend
the use of CGMS in patients with elevated HbA 1C, a
worrying increase of

ARTICLES 937
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HbA1C, in patients with known or suspected hypo-
glycemia during the night or tendency to severe
hypoglycemia, patients who lack motivation for self-
monitoring of BG or who do not understand how to
interpret BG profiles and how to adjust insulin dose, and
finally in patients who want to learn more about the effect
of meals or physical exercise on their BG.
ACKNOWLEDGMENTS
R. Hanas has received speakers honoraria and an unrestricted grant
from Minimed, Inc.
We thank our skillful diabetes nurses Catarina Andreasson, Eva
Isacson, and Elsie Johansson for their invaluable assistance, Dr Ulf
Samuelsson and Dr Sam Nordfeldt for helping with the CGMS
interpretation and dose adjustments, Anna Ter Veer for valuable help
with data adaptation and statistics, and Medtronic MiniMed for
providing the sensors.
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TESTS ARE SET FOR ADULT DRUGS CHILDREN TAKE

“The government announced plans to begin clinical tests this year on 12 drugs
commonly prescribed for children although their safety and effectiveness has been tested
only in adults. . . The drugs include azithromycin, an antibiotic used to treat bacterial
infections, and lithium, used to treat bipolar mood disorders. The others are baclofen,
bumetanide, dobutamine, dopamine, furosemide, heparin, loraz-epam, rifampin, sodium
nitroprusside and spironolactone. . . Congress passed legislation last year giving drug
makers financial incentives for conducting the tests. Congress also set up grants to finance
pediatric studies. . . the National Institutes of Health, which will oversee the tests, has set
aside $25 million.”

New York Times. January 21, 2003

Noted by JFL, MD

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Continuous Subcutaneous Glucose Monitoring Improved Metabolic Control in
Pediatric Patients With Type 1 Diabetes: A Controlled Crossover Study
Johnny Ludvigsson and Ragnar Hanas
Pediatrics 2003;111;933
DOI: 10.1542/peds.111.5.933

Updated Information & including high resolution figures, can be found at:
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References This article cites 19 articles, 6 of which you can access for free at:
http://pediatrics.aappublications.org/content/111/5/933#BIBL
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 Continuous Subcutaneous Glucose Monitoring Improved Metabolic Control in
Pediatric Patients With Type 1 Diabetes: A Controlled Crossover Study
Johnny Ludvigsson and Ragnar Hanas
Pediatrics 2003;111;933
DOI: 10.1542/peds.111.5.933

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/111/5/933

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