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Study Guide
Table of contents
Background
4
Aims and outcomes
5
Inclusion criteria
5
The continuous glucose monitor
6
Blood glucose levels
7
Randomisation
7
The gel and how to administer
7
Other blood tests
8
Discharge from hospital while still in study
8
References
9
Appendix A: Study flow diagram
10
Appendix B: Continuous glucose monitor flow diagram
11
Appendix C: Continuous glucose monitor instructions
12
Appendix D: Forms
13
Contact details
15
Background
Neonatal hypoglycaemia (low blood sugar level) is a common problem and the only known
common preventable cause of brain damage in the newborn period.1, 2 Hypoglycaemia is most
common in the first twenty four hours after birth, and is a common reason for admission to the
Newborn Intensive Care Unit. There are groups of babies who are at greater risk of neonatal
hypoglycaemia, including infants of diabetic mothers, growth restricted, small for gestational age
(< 2500g) and large for gestational age babies (> 4500g).4-6 After a baby is born the glucose levels
fluctuate as the baby adapts from continuous intravenous glucose supply from the placenta to the
intermittent, fat-based enteral nutrient supply after birth. In clinical practice, blood glucose levels
are measured in at-risk babies intermittently, commonly 1-4 hourly. However these intermittent
blood tests may easily miss significant periods of low blood glucose levels, for example before
feeds. Thus it is possible that some infants with hypoglycaemia that may threaten brain function are
not identified, or alternatively that some babies with only an occasional brief fall in blood glucose
levels are at no risk of impaired brain function but are inappropriately and invasively treated.
In diabetic patients, continuous monitoring of blood glucose levels can lead to improved metabolic
control. 7 Continuous glucose monitoring has been shown to be safe in preterm babies 8 but its
role in the management of neonatal hypoglycaemia has not yet been determined. The vast majority
of neonatal hypoglycaemia is transient and is the result of delayed metabolic adaptation following
birth.
There has been controversy regarding the blood glucose level at which treatment should be
provided to a baby. One of the reasons for the controversy is that it remains unclear how low the
blood glucose level needs to be, or for how long the blood glucose level needs to be low, before
neurological damage occurs. The most widely accepted clinical threshold at which treatment is
provided depends on the blood glucose level and the risk factors for the baby. Blood glucose levels
below 2.6mmol/l are generally accepted as requiring treatment. 3 Blood glucose levels below these
thresholds may increase the likelihood of neurological damage.9, 10 However, once diagnosed, the
best treatment for hypoglycaemia also remains unclear.
Current treatment choices vary depending on the baby’s birthweight, gestational age, and
associated risk factors. If the baby is able to feed then initial treatment focuses on encouraging
feeding. However, if the blood glucose level does not increase or the baby has difficultly with
feeding then admission to the newborn intensive care unit is usually indicated. Standard clinical
practice in the newborn intensive care can include breast feeds, additional feeding with infant
formula, intravenous dextrose, or specific medications such as glucagon. However, ideal treatment
would keep the mother and baby together wherever possible, optimise the establishment of breast
feeding and support the metabolic transition.
If additional feeding does not reverse hypoglycaemia, intravenous dextrose is a common next
standard treatment. A recommended regimen includes a bolus of 200mg/kg of glucose (2ml/kg
of dextrose 10%) followed by an infusion of 8 mg/kg.min. 13 This treatment has been shown to
improve the blood glucose level without unnecessary hyperglycaemia. 13 However, it does require
admission to the newborn intensive care unit.
Another less commonly used treatment is 40% dextrose gel. Oral carbohydrate is first line
treatment for low blood sugar levels in the conscious diabetic child or adult.14 However, the
Waikato Newborn Intensive Care Unit is the only unit in Australasia to use dextrose gel for the
management of hypoglycaemia. The dextrose is absorbed across the buccal membranes and
is reported to increase the blood glucose level and reduce the need for intravenous glucose
infusion.15 The dose used (0.5ml/kg or 200mg/kg) is the same as that recommended for an
intravenous bolus of dextrose.
Two studies regarding the use of dextrose gel have been reported in conference proceedings,
although neither has been published in full. The first study was observational and reported using
a dose of 0.5ml/kg in 14 babies. There was a mean increase in blood glucose levels of 1.8mmol/
l 20 minutes after administration. 16 The second study randomised 75 babies ≥ 36 weeks
gestation who had blood glucose levels <2.5mmol/l to feeding or feeding plus 40% dextrose gel
1ml/kg. The authors reported no differences in blood glucose levels in either group at 15 or 30
minutes after treatment. However, in bottle fed babies, the volume of the subsequent feed was
significantly reduced after dextrose gel.17 Therefore, the role of dextrose gel in the management of
hypoglycaemia remains unclear.
We propose a randomised double blind placebo controlled trial to investigate the effectiveness of
dextrose gel 40% as a treatment for hypoglycaemia in term and near term newborn infants.
Aim
To determine whether treatment with 40% dextrose gel is more effective than feeding alone in
reversing neonatal hypoglycaemia in term and near term babies in the first 48 hours after birth.
Hypothesis
1. That 40% dextrose gel is more effective than feeding alone in reversing neonatal
hypoglycaemia.
2. That intermittent blood glucose monitoring does not detect all episodes of hypoglycaemia.
Primary Outcome
Treatment failure, defined as a blood glucose level < 2.6mmol/l 30 minutes after the second of two
treatment attempts 30 minutes apart.
Secondary Outcomes
• The time taken to achieve an interstitial glucose level above 2.6mmol/l for >1 hour.
• Incidence of recurrent hypoglycaemia (blood or interstitial glucose concentration <2.6mmol/l)
after initial successful treatment (defined as blood or interstitial glucose concentration > 2.6mM
for >1 hour after initial treatment).
• Total duration of interstitial glucose levels < 2.6mM
• Incidence of admission to the neonatal intensive care unit
• Volume of expressed colostrum provided to babies in the first 48 hours
• Frequency and total volume of formula administered in the first 48 hours
• Total dose of dextrose gel administered
• Incidence and total dose of intravenous dextrose administered in the first 48 hours
• Rate of full breast feeding at two weeks of age
Study Design
Randomised, placebo controlled double-blinded study in hypoglycaemic
near-term and term babies, comparing the incidence of treatment failure in babies randomised to
receive either 40% dextrose gel (BioMed New Zealand Limited), or a placebo vehicle gel.
Inclusion Criteria
• 35 weeks gestation or greater
• Age < 48 hours after birth
• Parental written informed consent
Recruitment
Wherever possible at risk babies will be identified before birth and their parents invited to take part.
These babies include:
•Small for gestational age (estimated fetal weight <10th centile)
•Large for gestational age (estimated fetal weight > 90th centile)
•Estimated fetal weight < 2.5kg or greater than > 4.5kg
•Diabetic mothers
Additional at risk babies will be identified following birth including:
•Small for gestational age (birth weight <10th centile)
•Large for gestational age (birth weight > 90th centile)
•Birth weight < 2.5kg or greater than > 4.5kg
•Baby of diabetic mother
•Any baby thought to be at risk of hypoglycaemia for clinical reasons (eg. not feeding well,
possible symptoms)
When a baby is recruited prior to birth the researcher will
•Place a copy of the consent form in the mother’s notes and keep the original in a folder in the
Nurse Practitioners’ office within the Newborn Unit.
•Label the front of the mother’s notes with a study sticker.
•Document the recruitment in the Sugar Baby Study register.
•Give the parents a study card to be handed to the delivery staff prior to the birth of the baby.
This card will provide confirmation that parents have consented to the study and contact details
of the researchers.
•Send a letter to the Lead Maternity Carer (LMC), explaining the study and requesting the LMC
to contact the research team just before the birth.
The Continuous Glucose Monitor Sensor
The continuous glucose monitor sensor measures interstitial glucose levels via a small flexible metal
electrode. The continuous glucose monitor records 288 glucose readings in a 24 hour period (one
every 5 minutes). The results are only available when the data are downloaded at the end of the
study.
The sensor will be inserted immediately after birth (or after consent is obtained, if this is after birth)
using an aseptic technique into the lateral aspect of the baby’s thigh and secured in place with
a clear occlusive dressing. Insertion of the sensor will done using the trigger loader Sen-serter ®
device, which is specially designed for the insertion of the sensor.
Continuous glucose monitors and other equipment is kept in the Nurse Practitioners’ office in the
Newborn Intensive Care Unit. The sensors for the glucose monitors are kept in the blood gas room
fridge, in the Newborn Intensive Care Unit.
• The continuous glucose monitor sensor.
• The continuous glucose monitor.
Initialisation of the Continuous Glucose Monitor
Before the continuous glucose monitor will begin recording there is an initialisation period which
takes one hour. Therefore, it is important to place the Continuous Glucose Monitor immediately
after birth or after consent is obtained.
Removal of the Continuous Glucose Monitor
The Continuous Glucose Monitor will be removed by a member of the research team 48 hours
after insertion.
Blood glucose levels
All blood samples will be taken by heel prick and blood glucose levels will be measured in the
Newborn Unit using the blood gas analyser or in the laboratory. Blood glucose levels obtained
from the Precision or HemoCue cot-side blood glucose level analysers are unreliable and cannot
be used for this study.
Randomisation
Babies are only randomised when the blood glucose level is < 2.6 mmol/l.
Randomisation is done by a computer programme which is in the Newborn Intensive Care Unit
Office. A member of the research team will perform the randomisation process.
The Gel
Dose: 0.5ml/Kg.
Example: For a 3.5Kg baby, the dose is 1.75ml of gel.
Method:
It is essential to administer the gel using this method.
• Calculate the amount of gel required
• Wash hands
• Put on glove
• Dry the inside of the cheek (buccal membrane) with gauze square
• Squeeze the required volume of gel from the syringe and massage into the dried area.
• Discard the syringe and any remaining gel
The gel will be made up by the pharmacy and be kept in the fridge in the blood gas room, in the
Newborn Intensive Care Unit.
A member of the research team will bring the gel to the baby after randomisation.
There will be a bag with six labelled syringes of gel.
It is essential that:
• The number of the syringe is written on the data collection form.
• The data and time that the gel is given is written on the data collection form.
• Once the dose of gel is given to the baby, the syringe is immediately disposed of.
• At the end of the study (admission to neonatal unit or 48 hours after birth, whichever occurs
first), the bag with all remaining syringes should be returned to a member of the research team
for disposal
Other blood tests
If the baby remains hypoglycaemic (blood glucose level <2.6mmol/l) following two doses of gel 30
minutes apart, the baby will require admission to the Newborn Intensive Care Unit for management
of hypoglycaemia. During the admission process, at the time that other blood samples are being
taken, an addition study blood sample will be taken. Pre-prepared packs with the blood form and
green topped collecting tube are kept in the Nurse Practitioner office in the Newborn Intensive Care
Unit.
The sample can be taken as a capillary heel prick, a venous sample or an arterial stab, whichever
is convenient. Approximately one ml is collected into a green top blood tube, placed on ice and
sent to the lab for centrifuging and freezing. Ice is kept in the freezer in the dispensary room. These
samples will be analysed for insulin, ketones and lactate at a later date.
Data collection
There are three data collection forms for each baby (See attached). These forms will be kept in the
Nurse Practitioner Office in the Newborn Intensive Care Unit. A member of the research team will
assist as necessary.
Discharge from hospital within 48 hours
If the baby is considered to be well enough for discharge within the 48 h period, the Continuous
Glucose Monitor is to remain in place. The parents will be provided with instructions regarding how
to manage the monitor and document the feeds on the data collection sheet.
A member of the research team will be on call for the family at all times.
References
1. Cornblath M, Odell GB, Levin EY. Symptomatic neonatal hypoglycemia associated with
toxemia of pregnancy. Journal of Pediatrics 1949;55(5):545-562.
2. Volpe JJ. Hypoglycemia and brain injury. Neurology of the Newborn. 4th ed. Philadelphia: WB
Saunders Company, 2001:497-520.
3. Sinclair BA, Rowan JA, Hainsworth OT. Marcosomic infants are not all equal. Australian and
New Zealand Journal of Obstetrics and Gynaecology 2007;47:101-105.
4. Hay W. Fetal and neonatal glucose homeostasis and their relation to the small for gestational
age infant. Seminars in Perinatology 1984;8(2):101-116.
5. Ward-Platt MP, Deshpande S. Metabolic adaptation at birth. Seminars in Fetal and Neonatal
Medicine 2005;10:341-350.
6. Cheyne EH, Cavan DA, Kerr D. Performance of a continuous glucose monitoring system
during controlled hypoglycaemia in healthy volunteers. Diabetes Technology & Therapeutics
2002;4:607-613.
7. Beardsall K, Ogilvy-Stuart A, Ahluwalia J, Thompson M, Dunger D. The continuous glucose
monitoring sensor in neonatal intensive care. Archives of Disease in Childhood, Fetal and
Neonatal Edition 2005;90:F307-F310.
8. Cornblath MD, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz R,
et al. Controversies regarding definition of neonatal hypoglycemia:suggested operational
thresholds. Pediatrics 2000;105(5):1141-1145.
9. Koh TH, Aynsley-Green A, Tarbit M, Eyre JA. Neural dysfunction during hypoglycaemia.
Archives of Disease in Childhood 1988;63:1353-1358.
10. Lucas A, Morley R, Cole T. Adverse neurodevelopmental outcome of moderate neonatal
hypoglycaemia. British Medical Journal 1988;297:1304-1308.
11. Lilien L, D, Pildes R, S,, Srinivasan G, Voora S, Yeh T. Treatment of neonatal hypoglycaemia
with minibolus and intravenous glucose infusion. Journal of Pediatrics 1980;97(2):295-298.
12. Boyle P, Zrebiec J. Management of diabetes-related hypoglycaemia. Southern Medical
Journal 2007;100(2):183-194.
13. Bourchier D, Weston P, Heron P. Hypostop for neonatal hypoglycaemia. New Zealand
Medical Journal 1992;105(926):22.
14. New treatment of neonatal hypoglycaemia. 6th Congress of the Federation of Asian Oceania
Perinatal Society; 1990.
15. Troughton K, Corrigan N, Tait R. Hypostop gel in the treatment of neonatal hypoglycaemia: a
randomised controlled trial. Archives of Disease in Childhood 2000;82 Suppl 1:A30.
Appendix A: Flow diagram of the study
10
Appendix B: Instructions for how to enter blood glucose levels, feeds and gel administration
into the continuous glucose monitor.
11
Appendix C: Continuous glucose monitor instructions
Continuous glucose monitor instructions
All blood glucose levels, feeds and dextrose gel must be entered into the Continuous Glucose
Monitor
Event marking
There are four function buttons on the Continuous Glucose Monitor
1. On/Off button
2. SEL button which means “Select”. Pressing SEL allows you to scroll through the monitor
display screens
3. ACT button which means “Activate”. Pressing ACT opens up the screen or verifies something
that you have entered, e.g. a blood glucose level or a feed. The ACT button is the same as the
enter button on a computer or cell phone.
The button labelled
allows you to change the screen that you are in.
How to enter blood glucose levels into the Continuous Glucose Monitor
See flow diagram page 11.
1. Press the SEL button once.
2. Press the ACT button once and the word ENTER will appear on the screen.
3. By pressing the arrow buttons you can scroll to your current blood glucose level.
3. When the correct blood glucose level is entered, press the ACT button
The Continuous Glucose Monitor cannot accept a blood glucose level
< 2.2mmol/l. When a blood glucose level is < 2.2mmol/l, enter 2.2mmol/l into continuous glucose
monitor. Then write on the data collection sheet, the date, time and actual blood glucose level.
How to enter feeds into the Continuous Glucose Sensor Monitor
1. Press the SEL button twice
2. The screen will then flash event.
3. Press the ACT button once
4. Use the arrow key to scroll through events, eg, feeds, medication.
5. Press the ACT button when feeds are highlighted.
How to enter gel into the Continuous Glucose Sensor Monitor
1. Press the SEL button twice
2. The screen will then flash event.
3. Press the ACT button once
4. Use the arrow key to scroll through events, eg, feeds, medication.
5. Press the ACT button when the word medication is highlighted.
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Appendix D: Data collection sheets
SBS001
The Sugar Babies Study
Birth and Enrolment Form
Study Number:
Maternal Details
Age (years)
Pre-pregnancy:
Height
G
Weight (Kg)
If diabetic please tick
During pregnancy:
Weight gain (Kg)
BMI
Polycose test during pregnancy
Yes
No
BMI
Result:
¸:
Gestational diabetes
Medication required
P
Type I diabetes
Yes
Type II diabetes
No
If medication required please list:
Most recent HBA1C
Date
Last four blood glucose levels during labour
Date
Time
HBA1C
Test result
Intended method of feeding
Breastfeeding
Breast milk
Formula
Expressed breast milk prior to birth
Combination
Yes
No
Comments:
Baby Details
Apgars
1 min
5 min
10 min
Time of birth
Sex
M
Birth Weight (g)
F
Gestation (wks)
EDD scan:
EDD dates:
Clinically best estimate:
Delivery: please tick ¸
Normal vaginal delivery
Caesarian
Singleton
Twin
Triplet
Reason at risk for hypoglycaemia:
Small for Gestational age
Late Preterm 35-37 weeks
Poor Feeding
Large for Gestational age
Maternal Diabetes
Other
If other please explain:
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SBS002
The Sugar Babies Study
Randomisation and Treatment Form
Study Number:
To be completed for all babies
Insertion of continuous glucose monitor
Date:
Time:
Site:
Sensor number:
Time:
Blood glucose level:
Randomisation
Date:
Removal of continuous glucose monitor
Time of birth:
Date:
Birth weight:
Time:
Syringe pack number:
1 Status of baby prior to feed
3 Method codes
5 Bowel motion codes
1
Awake and hungry
S
Syringe
Colour
Volume
2
Awake and requiring encouragement to feed
C
Cup
1
Mec
S
Small
3
Required waking for feed
4
Too sleepy to feed
L
Lactaid
2
Dark transitional
M
Medium
B
Bottle
3
Light transitional
L
Large
F
Finger tubing
4
Mustard yellow
2 Breast feeding codes
4 Feeding or gel tolerance
6 Urine codes
Tolerated
S
Small concentrated
C
Clear
U
Urates
C
Latches on – no sucking
T
D
Latches on and off – few sucks
S
Small spill
M
Moderate spill
L
Large spill (all of feed or gel dose)
Hand express colostrum and give to baby
E
Good rhythmical sucking
F
Good rhythmical sucking audible swallowing
Skin-to-skin prior to first blood glucose level?
No intervention required
Yes
No
Comments
Temp ºC
Gel (vol)
4
Syringe number
Feeding or gel tolerance
3
Blood glucose level
Method code
Bowel motion
Volume
2
Expressed breast milk or
formula feeding
Breast feeding code
1
Time at breast
Status of baby prior to feed
Time (24h)
Date (dd/mm/yy)
Feeding codes
Urine code
Offered – rooting, does not latch
Volume
Offered – does not latch
B
Colour
A
5
5
6
If admitted to Newborn Intensive Care Unit:
Date/time of admission
Consent for Babies Study
Yes
No
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SBS003
The Sugar Babies Study
Outcome Form
Study Number:
Outcome
To be completed for all babies
Mothers label
Babies label
Christian name
Date baby will be two weeks old:
Best Contact Details
Randomised
Home ph:
E-mail:
Yes
Mob. ph:
No
Number of gel doses
Primary Outcome
Two Blood Glucose Levels <2.6 mmol/l following two doses of gel
Tick
¸
To Newborn Intensive Care Unit
Other
Data collection
To be completed by ____________________
Date
Sign
Data forms complete
Data forms checked
Data entered
Data checked
Queries resolved
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SBS003
The Sugar Babies Study
Outcome Form
Did the baby receive formula in first 48 hours
Study Number:
Yes
No
If yes, number of formula feeds
total formula volume (ml)
Did the baby receive expressed breast milk in first 48 hours
Yes
No
Yes
No
If yes, number of expressed breast milk feeds
total expressed breast milk volume (ml)
Did the baby receive intravenous dextrose in first 48 hours
If yes, total volume of 10% dextrose in the first 48 hours (ml)
Additional comments:
Did the baby receive bolus doses of 10% dextrose in first 48 hours
Yes
No
If yes, number of 10% dextrose bolus
total volume (ml)
Additional comments:
Feeding
Date the baby will be two weeks old
Feeding at two weeks of age
Breast feeding exclusively
Breast milk via bottle
Infant formula
Combination feeding
Additional comments:
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SBS004
The Sugar Babies Study
Parent Questionairre
Study Number:
Thank you for being part of the Sugar Babies Study.
What was the best thing about being in the Sugar Babies Study?
Yes
No
Being able to help with research that may help other families
Yes
No
Being in the study was easy for both myself and my baby
Yes
No
The researchers were very supportive
Other, please explain:
What didn’t you like about being in the Sugar Babies Study?
Yes
No
There was nothing that I disliked
Yes
No
My contact with the researchers
Yes
No
Being randomised made me feel worried
Yes
No
The continuous glucose sensor being attached to my baby’s leg
Yes
No
The continuous glucose monitor was heavy
Other, please explain:
If randomised
What did you think about the gel as a treatment?
Easy to give
Messy
Did you have a feeling about which gel group your baby was in?
Yes
No
If so which group?
Gel
Placebo
Finally
If you had your time again would you be involved in the study again?
Yes
No
Please explain:
Would recommend the Sugar Babies Study to friends?
Yes
No
Please explain:
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Contact Details
The best way to contact the research team for the Sugar Babies
Study is on the locator: 20965 or Deborah Harris on cell phone
021 471790
Deborah Harris
Neonatal Nurse Practitioner
021471790
Cathy McBride
Research Nurse
Locator: 20965.
Phil Weston
Clinical Unit Director Child Health
Ph 8398899 ext 6763
0212793319
Principal Investigator
Professor Jane Harding
Liggins Institute
University of Auckland
Park Avenue
Grafton
Auckland
Ph 3737599 ext 85872
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