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Neonatal Glucose Homeostasis:

NMH Policy on Neonatal


Hypoglycemia
Malika Shah, MD
January 15, 2013

Hypoglycemia most common metabolic


problem in newborns
Occurs in 1 - 3 out of every 1,000 births
Especially challenging for breastfeeding
mothers
HTTP://WWW.NCBI.NLM.NIH.GOV/PUBMEDHEALTH/PMH0004559

Outline of Lecture
1. Understand the biochemical basics of glucose
homeostasis
2. Understand relationship between maternal and fetal
glucose metabolism and normal physiologic changes
that occur post-natally
3. Review neonatal hypoglycemia data, including recent
literature and AAP position statement March, 2011
4. Discuss development and implementation of
Northwestern Memorial Hospital policy on hypoglycemia

Basics of Glucose Homeostasis

Why glucose homeostasis is important


What alternate fuels can be used
Definition of common terms
What substrates are used and where they enter
pathways

Importance of Glucose Homeostasis


Glucose is primarily metabolized by the brain
The brain primarily metabolizes glucose
Alternate fuels used by the brain
Pyruvate
Lactate
Ketones

NICHD Workshop Report, 2009

Common Terms with Definitions


Term
Definition
Gluconeogenesis Biosynthesis of new
glucose
Glycogenolysis
Breakdown of
glycogen into glucose
monomers
Glycolysis
Metabolic pathway
that converts glucose
into pyruvate

Energy
Consumed
Generated

Generated

Gluconeogenesis

Glycogenolysis

**(adult norms)

://physicianjobster.com/physician-guidelines/homeostasis-diagram-of-insulin-and-glucagon-in-controlling-blood-glucose/

http

Glycolysis

http://en.wikipedia.org/wiki/Glycolysis

Energy Yield from Complete Oxidation


of One Glucose Molecule
Step

Coenzyme yield

2 NADH

Source of ATP
Phosphorylation of glucose
and fructose 6-phosphate
uses two ATP from the
cytoplasm.
Substrate-level
phosphorylation
Oxidative phosphorylation

2 NADH

Oxidative phosphorylation

Glycolysis
preparatory
phase

Glycolysis payoff phase


Oxidative
decarboxylation
of pyruvate

ATP yield
-2

2
Krebs cycle

6 NADH
2 FADH2
Total yield

18
4
38 ATP

Substrate-level
phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation

Substrates for Gluconeogenesis

Lactate
Pyruvate
Amino acids
Glycerol
Propionate
Glutamine

Lactate and The Cori Cycle


Lactate produced by anaerobic
glycolysis in non-hepatic tissues
(muscle/erythrocytes)

Liver converts it back to glucose


Gluconeogenic leg of the cycle
net consumer of energy, costs
body 4 moles of ATP more than
are produced during glycolysis
CYCLE IS INEFFICIENT, CANT GO ON INDEFINITELY,
AND IS WHY HYPOXIA PREDISPOSES TO HYPOGLYCEMIA

Amino Acids
Depleted
glycogen
stores

Catabolism of
muscle proteins

Amino Acids
Glucogenic:

Ketogenic:
Carbon skeletons make
fatty acids

leucine, lysine

carbon skeletons make carbohydrate by


conversion to oxaloacetate and subsequently
into pyruvate

Isoleucine, phenylalanine,
threonine, tryptophan,
tyrosine

Glycine, serine, valine,


histidine, arginine cysteine,
proline, alanine, glutamate,
glutamine, aspartate,
asparagine, methionine

Fatty Acids

Oxidation of fatty acids generates Acetyl CoA as


the terminal oxidation product.
The Krebs cycle yields a lot of energy

Glycerol

Glycerol backbone of lipids can be used for


gluconeogenesis and is actually a major substrate.

Getting the Glucose You Need


Lacate
Amino Acids,

Glycerol

Glycogen

Outline of Lecture
1. Understand the biochemical basics of glucose
homeostasis
2. Understand relationship between maternal and fetal
glucose metabolism and normal physiologic changes
that occur postnatally
3. Review neonatal hypoglycemia, including recent
literature and AAP position statement March, 2011
4. Discuss development and implementation of
Northwestern Memorial Hospital policy on hypoglycemia

Maternal Glucose: Pregnancy


1st half
Anabolic period
Increased calories
facilitate fat deposition
Storage of maternal
energy facilitated by
increased secretion of
insulin in women with
normal carbohydrate
metabolism

2nd half
Maternal stores mobilized to
meet babys needs
Surge of anti-insulin factors
Human placental
lactogen, progesterone,
estrogen
Pregnant women have higher
blood glucose levels than
nonpregnant women (fasted)
Pregnancy becomes a
diabetogenic-like state

Avery's Neonatology: Pathophysiology and Management of the Newborn

Fetus Gets Glucose via Facilitated Diffusion

Maternal glucose provides majority of glucose for fetus via facilitated diffusion
Fetus can use alternate substrates if necessary, but depends entirely on
maternal supply and placental transfer of glucose, amino acids, free fatty
acids, ketones, and glycerol for energy needs.
Normal lower limit of fetal glucose concentration remains around 3 mmol/L
(54 mg/dL) over most of gestation, particularly after 20 weeks
Enzymes for gluconeogenesis are present by the third month of gestation, but
there is almost no fetal glucose production under normal conditions
NICHD Report, 2009

Immediately Postnatally
Glucose cut off
Fetal glucagon, epinephrine,
and cortisol increase; insulin decreases
Promote glycogenolysis
Stimulate gluconeogenesis

Lipolysis increases: Beta-oxidation of fatty acids to


make ketone bodies increases (especially true in
breastfed infants)
Glucose falls, reaches a nadir by 1-2 hours of age,
then stabilizes

Neonatal Glucose Requirements


Glucose turnover represents rate of
production of glucose versus rate of glucose
use
Measurements of glucose concentrations
roughly correlate with glucose turnover
Correlates with brain and body mass
Linear relationship between size of brain and
hepatic glucose production
Ratio of brain to body mass reflects the higher
need for glucose in premature babies

Glucose Turnover
I have a
big head
to body
ratio

Premature Neonate
6-8 mg/kg/min

Full-term Neonate
4-6 mg/kg/min

Adult
2-3 mg/kg/min

Averys/Hay Review, 2010

Aberrant Fetal Metabolism


SGA/ IUGR/ Preterm

LGA

Low glycogen stores can


cause hypoglycemia
Birth circumstances can
impair gluconeogenesis
Augmented insulin and
glucose sensitivity by
upregulation of transporters
can make glucose levels
unpredictable

Episodic hyperglycemia upregulates insulin secretion


in infants
Occurs in gestational
diabetics
Results in rapid insulin
secretion and rebound
hypoglycemia following
intravenous glucose
bolus infusions

Outline of Lecture
1. Understand the biochemical basics of glucose
homeostasis
2. Understand relationship between maternal and fetal
glucose metabolism and normal physiologic changes
that occur post-natally
3. Review neonatal hypoglycemia, including recent
literature and AAP position statement March, 2011
4. Discuss development and implementation of
Northwestern Memorial Hospital policy on hypoglycemia

Neonatal Hypoglycemia

Etiology
Clinical manifestations
Laboratory features
Approach to therapy (NICHD workshop report)
Potential sequelae

Etiology of Hypoglycemia
Inadequate
Production

Excessive Use

COLD STRESS
Limited glycogen
Hyperinsulinism
SGA
Prematurity
IDM
Glycogen storage
Beckwith-Wiedeman
disease
Nesidioblastosis
Limited gluconeogenesis
Erythroblastosis Fetalis
Inadequate substrate
(have b-cell hyperplasia)
SGA
Exchange transfusion
Inborn errors
Maternal medications
Asphyxia
Chlorpropamide
Benzothiazides
B-sympathomimetics
Malpositioned umbilical
catheters

Other

LGA
Sepsis
Polycythemia
Hyperviscosity
syndrome
Congenital
hypopituitarism

Multiple sources

Clinical Manifestations

Jitteriness
Tremors
Apnea
Cyanosis
Limpness/ lethargy
Seizures
None

Laboratory Features
Glucose concentrations in whole
blood 10-15% lower than in plasma
Glucose oxidation by erythrocytes
can cause falsely low levels
Glucometers tend to be less
accurate at lower levels
Full work-up of persistent
hypoglycemia extensive
pH, insulin, cortisol
ketones, FFA, lactate, pyruvate,
ammonia, LFTs, urine organic acids,
serum amino acids

Approach to Therapy

Approach to Treatment
Controversial

What We Agree On

Universal screening is NOT indicated


Symptomatic babies should be treated
Proper thermoregulation is important
Prolonged hypoglycemia should be worked-up
SGA, LGA, premature and babies requiring
resuscitation are particularly vulnerable but
respond differently to treatment
When glycogen stores are low, substrate important
When insulin high, glucose delivery may be more
important

What We Do Not Agree On: A Value


Author

Year

Publication

Value (blood)

Srinivasan

1986

J Pediatrics

<35 at 0-3 hours


<40 3-24 hours
<45 > 45 hours

Stanley

1999

NEJM Editorial

<60

Ogata

2005

Averys

<40

Kalhan and Parimi 2006

Fanaroff and
Martin

<36

McGowan and
Hay

Handbook of
Neonatal Care

<36-40

2006

of normal healthy breastfed babies will have a blood glucose level< 36 in the 1st
24 hours. These same babies have higher circulating levels of ketones (Hawdon,
1992; Swenne, 1994)

Cornblaths Operational Threshold


Cornblath developed the concept of an operational threshold,
Defined as that concentration of plasma or whole blood glucose at which
clinicians should consider intervention, based on the evidence currently
available in the literature.
1. Healthy term infants need no monitoring
2. Symptomatic infants need to keep plasma glucose above 45 mg/dl
3. Infants with risk factors for compromised metabolic adaptation should
be monitored and monitored closely/ fed if the plasma level is less
than 36 mg/dl and given IV fluids if less than 25 ml/dl (level should be
maintained over 60 mg/dl in cases of persistent hypoglycemia)
4. Preterm infants should not be treated differently
5. Infants on HAL should keep plasma levels > 45 mg/dl
May, 2000

Unclear When
Neuroimpairment Occurs
Unclear Whether Following
Operation Threshold
Prevents Adverse Sequelae

What are Adverse Sequelae?


Animal/ human postmortum studies
Distinct patterns of brain injury
Propensity for occipital and parietal cortex and
subcortical white matter involvement.
Regional susceptibility to occipital and parietal WM
involvement in hypoglycemic brain injury also has
been reported for infants with hypoglycemia
Studies were limited to small patient groups
Infants with hypoxic-ischemic changes included

Year

Population

Outcome/ Conclusion

Burns
2008

Symptomatic
hypoglycemic

94% of infants with symptomatic hypoglycemic had white matter injury,


developmental outcomes at 18 months associated more with MRI
abnormalities than with hypoglycemia duration or severity
(MRI did not correlate with degree of hypoglycemia or whether prolonged or
not)

Lucas
1988

Preterm Infants with


hypoglycemia

Number of days of hypoglycemia (<47) strongly correlated to reduced metal


and motor developmental scores at 18 months
If hypoglycemia was recorded on > 5 days, 42% had some
neurodevelopmental impairment
Gap narrowed by 7.5-8 years

Salhab
2004

Hypoglycemic
Acidotic Infants

Neurologic outcome measures (including death) , encephalopathy, and


seizures worse in hypoglycemic acidotic infants

Duvanel
1999

Preterm SGA
infants,

Recurrent neonatal hypoglycemia associated with smaller heads at 18 months


of age and lower scores on specific psychometric scores at five years.
Recurrent hypoglycemia more predictive than severity

Stenninger
1997

Hypoglycemic IDMs
compared to
nonhypoglycemic
non-IDMs

Neonatal hypoglycemia associated with a slightly higher incidence of longterm neurological dysfunction related to minimal brain dysfunction/deficits in
attention, motor control, and perception compared with non-hypoglycemic,
non-IDM control infants

Brand
2005

LGA infants
(not IDM)

Psychomotor development at the age of 4 years no different in


transient mild hypoglycemic healthy, term LGA newborns compared to
controls

Groenendaal
2006

LGA infants
(not IDM)

High incidence (16.2%) of hypoglycemia in admitted, non-IDM LGA full-term


infants; 1.3% had seizures as primary manifestation

Many Questions Remain

November, 2009

2009

November, 2009

Your Work

November, 2009

March 1, 2011

Abstract

Committee on Fetus and Newborn Pediatrics


2011;127:575-579
2011 by American Academy of Pediatrics

Outline of Lecture
1. Understand the biochemical basics of glucose
homeostasis
2. Understand relationship between maternal and fetal
glucose metabolism and normal physiologic changes
that occur postnatally
3. Review neonatal hypoglycemia, including recent
literature and AAP position statement March, 2011
4. Discuss development and implementation of
Northwestern Memorial Hospital policy on hypoglycemia

NMH Hypoglycemia Policy


Modified after AAP guidelines released 03/2011
Numbers reflected in policy 10 points higher than the
AAP guidelines due to inherent inaccuracy of
glucometer and capillary whole blood sampling
Extensive education prior to roll out
Compliance monitored by Pediatric Quality Committee

At Risk Infants

IDM
LGA
Late preterm 34 36 6/7 weeks gestation
SGA
APGAR < 6 at 5 mins
Symptomatic infants are always screened
Congenital anomalies, antenatally diagnosed endocrine
disorders
Infants typically admitted to NICU where routine glucose monitoring is
performed

Symptomatic Infants
Infants with a glucose
of less than 50 are
transferred to NICU
Are not typically
forcefed, IV route
preferred
Bolus of 2 ml/kg D10,
followed by GIR of 5.6
mk/kg/min

At Risk Asymptomatic Infants: Birth to 4 hours

Asymptomatic: 4-24 hours

NOTE: For asymptomatic infants with glucose <


25 mg/dl on any glucose check between 4 to 24
hours of age, feed and initiate transfer to
NICU for evaluation and IV glucose.

< 50

<35
<35
< 35

<45
<45

35-50

>55

2011 by American Academy of Pediatrics

45-55

Duration of Screening

Risk factor
Birth time

Age of infant
30 mins
after 1st
feed
3hr

34-36 6/7
weeks or
SGA
LGA or
IDM
APGAR <
6 at 5 mins

6hr

9hr

12hr 15hr 18hr

21hr 24hr

Discontinue if last 3
readings were > 55

Discontinue if last reading was > 55

Implications on Breastfeeding
Previous policy more detrimental to
breastfeeding
Cut-off of 55 used even in 1st 4 hours
Volume of 10 ml/kg formula
recommended
Current policy has reduced admissions
Extensive educational efforts used to promote
breastfeeding and weaning of IVF without aggressive
supplementation in NICU
GIR weaned by 2 mg/kg/min each 6 hours

Promoting Breastfeeding Once on IVF

Nursed every 2-3 hours in NICU

SNS, 30 ml

SNS, 10 ml

NICU-IVF

50 ml, 42 ml

Nursed 11x
in Newborn unit

Acknowledgements
Catherine Willows RN, BA, IBCLC
Samantha Schoenfelder, RN, MSN
Kathy Christoffel, MD, MPH
Gina Siggia, MSN, WHNP, C-EFM
Yasmin Khan, MD
Praveen Kumar, MD
Hospital Breastfeeding Council of
Metro Chicago

Aria and Sareena Shah,


Its worth it!

References
1.
2.
3.

4.
5.
6.
7.
8.

http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004559
https://www.abp.org/abpwebsite/certinfo/subspec/suboutlines/neon20
10.pdf
Hay WW Jr, et al Knowledge gaps and research needs for understanding
and treating neonatal hypoglycemia; workshop report from the Eunice
Kennedy Shriver NICHD, 2009
Avery, Fletcher, MacDonald, eds. 1999. Neonatology, Pathophysiology
and Management of the Newborn, 5th edition (Ed Ogatas chapter)
Fanaroff and Martin, eds. 2002. Neonatal-Perinatal Medicine, Diseases of
the Fetus and Infant, 7th edition
http://www.indstate.edu/thcme/mwking/home.html
http://physicianjobster.com/physician-guidelines/homeostasis-diagramof-insulin-and-glucagon-in-controlling-blood-glucose/
http://en.wikipedia.org/wiki/Glycolysis

References
9.

10.

11.

12.

13.

14.

Rozance PJ, Hay WW Jr. Describing hypoglycemia- definition or


operational threshold? Early Hum Dev. 2010
Hawdon JM, Ward Platt MP, Aynsley-Green A. Patterns of metabolic
adaptation for preterm and term infants in the first neonatal week. Arch
Dis Child 1992;67:357-65.
Swenne I, Ewald U, Gustafsson J, et al. Inter-relationship between serum
concentrations of glucose, glucagon and insulin during the first two days
of life in healthy newborns. Acta Paediatr 1994;83:915-9.
Kalhan S, Kilic I`. Carbohydrate as nutrient in the infant and child: range
of acceptable intake. Eur J Clin Nutr 1999;53:S94-S100.
Sunehag A, Ewald U, Larsson A, Gustafsson J. Glucose production rate
extremely immature neonates (<28 weeks) studied by use of deuterated
glucose. Pediatr Res 1993;33:97-100.
Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human
newborns. Am J Physiol 1986;251:E71-7.

References
15. Sunehag A, Gustafsson J, Ewald U. Glycerol carbon contributes to hepatic
glucose production during the first eight hours in health, term infants.
Acta Paediatr 1996;85:1339-43.
16. Sunehag A, Ewald U, Gustafsson J. Extremely preterm infants (<28 weeks)
are capable of gluconeogenesis from glycerol on their first day of life. Pediatr Res
1996;40:553-7.
17. Kalhan SC, Parimi P, Van Beek R, et al. Estimation of gluconeogenesis in
newborn infants. Am J Physiol 2001;281:E991-7.
18. Glucose Testing and Management of Neonatal Hypoglycemia,
Northwestern Memorial Hospital Protocol/Guideline, 2001
Others noted within text or see me!

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