Neonatal Glucose Homeostasis

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
6
Source of ATP
Phosphorylation of glucose
and fructose 6-phosphate
uses two ATP from the
cytoplasm.
Substrate-level
phosphorylation
Oxidative phosphorylation
2 NADH
6
Oxidative phosphorylation
Glycolysis
preparatory
phase
Glycolysis payoff phase
Oxidative
decarboxylation
of pyruvate
ATP yield
-2
4
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, CAN’T 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 Kreb’s 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 baby’s 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
Avery’s/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, LFT’s, 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
Avery’s
<40
Kalhan and Parimi 2006
Fanaroff and
Martin
<36
McGowan and
Hay
Handbook of
Neonatal Care
<36-40
2006
½ 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)
Cornblath’s 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 IDM’s
compared to
nonhypoglycemic
non-IDM’s
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
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
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
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
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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,
It’s 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 Ogata’s 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!