FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
A14b
Hypoglycemia/Hyperglycemia
Reese H. Clark, MD
Director of Research
Pediatrix Medical Group
Neonatologist
Greenville Memorial Hospital, Greenville, SC
The speaker has signed a disclosure form and indicated he has no significant financial interest or relationship with companies or the
manufacturer(s) of any commercial product/service that will be discussed as part of this presentation.
Session Summary
During this session Dr. Clark will discuss the new AAP guidelines for management of hypoglycemia and how
best to prevent hypo- and hyperglycemia. Brain injury patterns see in infants who are hypo- or
hyperglycemia will also be reviewed.
Session Objectives
Upon completion of this presentation, the participant will be able to:
 discuss the physiology of glucose metabolism;
 state the derivation of the definition of hypoglycemia;
 identify the most common causes for hypo- and hyperglycemia;
 discuss management strategies to reduce the problems associated with both.
References
Beardsall, K., Vanhaesebrouck, S., Ogilvy-Stuartet, A.L., et al. (2008). Early insulin therapy in very-low-birth-weight infants. New
England Journal of Medicine, 359: 1873-84.
Burns, C.M., Rutherford, M.A., Boardman, J.P. & Cowan, F.M. (2008). Patterns of cerebral injury and neurodevelopmental
outcomes after symptomatic neonatal hypoglycemia. Pediatrics, 122(1): 65-74.
Committee on Fetus and Newborn. (2011). Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics, 127(3):
575-9.
CPS Statement: Retrieved at www.cps.ca/english/statements/FN/fn04-01.htm
Cranmer, H. & Shannon, M. (2009). Retrieved at Emedicine,Pediatrics, Hypoglycemia.
Glucose Utilization, retrieved at http://www.umanitoba.ca/dnalab/graduate/pancreas10.htm
Hay, W.W. & Cornblath, M. (2003). Historical perspectives: Transient symptomatic neonatal hypoglycemia. NeoReviews,
4(1): e1-e5.
Harris, D.L., Weston, D.L. & Harding, J.E. (2012). Incidence of neonatal hypoglycemia in babies identified as at risk. Journal of
Pediatrics, E-pub ahead of print June 23, 2012.
Hemachandra, A.H. & Cowett, R.M. (1999). Neonatal hyperglycemia. Pediatrics in Review, 20: e16-e24.
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Page 1 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Inder, T. (2008). How low can I go? The impact of hypoglycemia on the immature brain. Pediatrics, 122(2): 440-441.
Markham, L.A. (2003). Persistent hyperinsulinemic hypoglycemia in infants physiology. Newborn & Infant Nursing Reviews,
3: 156-165.
Mejri, A., Dorval, V., Nuyt, A. & Carceller, A. (2010). Hypoglycemia in term newborns with a birth weight below the 10th
percentile. Paediatrics Child Health, 15(5): 271–275.
Sinclair, J.C., Bottino, M. & Cowett, R. M. (2009). Interventions for prevention of neonatal hyperglycemia in very low birth weight
infants. Cochrane Database of Systematic Reviews, Jul 8, (3): CD007615.
Zumkeller, W. (1999). Nesidioblastosis. Endocrine-Related Cancer, 6(3): 421-428.
*Please review additional references denoted on the slides.
Session Outline
See handout on the following pages.
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Page 2 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Glucose Metabolism In The NICU
Knowing When They Are Too Sweet
And
When They are Not Sweet Enough
Reese H. Clark, MD
Pediatrix Medical Group
Objectives
• To discuss the physiology of glucose
metabolism
• To review the derivation of the definition of
hypoglycemia
• To identify the most common causes for
hypo- and hyper-glycemia
• To discuss management strategies to
reduce the problems associated with both.
Glucose Utilization
http://www.umanitoba.ca/dnalab/graduate/pancreas10.htm
Physiology
Pancreas
• The pancreas secretes two important hormones that
regulate glucose, lipid, and protein metabolism: glucagon
and insulin.
• Two major types of tissues:
– acini, which secrete digestive juices into the duodenum
– islets of Langerhans, which secrete the hormones insulin and
glucagon directly into the blood.
• The islets of Langerhans contain three types of
hormone-secreting cells:
– alpha cells, which secrete glucagon,
– beta cells, which secrete insulin,
– delta cells, which secrete somatostatin and/or gastrin.
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Page 3 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Medscape -- Persistent Hyperinsulinemic Hypoglycemia in Infants: Physiology
Lori A. Markham, MSN, RNC, NNP, CCRN, Baylor University Medical Center,
3500 Gaston Avenue, Dallas, Texas
Glycogenolysis –
breakdown of hepatic
glycogen yielding glucose
Gluconeogenesis –
production of glucose from
noncarbohydrate
p
precursors
Lipolysis – breakdown of
fat
Ketogenesis – creation of
ketones
http://www.umanitoba.ca/dnalab/graduate/pancreas4.htm
Insulin Regulation
Medscape -- Persistent Hyperinsulinemic Hypoglycemia in Infants: Physiology
Lori A. Markham, MSN, RNC, NNP, CCRN, Baylor University Medical Center
http://www.umanitoba.ca/dnalab/graduate/pancreas7.htm
Glucose Balance
• Blood glucose concentration is a reflection of the
balance between glucose input into the
circulation from food intake and glucose
extraction from blood for consumption by the
tissues.
• Glucose input includes sugars and
carbohydrates in the diet, glucose release from
glycogen stores, and gluconeogenesis.
• Pathways of glucose extraction include glucose
storage as glycogen in the liver and muscles,
glucose conversion to lipid, and glucose
oxidation.
Medscape -- Persistent Hyperinsulinemic Hypoglycemia in Infants: Physiology
Lori A. Markham, MSN, RNC, NNP, CCRN, Baylor University Medical Center
Influence Of Feeding On Hormones
Glucose Balance
http://www.umanitoba.ca/dnalab/graduate/pancreas8.htm
• During feeding, increased blood glucose and amino acid
levels, as well as gut hormones, stimulate insulin
secretion and suppress glucagon release.
• The main action of insulin is in the liver, where it
stimulates conversion of glucose to glycogen and
d
decreases
gluconeogenesis
l
i and
d glycogenolysis.
l
l i
• Glucose is also stored as glycogen in the muscles. It is
oxidized in the muscle and adipose tissue and converted
to lipid in the liver and adipose tissue.
• Insulin stimulates amino acid incorporation into protein
and fatty acid incorporation into lipids.
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Page 4 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Medscape -- Persistent Hyperinsulinemic Hypoglycemia in Infants: Physiology
Lori A. Markham, MSN, RNC, NNP, CCRN, Baylor University Medical Center
Glucose Balance
• During periods of fasting, the source of energy shifts from the
oxidation of glucose to the oxidation of fat.
• Early in fasting, glucose is supplied by the breakdown of hepatic
glycogen stimulated by epinephrine and glucagon.
• After hepatic glycogen stores are depleted, the body depends on
new glucose produced from precursors in muscle and adipose
tissue.
• Gluconeogenesis is stimulated by growth hormone and cortisol.
• With prolonged fasting, adipose tissue is broken down into free fatty
acids (FFA) and glycerol.
• FFA can be used directly as a fuel by tissues and are oxidized in the
liver to provide energy with resultant formation of ketone bodies
(acetoacetate and β-hydroxy-butyrate).
• Ketone bodies can be used as an alternate fuel as previously
mentioned.
Defining Hypoglycemia is a
Problem
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Hypoglycemia
Screening guidelines for newborns at risk for
low blood glucose
Fetus and Newborn Committee, Canadian
Paediatric Societyy (CPS)
(
)
Paediatr Child Health 2004;9(10):723-9
Reference No. FN04-01
Reaffirmed February 2009
Page 5 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Canadian Paediatric Society (CPS)
Paediatr Child Health 2004;9(10):723-9
Canadian Paediatric Society (CPS)
Paediatr Child Health 2004;9(10):723-9
• Neonatal hypoglycemia cannot be defined
by a single value of glucose applicable to
all clinical situations and to all infants.
• It appears that infants may develop signs
suggestive of hypoglycemia over a range
of blood glucose levels that is substantially
lower than normal adult levels.
• Neonatal hypoglycemia cannot be defined
by a single value of glucose applicable to
all clinical situations and to all infants.
• It appears that infants may develop signs
suggestive of hypoglycemia over a range
of blood glucose levels that is substantially
lower than normal adult levels.
Hay WW, Jr., Cornblath M. Historical Perspectives:
Transient Symptomatic Neonatal Hypoglycemia.
NeoReviews 2003; 4(1):e1-e5.
Hilarie Cranmer, MD, MPH, FACEP, Assistant Professor, Harvard University School of
Medicine; Michael Shannon, MD, MPH,†, Professor, Department of Pediatrics, Harvard
Medical School; Chief and CHB Chair, Division of Emergency Medicine, Children's
Hospital; Updated: Aug 10, 2009.
• The magnitude of concern about a medical
disorder often is inversely related to the
amount of accurate data defining it.
• Dr. Cornblath describes how concern for
neonatal hypoglycemia has grown exponentially
over the past 50 years.
• He also points out that those characteristics of
low glucose concentration that might cause
irreversible neuronal injury remain relatively
undocumented and poorly defined.
• Hypoglycemia is the most common metabolic
problem in neonates.
• In children, a blood glucose value of less than
40 mg/dL
g
((2.2 mmol/L)) represents
p
hypoglycemia.
• A plasma glucose level of less than 30 mg/dL
(1.65 mmol/L) in the first 24 hours of life and less
than 45 mg/dL (2.5 mmol/L) thereafter
constitutes hypoglycemia in the newborn.
Committee on Fetus and Newborn. Postnatal Glucose
Homeostasis in Late-Preterm and Term Infants.
Committee on Fetus and Newborn. Postnatal Glucose
Homeostasis in Late-Preterm and Term Infants.
Pediatrics 2011;127(3):575-9.
Pediatrics 2011;127(3):575-9.
• Blood glucose concentrations as low as 30
mg/dL are common in healthy neonates by 1 to
2 hours after birth; these low concentrations,
seen in all mammalian newborns, usually are
transient, asymptomatic, and considered to be
part of normal adaptation to postnatal life.
• Most neonates compensate for “physiologic”
hypoglycemia by producing alternative fuels
including ketone bodies, which are released
from fat.
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Emedicine article -Pediatrics, Hypoglycemia
• There is not a specific plasma glucose concentration or duration of
hypoglycemia that can predict permanent neurologic injury in highrisk infants.
• Data that have linked plasma glucose concentration with adverse
long-term neurologic outcomes are confounded by variable
definitions of hypoglycemia and its duration (seldom reported)
reported), the
omission of control groups, the possible inclusion of infants with
confounding conditions, and the small number of asymptomatic
infants who were followed.
• In addition, there is no single concentration or range of plasma
glucose concentrations that is associated with clinical signs.
Therefore, there is no consensus regarding when screening should
be performed and which concentration of glucose requires
therapeutic intervention in the asymptomatic infant.
Page 6 of 16
300
250
200
150
200
100
100
50
50
150
0
0
41 (734)
40 (2680)
39 (3293)
38 (3908)
37 (3404)
36 (4088)
35 (4893)
34 (6708)
33 (4640)
32 (3429)
31 (2318)
30 (1774)
29 (1243)
28 (1100)
27 (870)
26 (631)
25 (570)
24 (481)
23 (225)
41 (289)
40 (881)
39 (1288)
38 (1482)
37 (1327)
36 (1438)
35 (1671)
34 (2192)
33 (1603)
GT97th
(2377)
GT90 and
LTE97th
(3731)
GT75 and
LTE90th
(9369)
GT50 and
LTE75th
(18719)
GT25 and
LTE50th
(20921)
GT10 and
LTE25th
(11973)
GT3rd and
LTE10th
(5493)
LTE3rd
(3144)
Day 2
(945)
Day 1
(2680)
Day 0
(881)
Page 7 of 16
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Day Since Birth
Day Since Birth
Median
Quantiles5
Quantiles95
Median
Quantiles5
Quantiles95
Glucose Based on Growth Group
Glucose EGA = 40
Median
Quantiles5
Quantiles95
Median
Quantiles5
Quantiles95
32 (1263)
31 (847)
30 (640)
29 (527)
28 (495)
27 (406)
26 (364)
25 (318)
24 (235)
23 (143)
Glucose
e Level
350
250
160
140
120
100
80
60
40
20
0
160
140
120
100
80
60
40
20
0
Glucose
e Level
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Distribution of Glucose in the NICU
Percentiles for Neonates With No
Report of Glucose Problems
Glucose Day 0
Glucose Day 1
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Median Glucose
Glucose
Symptoms
•
•
•
•
•
•
•
•
Jitteriness
Cyanosis (blue coloring)
Apnea (stopping breathing)
Hypothermia (low body temperature)
Poor body tone
Poor feeding
Lethargy
Seizures
Emedicine article -Pediatrics, Hypoglycemia
Causes of Hypoglycemia
Emedicine article -Pediatrics, Hypoglycemia
Hilarie Cranmer, MD, MPH, FACEP, Assistant Professor; Michael Shannon, MD, MPH,†,
Professor, Department of Pediatrics, Harvard Medical School; Children's Hospital;
Updated: Aug 10, 2009.
Hilarie Cranmer, MD, MPH, FACEP, Assistant Professor; Michael Shannon, MD, MPH,†,
Professor, Department of Pediatrics, Harvard Medical School; Children's Hospital;
Updated: Aug 10, 2009.
• The overall incidence of symptomatic
hypoglycemia in newborns varies from 1-3 per
1000 live births.
• Incidence varies with the definition, population,
method and timing
g of feeding,
g and the type
yp of
glucose assay. Serum glucose levels are higher
than whole blood values.
• The incidence of hypoglycemia is greater in
high-risk neonatal groups.
• Early feeding decreases the incidence of
hypoglycemia.
• Causes of hypoglycemia in neonates differ
slightly from the causes of hypoglycemia in older
infants and children.
• Hyperinsulinism, or persistent hyperinsulinemic
hypoglycemia
yp g y
of infancy
y (PHHI),
(
) is the most
common cause of hypoglycemia in the first 3
months of life. It is well recognized in infants of
mothers with diabetes.
• Other causes in all ages include gram-negative
sepsis; endotoxin shock; and ingestions,
including salicylates, alcohol, hypoglycemic
agents, and beta-adrenergic blocking agents.
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Page 8 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Transient Hypoglycemia
Harris, DL; et al. Incidence of Neonatal Hypoglycemia in Babies
Identified as at Risk J. Pediatrics 2012
• Infants (n = 514) were recruited who were born in a tertiary hospital,
>35 weeks gestation and identified as at risk of hypoglycemia
(small, large, infant of a diabetic, late-preterm, and other).
• One-half of the babies (260/514, 51%) became hypoglycemic, 97
(19%) had severe hypoglycemia, and 98 (19%) had more than 1
episode.
episode
• Most episodes (315/390, 81%) occurred in the first 24 hours.
• The median number of blood glucose measurements for each baby
was 9 (range 1-22).
• The incidence and timing of hypoglycemia was similar in all at risk
groups, but babies with a total of 3 risk factors were more likely to
have severe hypoglycemia.
Persistent Hypoglycemia
•
PHHI
Beta-cell adenoma
Exogenous insulin administration
Sulfonylurea use
Growth hormone
Adrenall iinsufficiency
Ad
ffi i
Glucagon
Hypothyroidism
Panhypopituitarism
Errors of metabolism
–
–
–
–
•
Diagnosis of Hyper and Hypoglycemia
Hormone deficiency
–
–
–
–
–
•
Infants of diabetic mothers
Prematurity
Hypothermia
Intrauterine growth restriction (IUGR)
Small for gestational age (SGA)
Septicemia, asphyxia/birth depression
Erythroblastosis fetalis
Beckwith-Wiedemann syndrome
Hyperinsulinemia
–
–
–
–
•
•
•
•
•
•
•
•
•
Carbohydrate metabolism disorders
Fat metabolism disorders
Amino acid metabolism disorders
Ketotic hypoglycemia
Liver Disease
Diagnosis of Hypoglycemia and
Hyperglycemia
Rare Causes of Hypoglycemia
• The incidence of inborn errors of metabolism
that lead to neonatal hypoglycemia are rare but
can be screened in infancy:
–
–
–
–
–
–
–
–
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Carbohydrate metabolism disorders (>1:10,000)
F tt acid
Fatty
id oxidation
id ti disorders
di d
(1
(1:10,000)
10 000)
Hereditary fructose intolerance (1:20,000 to 1:50,000)
Glycogen storage diseases (1:25,000)
Galactosemia (1:40,000)
Organic acidemias (1:50,000)
Phosphoenolpyruvate carboxykinase deficiency (rare)
Primary lactic acidosis (rare)
Page 9 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
W Zumkeller. Nesidioblastosis.
Endocrine-Related Cancer (1999) 6 421-428
Nesidioblastosis
• The underlying genetic defects of b-cell regulation
include a severe recessive disorder of the sulphonylurea
receptor, a milder dominant form of hyperinsulinism, and
a syndrome of hyperinsulinism plus hyperammonaemia.
• Estimates for the incidence of congenital hyperinsulinism
vary from
f
1/40
1/40,000
000 lilive bi
births
th iin northern
th
E
Europe tto 1/
2675 live births in Saudi Arabia where consanguineous
marriages are common.
• This condition requires prompt medical and surgical
therapy in order to prevent permanent brain damage.
Genetics
• Most cases of PHHI are sporadic. In approximately 50% of cases,
no known genetic abnormality is found.
• Familial forms of PHHI are rare but well documented. These cases
of PHHI involve autosomal recessive or dominant defects in 4
genes.
– Beta-cell high-affinity sulfonylurea receptor gene (ABCC8, also known
as SUR1)
– Inwardly rectifying potassium channel gene (KCNJ11, also known as
Kir6.2)
– Glucokinase gene (GCK, also called GK): Only 5 persons have been
described with this mutation.
– Glutamate dehydrogenase gene (GLUD1, also called GUD1): This gene
is associated with hyperinsulinism with hyperammonemia. It is unclear
whether this disorder (described below) is a variant of persistent
hyperinsulinemic hypoglycemia of infancy or a distinct clinical entity
• The abnormal histologic aspects of the
tissue include:
– the presence of islet cell enlargement,
– islet cell dysplasia
dysplasia,
– beta cells budding from ductal epithelium,
– and islets in apposition to ducts.
Evaluation
Pancreatic specimen showing diffuse persistent hyperinsulinemic hypoglycemia of infancy (PHHI)
viewed at low power. The paler-staining cells are the neuroendocrine (islet) cells, which should be
arranged in discrete islands within the acinar lobules. Acinar cells are the exocrine cells that have
denser-staining, dark eosinophilic cytoplasm. These acinar cells are arranged in acini-small
glands. In PHHI, more of the neuroendocrine cells are present, and they are arranged more
diffusely throughout the lobules. Image courtesy of Phil Collins, MD; eMedicine Specialties >
Pediatrics: General Medicine > Endocrinology -- Persistent Hyperinsulinemic Hypoglycemia of
Infancy Author: Robert S Gillespie, MD, MPH, Department of Pediatrics, Cook Children's Medical
Center; Coauthor(s): Stephen Ponder, MD, CDE, Director, Division of Pediatric Endocrinology,
Department of Pediatrics, Driscoll Children's Hospital; Professor, Texas A&M College of Medicine
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Page 10 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
High-risk groups who need screening
•
•
•
•
•
•
•
•
•
Newborns who weigh more than 4 kg or less than 2 kg
Large for gestational age (LGA) infants who are above the 90th percentile,
small for gestational age (SGA) infants below the 10th percentile, and
infants with intrauterine growth restriction
Infants born to insulin-dependent mothers (1 in 1000 pregnant women) or
mothers with gestational diabetes (occurs in 2% of pregnant women)
Gestational age less than 37 weeks
N b
Newborns
suspected
t d off sepsis
i or b
born tto a mother
th suspected
t d off h
having
i
chorioamnionitis
Newborns with symptoms suggestive of hypoglycemia, including jitteriness,
tachypnea, hypotonia, poor feeding, apnea, temperature instability,
seizures, lethargy
Significant hypoxia; perinatal distress; or 5-minute Apgar scores less than 5
Mother on terbutaline, beta-blockers, or oral hypoglycemic agents;
Possibility of an inborn error of metabolism or genetic disorder.
Which infants should we screen?
• The AAP suggest that “at risk infants” should be
screened.
–
–
–
–
SGA
LGA
IDM
Preterm
• “Routine screening and monitoring of blood
glucose concentration is not needed in healthy
term newborn infants after an entirely normal
pregnancy and delivery.”
Pediatrics 2011;127(3):575-9.
Medscape -- Persistent Hyperinsulinemic Hypoglycemia in Infants: Physiology
Lori A. Markham, MSN, RNC, NNP, CCRN, Baylor University Medical Center
• When the patient is hypoglycemic (glucose
<40 mg/dl), the diagnosis can usually be
made by measuring
– plasma glucose
– serum insulin, cortisol, growth hormone
– lactate, free fatty acids, and βhydroxybutyrate (ketones)
Importance of Glucose to the Brain
Morbidity Associated with
Hypoglycemia
yp g y
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
• The brain and formed elements of blood have an
obligatory glucose requirement.
• Brain cells are permeable to glucose and can
utilize g
glucose without the intermediation of
insulin.
• The brain is able to metabolize ketone bodies,
acetoacetate, and beta-hydroxybutyrate for up to
two-thirds of its energy requirements in the
absence of glucose.
Page 11 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of
Cerebral Injury and Neurodevelopmental Outcomes After Symptomatic
Neonatal Hypoglycemia. Pediatrics 2008; 122(1):65-74
Burns CM, Rutherford MA, Boardman JP, Cowan FM. Patterns of
Cerebral Injury and Neurodevelopmental Outcomes After Symptomatic
Neonatal Hypoglycemia. Pediatrics 2008; 122(1):65-74
•
• Patterns of injury associated with symptomatic neonatal
hypoglycemia were more varied than described
previously.
• White matter injury was not confined to the posterior
regions; hemorrhage, middle cerebral artery infarction,
and basal g
ganglia/thalamic
g
abnormalities were seen,, and
cortical involvement was common.
• Early MRI findings were more instructive than the
severity or duration of hypoglycemia for predicting
neurodevelopmental outcomes
•
•
•
•
•
•
Studied 35 term infants with early brain MRI scans after symptomatic
neonatal hypoglycemia (median glucose level: 1 mmol/L) without evidence
of HIE.
Compared with equivalent data from 229 term, neurologically normal infants
(control subjects), to identify risk factors for hypoglycemia.
White matter abnormalities occurred in 94% of infants with hypoglycemia,
being severe in 43%, with a predominantly posterior pattern in 29%
Cortical abnormalities occurred in 51% of infants; 30% had white matter
hemorrhage, 40% basal ganglia/thalamic lesions, and 11% an abnormal
posterior limb of the internal capsule. Three infants had middle cerebral
artery territory infarctions.
Twenty-three infants (65%) demonstrated impairments at 18 months, which
were related to the severity of white matter injury and involvement of the
posterior limb of the internal capsule.
Fourteen infants demonstrated growth restriction, 1 had macrosomia, and 2
had mothers with diabetes mellitus.
Pregnancy-induced hypertension, a family history of seizures, emergency
cesarean section, and the need for resuscitation were more common
among case subjects than control subjects.
Inder T. How Low Can I Go? The Impact of Hypoglycemia
on the Immature Brain. Pediatrics 2008; 122(2):440
Inder T. How Low Can I Go? The Impact of Hypoglycemia
on the Immature Brain. Pediatrics 2008; 122(2):440
• The impact of isolated hypoglycemia on the developing
brain has been well documented in animal experiments,
including those on primates.
• 3 important principles
• The level or duration of hypoglycemia that is
harmful to an infant's developing brain is not
known.
• Major long-term sequelae include neurologic
damage resulting in mental retardation
retardation,
recurrent seizure activity, developmental delay,
and personality disorders.
• Some evidence suggests that severe
hypoglycemia may impair cardiovascular
function.
– First, prolonged and severe, rather than transient or minor,
h
hypoglycemia
l
i was required
i d ffor cerebral
b l iinjury.
j
– Second, the pattern of injury involved neuronal injury to the
upper cortical layers (2 and 3), particularly affecting the parietooccipital regions, as well as injury to the hippocampus, caudate,
and white matter.
– Finally, mild hypoglycemia combined with mild hypoxia-ischemia
resulted in cerebral injury, whereas either of the 2 conditions in
isolation did not.
Management
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Page 12 of 16
FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Glucose infusion
• Main treatment is to provide glucose
– Feeding provide carbohydrates that can be
used to produce glucose
– IV infusion (normal glucose infusion rate 6-8
mg/kg/min)
– If higher rates of glucose infusions are
required a central line should be placed
CPS Statement:
www.cps.ca/english/statements/FN/fn04-01.htm
Drugs Used
• Initiate intravenous infusion of 10% dextrose at a rate of
80ml/kg/day (5.5mg glucose/kg/min). Check glucose 30
min after any change and adjust therapy (up to 100
ml/kg/day and/or 12.5% dextrose) in order to maintain
glucose level ≥ 2.6mmol/l (approximately 45mg/dl).
• If rates
t iin excess off 100 ml/kg/day
l/k /d off 12
12.5%
5% d
dextrose
t
are
required investigation, consultation and/or
pharmacological intervention are indicated.
• May start weaning IV 12 hours after stable blood glucose
is established. Continued breastfeeding is encouraged.
• Diazoxide acts to inhibit insulin secretion. Can cause
fluid retention
• Octreotride is a long-acting somatostatin analog that also
acts to inhibit insulin secretion but it can suppress
growth hormone, and increase abdominal distention
• Nifedipine is a calcium channel blocking agent and acts
to decrease insulin secretion by closing the ATP
potassium channels in the pancreatic beta cells.
• Glucagon is used as a temporizing agent and
antagonizes insulin action by mobilizing hepatic
glycogen stores
• Glucocorticoids have also been shown to be effective in
managing hypoglycemia, but their use is minimal.
http://www.cps.ca/english/statements/fn/FN04-01-fig1.pdf
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
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FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
To convert mmol/l of glucose to mg/dl, multiply by 18
To convert mmol/l of glucose to mg/dl, multiply by 18
Definition
Hyperglycemia
• Hyperglycemia is a serum glucose
concentration > 125 mg/dL.
• The most common cause of neonatal
hyperglycemia is Iatrogenic
• Iatrogenic causes usually involve too-rapid
IV infusions of dextrose during the first few
days of life in very low-birth-weight infants
(< 1.5 kg).
Causes of Hyperglycemia
• The other important cause of hyperglycemica is
physiologic stress
–
–
–
–
Surgery,
Hypoxia,
Respiratory distress
Sepsis
p
• In premature infants, partially defective processing of
proinsulin to insulin and relative insulin resistance may
cause hyperglycemia.
• In addition, transient neonatal diabetes mellitus is a rare
self-limited cause that usually occurs in small-forgestational-age infants
• Corticosteroid therapy may also result in transient
hyperglycemia.
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Risks for Hyperglycemia
•
•
•
•
Preterm birth
Higher-than-needed rates of IV glucose infusion
Intrauterine growth restriction (IUGR)
Increased stress hormones
– Increased catecholamine infusions and plasma concentrations
– Increased
I
d glucocorticoid
l
ti id concentrations
t ti
(from
(f
use off antenatal
t
t l
steroids, postnatal glucocorticoid administration, and stress)
– Increased glucagon concentrations
• Early and high rates of intravenous (IV) lipid infusion
• Insufficient pancreatic insulin secretion
• Absence of enteral feedings, leading to diminished
“incretin” secretion and action, limiting their potential to
promote insulin secretion.
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FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Diagnosis of Hyper and Hypoglycemia
Among preterm infants receiving continuous glucose infusions at 8 mg/kg per minute, 11 mg/kg per
minute, or 14 mg/kg per minute, practically none of the infants in the lowest glucose infusion group
developed hyperglycemia. In contrast, 50% or more of the infants in the middle infusion group and
all of the infants in the highest infusion group developed increased blood glucose concentrations
Hemachandra, A. H. et al. Pediatrics in Review 1999;20:16-24e
Sinclair JC, Bottino M, Cowett RM. Interventions for prevention of
neonatal hyperglycemia in very low birth weight infants. Cochrane
Database Syst Rev. 2009 Jul 8;(3):CD007615
• Four eligible trials
• Two trials compared lower vs. higher rates of glucose
infusion in the early postnatal period. These trials were
too small to assess effects on mortality or major
morbidities.
• Two trials,
trials one a moderately large multicentre trial
(NIRTURE, Beardsall 2008), compared insulin infusion
with standard care.
• Insulin infusion reduced hyperglycemia but increased
death before 28 days and hypoglycemia.
• Reduction in hyperglycemia was not accompanied by
significant effects on major morbidities; effects on
neurodevelopment are awaited.
Beardsall et al. Early Insulin Therapy in Very-Low-BirthWeight Infants. N Engl J Med 2008;359:1873-84.
•
•
•
•
•
•
•
195 assigned infants to continuous infusion of insulin at a dose of 0.05 U
per kilogram of body weight per hour with 20% dextrose support
194 to standard neonatal care on days 1 to 7. The efficacy of glucose
control was assessed by continuous glucose monitoring.
Compared with the control group, infants in the early-insulin group had
lower mean glucose levels 112±25 vs. 121±40 mg/dl], P <0.01).
Fewer infants in the early-insulin group had hyperglycemia for more than
10% off th
the fi
firstt week
k off lif
life (21% vs. 33%,
33% P = 0
0.008).
008)
The early-insulin group had significantly more carbohydrate infused (51±13
vs. 43±10 kcal per kilogram per day, P<0.001) and less weight loss in the
first week (standard-deviation score for change in weight, −0.55±0.52 vs.
−0.70±0.47; P = 0.006).
More infants in the early-insulin group had episodes of hypoglycemia
(defined as a blood glucose level of <2.6 mmol per liter [47 mg per deciliter]
for >1 hour) (29% in the early-insulin group vs. 17% in the control group, P
= 0.005), and the increase in hypoglycemia was significant in infants with
birth weights of more than 1 kg.
In the intention-to-treat analysis, mortality at 28 days was higher in the
early insulin group than in the control group (P = 0.04).
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
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FANNP 23RD NATIONAL NNP SYMPOSIUM: CLINICAL UPDATE AND REVIEW
Treatment
Complications
• Reduction of IV dextrose concentration, rate, or both
• Rarely insulin
• “Reasonable guidelines indicate that insulin treatment
should be reserved until plasma glucose concentrations
exceed 16.7 to 22.2 mmol/L (300 to 400 mg/dL) despite
reducing the glucose infusion rate to less than 3 to 4
mg/kg per minute. The usual method of insulin
administration involves a continuous infusion, beginning
at 0.02 to 0.05 U/kg per hour. Although higher infusion
rates have been used, they usually are not necessary
and increase the risks of hypokalemia and subsequent
hypoglycemia.”
•
A14b: HYPOGLYCEMIA/HYPERGLYCEMIA
Hay -http://pedsinreview.aappublications.org/cgi/content/full/20/7/e16
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