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CHAPTER 15 Glucose Homeostasis
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439
caused by placental dysfunction also could stimulate
increased production of adrenaline and noradrenaline,
leading to increased glycogen breakdown and further compromising substrate supply. Evidence from
more recent animal studies and human observations,
however, suggest that because of increased glucose
uptake mechanisms in response to glucose deficiency (e.g., increased expression of cell membrane glucose transporters), muscle and hepatic
glycogen stores are normal or even increased in
IUGR infants.
26,92,109,122,154
Postnatally, catecholamine- and glucagon-stimulated glycogenolysis rapidly depletes glycogen
supplies at a time when gluconeogenesis may be
insufficient to provide enough endogenous glucose,
resulting in hypoglycemia. After the first few post-
natal days, preterm infants may still be at risk
for hypoglycemia even though glycogen stores
are adequate, because of low levels of hepatic mic-
rosomal glucose-6-phosphatase activity. Activity of
this enzyme in preterm infants is low before birth
and can remain low for several months after birth
in some infants.
124,142,145
Because this enzyme catalyzes the dephosphorylation of glucose-6-phosphate
to glucose and regulates the final step in hepatic
glucose production, the decreased activity could
contribute to diminished glucose production from
both glycogenolysis and gluconeogenesis. Infants
with low hepatic glucose-6-phosphatase activity
may not be symptomatic with the initial episode of
hypoglycemia but can become symptomatic if the
hypoglycemia persists.
Up to 18% of preterm infants have problems maintaining normoglycemia at the time of
discharge if a feeding is omitted or delayed.59
Inadequate cortisol secretion in very preterm
infants, particularly during periods of stress, also has
been cited as a cause of limited activation of gluconeogenic enzymes. The underlying mechanisms for
cortisol deficiency are not clear but may be related
to a lack of adrenal stimulation as a result of limited
hypothalamic-pituitary axis activity.
ABNORMALITIES OF ENDOCRINE
REGULATION
Hyperinsulinemia is the most common endocrinologic disturbance producing neonatal hypoglycemia and may be the leading cause of the
infrequent cases of persistent hypoglycemia in
infants. Excessive insulin secretion in the newborn increases glucose utilization by stimulating
cellular glucose uptake in insulin-dependent tissues,
including muscle and liver. Brain glucose uptake,
however, does not appear to be significantly altered
by increased insulin levels. At the same time, the
high circulating insulin concentrations promote
continued glycogen synthesis and inhibit both
glycogenolysis and gluconeogenesis, impairing the
infant’s glucogenic response to the increased glucose
demand and decreasing plasma glucose concentrations. Suppression of ketone body production from
free fatty acids by high levels of insulin also might
limit the availability of alternative fuels for cerebral
metabolism, thereby contributing to the increased
risk for adverse long-term outcomes in this patient
population.
The most common clinical condition in
which hyperinsulinemia occurs is in the infant
of a diabetic mother (IDM). In utero, the fetus
becomes hyperglycemic because of increased transfer of glucose across the placenta during episodes of
maternal hyperglycemia. The fetal pancreatic beta
cells are stimulated by the increased fetal glucose concentration to produce increased quantities of insulin. The pancreatic islet beta cells
also appear to become abnormally sensitive to
increases in glucose concentration after repeated
hyperglycemic stimuli. Before birth, the increase in
cellular glucose uptake in response to the increased
insulin secretion is matched by the increased availability of glucose from the mother. After deliv-
ery, the maternal source of glucose is abruptly
removed, whereas the hyperinsulinemia persists,
producing hypoglycemia. The decrease in glucose
concentration after birth is a result of insulin-stimulated peripheral glucose uptake and inhibition of
gluconeogenesis and glycogenolysis by the high
insulin concentrations. Although some studies have
reported other abnormalities in glucose metabolism
in IDMs, Cowett and colleagues37 found no difference in glucose kinetics in IDMs versus controls,
perhaps because maternal diabetic control was well
maintained during pregnancy in the group studied.
A large review of pregnancies in diabetic mothers
found no association between the incidence of neonatal hypoglycemia and the number of episodes of
maternal hyperglycemia (a reflection of the degree
of control) late in pregnancy.67 The incidence of
neonatal hypoglycemia in IDMs correlates better with intrapartum, rather than antepartum,
maternal glucose concentrations. The results of
these studies emphasize that it is a sudden increase
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in glucose concentration that stimulates insulin
secretion after a longer period in utero during
which the fetal pancreatic beta cells have been sensitized to hypersecrete insulin as a result of repeated
episodes of hyperglycemia.
38
The incidence of hypoglycemia in IDMs
is approximately 50%62; these infants usually
are asymptomatic. The large and comprehensive
Hyperglycemia and Adverse Pregnancy Outcome
study has shown (1) that the complications typically
associated with IDMs, including neonatal hypoglycemia, may be seen in women without overt
gestational diabetes but with values at the upper end
of the “normal” range on formal glucose tolerance
testing; and (2) that the incidence correlates with
the elevation in glucose values. This suggests that
there is a continuum of abnormal glucose tolerance
during pregnancy that is associated with increased
fetal insulin secretion and that gestational diabetes
represents the most severe degree of disturbed glucose homeostasis.
108
Other causes of islet cell hyperplasia and resultant hyperinsulinemia include (1) severe erythroblastosis fetalis,11 possibly resulting from inactivation
of insulin by glutathione released from hemolyzed
red blood cells; (2) exchange transfusion,
127
in
which insulin release is stimulated by the high dextrose content of commonly used blood preservative
agents; and (3) in utero exposure to drugs such as
beta-agonist tocolytics.
115
In utero exposure to valproate and postnatal exposure to indomethacin also
may result in hypoglycemia, but the mechanisms
responsible are not known.
Idiopathic hyperinsulinism (i.e., increased,
persistent insulin secretion without a known predisposing factor) may occur as a result of altered
regulation of insulin secretion in pancreatic
beta cells.
59,72
Two general forms of persistent
idiopathic hyperinsulinism are recognized: prolonged neonatal hyperinsulinism and congenital
(genetic) hyperinsulinism. Prolonged idiopathic
neonatal hyperinsulinism appears to be common
although not well recognized or understood. Affected
neonates usually have some evidence of stress before
or during delivery, such as low birth weight (LBW)
with IUGR (this disorder may affect 10% or more
of IUGR/SGA infants), birth asphyxia, or maternal
preeclampsia. Prolonged neonatal hyperinsulinism
usually manifests in the first days after birth and
often may be severe, requiring high dextrose
infusion rates of 15 mg/kg/min of glucose or
more. Prolonged neonatal hyperinsulinism also may
last several weeks to months and does not respond
well to glucocorticoids but can be treated with
diazoxide at doses of 5 to 10 mg/kg/day.
8,71
Congenital (genetic) persistent hyperinsulinism
is the most common form of persistent hypoglycemia in neonates and infants and is the most difficult
to diagnose and treat.77 The pancreatic abnormalities
observed may be diffuse or focal, depending on the
mutation present. Although the overall incidence
of persistent hyperinsulinemic hypoglycemia (PHIHG) is
low (approximately 1 in 50,000 births), the incidence
of the inherited forms may be as high as 1 in 2500
infants in certain genetically homogeneous populations.60 Depending on the degree of hyperinsulinemia in utero, these infants also may be macrosomic
at birth. Most often, infants with PHIHG present
with repeated episodes of hypoglycemia in the
immediate neonatal period, followed by severe,
recurrent hypoglycemia after the first few days
of life, often after discharge from the newborn
nursery. Recognizing such infants requires pro-
longed evaluation of an infant’s capacity to maintain normal blood glucose concentrations between
feedings after initial episodes of hypoglycemia
are noted.
Several different genes have been associated with
congenital hyperinsulinism.
119
Mutations in several
regions on the short arm of chromosome 11 occur
in many of infants with PHIHG; these mutations
most often are inherited in an autosomal recessive
pattern. Abnormalities of either the SUR1 or the
Kir6.2 component of the K
common. Because the K
complex are most
ATP
complex—the site of
ATP
diazoxide action—is disrupted by the mutations,
these infants usually do not respond to diazoxide
treatment. Octreotide (long-acting somatostatin)
can be more helpful in the short term, but neartotal (95% to 98%) pancreatectomy usually is necessary. Pancreatectomy often requires continuous
feedings and even insulin therapy
119
and replacement of pancreatic enzymes. Infants who have this
form of hyperinsulinism typically are LGA, present
with early neonatal hypoglycemia, and often require
high rates of IV glucose infusion.
Hyperinsulinism resulting from a focal pancreatic lesion (focal adenomatosis) may occur in 50% of
patients with congenital hyperinsulinism.
135
The
adenomas are small—3 to 5 mm in diameter—and
represent a localized clone of beta cells expressing a
paternally derived mutation in the gene for either
CHAPTER 15 Glucose Homeostasis
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441
SUR1 or Kir6.2 because of loss of heterozygosity
for the maternal allele. The clinical course of these
infants is similar to that of infants with hyperinsulinism due to widespread mutations of the
pancreatic K
channel. Localization of the focal
ATP
adenomatous region of the pancreas via positron
emission tomography (PET) with 18F-fluoro-ldopa may allow definition of the abnormal region
of the pancreas, thereby guiding limited resection and avoiding more extensive, often near-total
pancreatectomy.
20,86
Several other mutations lead to genetic forms
of PHIHG, including mutations in genes coding
for glucokinase (GCK HI), glutamate dehydrogenase (GDH), hexokinase (HK1), hydroxyacyl-CoA
dehydrogenase (HADH), and the nuclear transcription factors HNF1A and HNF4A.
119
These
different genetic disorders are much less common
and have variable presentations, usually later in the
neonatal period or even in early infancy.
In addition to hyperinsulinemia, global endo-
crine disturbances also can result in hypoglycemia. These disturbances include a range of
abnormalities of the hypothalamic-pituitary axis, the
most severe being panhypopituitarism. Such infants
frequently have growth hormone deficiency and
hypothyroidism in addition to severe hypoglycemia.
If pituitary dysfunction has resulted from a structural
central nervous system (CNS) lesion, other neurologic problems may be present, including abnormal
muscle tone and neonatal seizures. Adrenal failure
and hypoglycemia can occur as a result of adrenal
hemorrhage, often in association with neonatal
sepsis. Isolated endocrine defects, including primary
hypothyroidism and cortisol deficiency, also may be
associated with hypoglycemia.
Infants with Beckwith-Wiedemann syndrome
also are macrosomic and hyperinsulinemic; in
addition, they have other associated anomalies,
including macroglossia, which may cause airway
obstruction, and omphalocele.49 Asymptomatic
hypoglycemia may occur in 30% to 50% of infants
with Beckwith-Wiedemann syndrome and usually
resolves in the first 3 days of life. However, up to
5% of affected infants may have persistent, frequently symptomatic hypoglycemia.41 Infants with
Beckwith-Wiedemann syndrome have abnormalities with a specific region on the short arm of chromosome 11, the same region in which mutations
associated with other hyperinsulinemic syndromes
have been identified.
ENZYMATIC AND GENETIC DISORDERS
(TABLE 15.1)
Hypoglycemia can result from a wide variety of
hormonal and enzymatic deficiencies.75 Growth
hormone and cortisol are counterregulatory hormones (i.e., they oppose the actions of insulin) and
increase blood glucose concentrations by reducing
glucose uptake in muscle tissue and stimulating
lipolysis and gluconeogenesis during hypoglycemia. Hypoglycemia is a common complication
of growth hormone and cortisol deficiency.
Thyroid hormone deficiency is another situation
in which hypoglycemia can develop. Deficiency
of one or all of these hormones can be seen in
cases of panhypopituitarism. Appropriate hormone
replacement is the treatment of choice.
Hereditary disorders associated with deficiencies
of specific enzymes that regulate substrate mobilization, interconversion, or utilization of carbohydrate,
fat, or amino acids individually are rare disorders but
collectively are frequently associated with hypoglycemia. These disorders are almost always inherited as
autosomal recessive traits. Many infants with these
disorders can be identified on routine and expanded
neonatal screening, and early dietary interventions
can be critical in the long-term management of
their condition.
Glycogen storage disorders cause hypoglycemia from one of several enzyme deficiencies
that prevent or limit glycogenolysis and release
of glucose into the circulation.
INCREASED GLUCOSE UTILIZATION
Some term infants may have normal energy stores
at birth and intact regulating mechanisms but may
be stressed by one of several conditions so that the
available supplies do not meet their energy requirements. An asphyxiated newborn is one common
example. During and after asphyxia, when tissue
oxygen supply is limited, the neonate relies
largely on anaerobic metabolism for energy
production. Anaerobic metabolism utilizes more
glucose than aerobic metabolism to produce a given
amount of energy. As a result, glucose produced
by lipolysis and glycogenolysis is rapidly consumed. Hypoxic-ischemic damage to the liver
may further impair synthesis of gluconeogenic
enzymes and thus delay the normal postnatal
onset of gluconeogenesis. Elevated insulin concentrations also may be present, providing an
additional cause for the hypoglycemia.39 Other
200
Percent of normal values
Body
Liver
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UNIT THREE Metabolic and Nutritional Care of the Neonate442
150
100
50
0
FIGURE 15.4 Differences in organ/body weight ratios in small-for-gesta-
tional-age infant compared with appropriate-for-gestational-age counterpart.
(From Lafeber HN, Jones CT, Rolph TP. Some of the consequences on intrauterine growth retardation. In Visser HKA, editor: Nutrition and Metabolism of the
Fetus and Infant. Boston: Martinus Nijhoff; 1979.)
Body
Brain Brain
Brain
conditions in neonates that lead to a shift from
aerobic to anaerobic metabolism, thus predisposing the infant to hypoglycemia, include
hypotension, severe lung disease with hypoxemia and hypoventilation, and septic shock.
Hypothermia may result in hypoglycemia through
rapid depletion of brown fat stores for nonshivering thermogenesis and secondary breakdown and
exhaustion of glycogen stores. Hypothermia is most
often seen in infants born at home, but milder degrees
may occur in the delivery room. Hypoglycemia also
has been observed in some infants with sepsis. A
study done in several such infants found that they had
an increased rate of glucose disappearance in response to
an IV glucose infusion, suggesting an increased rate of
glucose utilization.87 Stimulation of glucose utilization
may be a result of circulating endotoxins, which increase
the rate of glycolysis.
Several other factors also contribute to the risk
for hypoglycemia in infants with other identified
risk factors. Preterm infants with respiratory
distress syndrome (RDS), for example, have
increased metabolic demands because of the
increased work of breathing. Chronic hypoxia
in IUGR fetuses stimulates catecholamine secretion, which can deplete glycogen stores. Infants
with IUGR and hypoglycemia may have increased
rates of glucose disappearance when receiving an
IV glucose infusion and reduced fat mobilization in
response to hypoglycemia compared with normoglycemic SGA newborns. Because of the increased
brain weight/liver weight and brain weight/
body weight ratios in all newborns (12% in
term newborns for the latter comparison vs.
2% in adults), cerebral glucose requirements are
markedly higher relative to the liver’s capacity
to respond than in the adult, even if glycogen
stores are normal for size (Fig. 15.4).85 This is
especially true in infants with asymmetric growth
restriction. In addition, increased insulin sensitiv-
ity has been reported in SGA newborns within
the first 48 hours of life.
14,130
These observations
indicate that disturbances in glucose metabolism in
addition to lower-than-normal energy stores may
be present in some growth-restricted infants.
PREVENTION OF
HYPOGLYCEMIA
Recognition of those infants at risk for disturbances in glucose homeostasis is the most
important step in preventing both hypoglycemia
and hyperglycemia. In infants with conditions
predisposing to hypoglycemia, such as preterm
infants, infants with IUGR, or IDMs, early feed-
ing and frequent monitoring of blood glucose
concentrations may prevent a decrease in blood
glucose concentration or allow early detection
of decreased blood glucose levels. Maintenance
of a neutral thermal environment is especially
critical to minimize energy expenditure in
those infants at risk for hypoglycemia. Other
conditions associated with hypoglycemia, such as
asphyxia and hypothermia, may be avoided through
appropriate obstetric and neonatal intervention. As
many as 70% of infants requiring transport may
not have had appropriate glucose evaluations documented in the referring centers.44 A prompted
intervention (STABLE Pretransport Stabilization
Self-Assessment Tool [PSSAT])44 may result in significant improvement in glucose monitoring.
DATA COLLECTION
History
The history of any neonate at risk of hypoglycemia
must include a detailed prenatal and family history.
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Important maternal risk factors associated with
neonatal hypoglycemia are listed in Box 15.1.
Other important data include a history of family
members with atypical diabetes or other abnormalities of glucose homeostasis, family history of metabolic disease, and previous unexplained stillbirths.
The most important information to be obtained
from the infant’s history is gestational age, Apgar
scores, and details of events in the delivery room,
especially any findings that suggest the presence of
significant perinatal compromise. An infant with
a history of any of the conditions listed in Box
15.1 or Table 15.1 should be considered at high
risk for developing a problem with glucose
homeostasis.
Physical Examination
Careful measurement of birth weight and head
circumference in combination with accurate
gestational age assessment will establish whether
the infant is preterm, LBW, SGA, or LGA and
thus at increased risk for hypoglycemia. IDMs
frequently have small heads relative to their general
macrosomia and have been described as having
“tomato facies” because of plethora and increased
buccal fat. The physical findings associated with
Beckwith-Wiedemann syndrome have already been
described. The presence of midline facial defects,
such as cleft lip or hypertelorism, may indicate the
presence of a CNS malformation with associated
pituitary dysfunction. Glycogen storage diseases
should be considered in infants with hepatomegaly.
Clinical Signs
Signs of neonatal hypoglycemia are nonspecific and extremely variable (Box 15.2).
include general findings, such as abnormal cry, poor
feeding, hypothermia, and diaphoresis; neurologic
signs, including tremors and jitteriness, hypotonia,
irritability, lethargy, and seizures; and cardiorespiratory disturbances, including cyanosis, pallor,
tachypnea, periodic breathing, apnea, and cardiac
arrest. These features also occur in preterm infants
and in neonates with sepsis, intraventricular hemorrhage, asphyxia, hypocalcemia, congenital heart
disease, and structural CNS lesions, among other
causes. In the presence of any of the preceding
signs, however, hypoglycemia always should
be considered, because the diagnosis can be
121
They
BOX
15.2
• Mild to moderate changes in level of consciousness*
• Stupor or lethargy
• Tremulousness
• Irritability
• Coma
• Seizures (depend on duration, repetitive occurrence, and severity of
• Respiratory depression or apnea, leading to cyanosis
• Hypotonia, limpness, inactivity
• High-pitched cry
• Poor feeding (after previously feeding well)
• Hypothermia
* Most frequent and should be alleviated with correction of low glucose concentrations.
CLINICAL SIGNS OF HYPOGLYCEMIA
hypoglycemia)
made relatively easily and prompt treatment is
essential.
If a problem with glucose homeostasis is sus-
pected, documentation of the aforementioned
data, history (see Box 15.1), physical examination, and clinical signs (see Box 15.2) must
reflect ongoing monitoring and measures taken.
The use of risk assessments, guidelines, or protocols that consider the data just mentioned
helps systematize detection (Fig. 15.5).
Laboratory Data
When hypoglycemia is suspected, the plasma or blood
glucose concentration must be determined promptly.
Ideally, this determination should be made with
one of the laboratory enzymatic methods, such as
the glucose oxidase or hexokinase method, but
even bedside reagent test strip glucose analyzers
(i.e., glucometers) can be used if the test is performed carefully and with awareness of the more
limited accuracy of these devices. Although more
expensive, some blood gas analyzers have the capability of measuring glucose concentrations as accurately
as laboratory enzymatic methods. If present in the
nursery or as a portable device, these instruments may
offer the optimal combination of short turnaround
time and accuracy.73 In the clinical setting, early
and rapid determination of glucose concentrations
in the high-risk or symptomatic neonate is essential.54 Prompt detection of hypoglycemia permits
early treatment and potentially helps prevent
UNIT THREE Metabolic and Nutritional Care of the Neonate444
Levels arbitrary and not “normal” or “hypoglycemic.”
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HIGH-RISK OR SYMPTOMATIC NEONATE
Check glucose level
(reagent strip, glucometer, or laboratory)
Symptomatic and/or glucose
25-30 mg/dL
IV bolus 2 mL/kg D
Infuse D10W at
4-8 mg/kg/min
Recheck serum glucose
within 30 min
Serum glucose
40-45 mg/dL
Continue glucose
infusion
Recheck serum
glucose every
1-2 hr
∗
∗
W
10
Serum glucose
40-45 mg/dL
Repeat D
Increase infusion
rate of D10W 10%-15%
Recheck serum glucose
10
within 30 min
∗
∗
W bolus
40-50 mg/dL
Serum glucose
40-45 mg/dL
or not tolerating
feeding
FIGURE 15.5 Decision tree for management of neonate with acute hypoglycemia. IV, Intravenous.
long-term neurologic sequelae.34 Although laboratory measurements of glucose concentrations
are the most effective methods for detecting
hypoglycemia, requests for confirmatory glucose
concentration measurements by the laboratory
must be requested and accomplished STAT (15
minutes or less). Routine requests are often
not available for up to 1 hour—far longer than
appropriate for diagnosing hypoglycemia and
thereby delaying the initiation of critically import-
ant treatment. The sample of blood can be obtained
from a warmed heelstick or venipuncture specimen.
These methods can be useful in screening infants
in whom abnormal glucose concentrations are suspected if the user is aware of their limitations. The
accuracy of test strip results depends in part on
the technique used. An adequate sample must be
placed on the test strip pad, and the timing of reading the result is critical. Recently developed devices
automatically read the result at the appropriate time,
reducing one source of error. Hospital personnel
∗
Asymptomatic
Begin feeding
Recheck serum
glucose within
30 min
∗
Serum glucose
40-45 mg/dL
Continue feeding
every 3 hr
Recheck serum
glucose every
1-2 hr
40-45 mg/dL
Begin feeding
Follow clinically
Other evaluation
as indicated
∗
If symptoms
persist, consider
IV glucose
therapy
should be trained and certified in the use of test
strip methods and the bedside instruments used
to quantify glucose concentration. With proper
technique, test strip results demonstrate a reasonable correlation with actual blood glucose
concentrations, but the variation from the actual
blood glucose value may be as much as 10 to
20 mg/dL. A number of studies have compared the
results obtained with specific commercial products
with results obtained with laboratory methods.
Regardless of the test strip or instrument used, correlations with actual blood glucose concentrations
are lowest at the lower glucose concentrations at
which neonatal hypoglycemia must be accurately
determined. Several studies have shown that use
of test strips alone may fail to detect from 11%
to as many as 67% of infants with statistically
defined hypoglycemia.
56,57,88
There also is a sig-
nificant incidence of false-positive results.
Because of the limitations of these meth-
ods, whenever a diagnosis of hypoglycemia is
∗
6,57,99
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445
suspected by test strip or glucometer results,
the blood glucose concentration should be
confirmed by a specimen sent to the chemistry
laboratory for rapid (STAT) determination and
reporting. Although laboratory results are more
accurate and reliable than screening methods, a
long delay in processing the specimen can result in
a falsely low level as the erythrocytes in the sample
metabolize the glucose in the plasma. This problem
can be avoided by transporting blood in a tube containing a glycolytic inhibitor. Treatment of suspected
hypoglycemia, however, should not be postponed until
confirmation is obtained from the laboratory. Also,
if hypoglycemia is suspected on the basis of clinical
symptoms, initial treatment should be instituted even
if the test strip result is “normal.” If the actual value
is abnormal, a delay in therapy could be harmful; if
the actual value is within the normal range, therapy
can be stopped without serious side effects.
Most cases of neonatal hypoglycemia have
an identifiable cause (e.g., maternal diabetes
or IUGR). In a term infant with no known
risk factors for hypoglycemia, sepsis must be
considered as the most likely cause of hypoglycemia and an appropriate evaluation should
be performed. Of those infants without an iden-
tifiable cause, most have idiopathic hypoglycemia,
which resolves spontaneously within 2 to 5 days,
and no further evaluation is needed. However, in
rare cases, hypoglycemia persists beyond the first
week of life with no obvious cause, requiring a
logical and rapid approach to diagnosis of the
particular form of persistent hypoglycemia.
70,155
The diagnostic evaluation of these infants should
include (1) simultaneous determination of glucose
and insulin concentrations and alternate substrates,
such as ketones and FFAs; (2) evaluation of pituitary function, including measurement of thyroid-stimulating hormone (TSH), thyroxine (T4),
adrenocorticotropic hormone (ACTH), cortisol,
and growth hormone levels; and (3) appropriate
studies to diagnose inborn errors of metabolism,
such as lactate and pyruvate concentrations. Ideally,
these studies should be obtained during an episode
of hypoglycemia. Once hypoglycemia is identified
in a neonate as persistent, a fasting study should be
performed to measure plasma insulin concentration
when plasma glucose concentration drops below
45 to 50 mg/dL. If this fasting study demonstrates
hyperinsulinism, treatment should be immediately
instituted.
77
TREATMENT OF
HYPOGLYCEMIA
Early identification of an infant at risk for
developing hypoglycemia and institution of
prophylactic measures to prevent its occurrence
provide the best treatment for this disorder.
The goals are to recognize at-risk infants, evaluate
early and frequently for decreasing glucose concentrations, treat when indicated, and provide glucose
and enteral feeding as needed to achieve and maintain glucose concentrations in the range that most
normal infants achieve via their own homeostatic
mechanisms within 6 to 12 hours after birth.
A decision tree suggesting guidelines for
management of infants with hypoglycemia is
shown in Fig. 15.5. Most asymptomatic infants
can be managed with early and frequent feedings (by breastfeeding or with expressed milk,
with donor milk when appropriate as for very
preterm infants, or with formulas). All symptomatic neonates should receive treatment
with IV dextrose infusion to provide glucose
at an initial rate of 4 to 6 mg/kg/min. These
suggested infusion rates cover the range of hepatic
glucose production in normal term newborns. In
some circumstances (neonates with glucose
concentrations of 20 mg/dL or less and/or
with very severe clinical signs, such as seizures and/or coma), it may be useful to use
a minibolus of 200 mg/kg dextrose (2 mL/kg
of D10W) plus the dextrose infusion regimen
originally described by Lilien and colleagues.90
Rapid normalization of blood glucose may be
particularly beneficial in such severely symptomatic infants, although no data confirm this
assumption. However, in asymptomatic new-
borns it may not be necessary to use the 200
mg/kg dextrose minibolus.
infants suspected of having hyperinsulinism
with asymptomatic hypoglycemia, the initial
minibolus can be eliminated and the infusion
rate kept at the minimum necessary to produce
and maintain normal blood glucose concentrations (3 to 5 mg/kg/min).
prevent an excessive insulin response to the sudden increase in glucose concentration produced
by the minibolus. When glucose infusion rates are
being calculated, it is important to remember that
commercially prepared glucose solutions actually
contain glucose in its hydrated form (molecular
120
In IDMs or other
120
This practice helps
UNIT THREE Metabolic and Nutritional Care of the Neonate446
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weight [MW] 198, versus MW 180 for anhydrous
glucose), which lowers the actual glucose content
of the solution by approximately 8%. Thus D10W
contains approximately 9.2 g of glucose per
deciliter.
Once the infant’s glucose requirement has been
determined, the glucose infusion should be
maintained at that level until blood glucose concentrations are stable and in the desired range.
The target blood glucose concentration during
IV therapy should be above the “hypoglycemic
threshold” defined for that particular infant. For
example, if the hypoglycemia threshold is defined as
40 mg/dL, glucose concentrations should be maintained at or above 50 mg/dL.
33
Adjusting therapy to maintain a blood glu-
cose concentration higher than the “symptomatic” threshold allows a margin of safety in
the absence of any data establishing a correlation
between specific glucose concentrations in this
range and long-term outcome. There is no evidence
that diagnosis or treatment thresholds for preterm
infants should differ from those for term infants.
If the infant was being fed before IV therapy was instituted, feedings may be continued. However, the calculated minimum glucose
requirement should be provided by the IV
infusion alone rather than by the combination
of glucose infusion and feedings. In infants who
were not previously fed, feedings can be instituted when clinically indicated. There are several
advantages to feeding a hypoglycemic infant during
treatment with IV glucose. In the hyperinsulinemic infant, galactose (one of the components of
lactose) stimulates less insulin release than glucose
and therefore helps stabilize blood glucose concentrations. Continuation of oral feedings also
aids in the process of weaning the infant off
IV glucose. When feedings are well tolerated,
the IV infusion generally can be slowly tapered
if the glucose concentration and clinical status
remain stable. Although enteral feeding has the
theoretical risk for augmenting insulin secretion
and subsequent hypoglycemia as a result of the
food-stimulated release of gut peptides that may
potentiate insulin release from the pancreas, there
is no evidence that withholding feedings actually
prevents this potential problem. It probably is bet-
ter to continue breast milk or formula feedings
using smaller, more frequent amounts or even
continuous gastric infusion than to stop enteral
feedings and try to maintain normoglycemia
exclusively with IV glucose.
Additional consideration should be given to
the use of buccal dextrose gel.
120
In a large place-
bo-controlled, randomized trial, 40% oral dextrose
gel, 200 mg/kg, placed on the buccal mucosa,
restored normal glucose concentrations, reduced
the recurrence rate of low glucose concentrations, and allowed enteral feeding, particularly
breastfeeding, to continue or even advance.
This therapy also decreased rates of NICU
admissions for hypoglycemia and increased rates
of continued successful breastfeeding.63 Such
therapy seems appropriate for the term or late
preterm infant with transient hypoglycemia and
probably for SGA, LGA, and IDM infants who
are otherwise clinically stable.
120
When buccal
dextrose gel is utilized and these infants are managed outside the NICU, nursing staffing must allow
for additional observation and monitoring. Parental
teaching regarding the signs of hypoglycemia
and the need to avoid hypothermia must be
provided and documented.
In rare cases, such as infants with severe, refractory hyperinsulinemic hypoglycemia or infants
with other morbidities such as hypoxic-ischemic
encephalopathy or heart failure, enteral feedings might be contraindicated. In these infants,
once glucose concentrations are stabilized and/
or the other adverse clinical conditions have
resolved, then enteral feedings can be used to treat
hypoglycemia.
Adjunctive Therapy
Table 15.2 offers a summary of adjunct therapies for
hypoglycemia.
GLUCAGON
Glucagon, 30 mcg/kg IV or intramuscular (IM),
releases glycogen from hepatic stores when insulin concentrations are normal. However, IDMs and
other infants with hyperinsulinemia may require much
larger doses, up to 300 mcg/kg IV or IM, to produce
a response. Administration of glucagon may be
useful diagnostically, because failure to respond
to glucagon administration with an increase in
serum glucose concentration suggests depletion of
hepatic glycogen stores or a glycogen storage disorder. Glucose infusion should be maintained after
injections of glucagon are administered, because
CHAPTER 15 Glucose Homeostasis
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TABLE
15.2
THERAPY EFFECT DOSAGE
Corticosteroids Decrease peripheral glucose utilization
Glucagon Stimulates glycogenolysis
Diazoxide Inhibits insulin secretion 15 mg/kg/day
Somatostatin (long-acting: octreotide acetate) Inhibits insulin and growth hormone release 5–10 mcg/kg every 6–8 hr
Pancreatectomy
IM, Intramuscular; IV, intravenous.
From McGowan JE. Neonatal hypoglycemia, Pediatr Rev. 1999;20:6–15.
ADJUNCT THERAPIES FOR HYPOGLYCEMIA
Enhance gluconeogenesis
Releases glycogen from hepatic stores when insulin
concentrations are normal
Decreases insulin production/secretion
Hydrocortisone 5–15 mg/kg/day
or
Prednisone 2 mg/kg/day
30 mcg/kg IV or IM
300 mcg/kg if hyperinsulinism is
present
447
there is a risk for rebound increased insulin secretion in response to the glucagon-produced surge
in glucose production. Some have suggested using
continuous IV glucagon infusions, but this practice is
not universal.
109
In addition, the rapid but transient
increase in glucose concentration immediately after
glucagon injection may produce a false sense that the
hypoglycemia has resolved, even though the underlying cause still exists. Continuous infusions of glucagon
have been used to treat refractory hypoglycemia.
OTHER AGENTS
26
Glucocorticoids (hydrocortisone), somatostatin, and
diazoxide have been used to treat hypoglycemia
in refractory cases. Glucocorticoids can be used
to reduce peripheral glucose utilization and
increase gluconeogenesis, particularly when glucose infusion rates of 12 to 15 mg/kg/min or
more are needed to maintain normal glucose
concentrations. Somatostatin and diazoxide, which
suppress insulin release, are most often used in
infants with islet cell dysplasias.
MISCELLANEOUS THERAPIES
77
In infants with hypoglycemia caused by a specific
medical problem, therapy should be directed
toward alleviating the underlying illness. This
includes administration of antibiotics to treat sepsis,
partial exchange transfusion to reduce hyperviscosity, hormone replacement in cases of hypopituitarism, and dietary intervention for metabolic
disorders. A trial of diazoxide should be initiated in
infants who have been identified as having hyperinsulinism. If diazoxide is not effective at a maximum
dose of 15 mg/kg/day divided into two doses per
day for 2 to 3 days, it may be stopped and octreotide
could be tried. However, medical therapy alone fails
to control hypoglycemia in 40% to 90% of infants
with severe PHIHG.42 If octreotide is not successful,
surgical management is generally necessary. Before
surgery, imaging procedures should be performed
to determine whether the pancreatic abnormalities
are focal or diffuse. Focal disease generally is cured
with partial pancreatectomy, whereas diffuse disease
requires near-total pancreatectomy and then treatment of the exocrine and endocrine deficiencies
that invariably result.
51
COMPLICATIONS OF
HYPOGLYCEMIA
The outcome for infants with neonatal hypoglycemia appears to be related to the duration,
repetitive occurrence, and severity of the hypoglycemia and the underlying etiology. Those with
asymptomatic hypoglycemia usually have clinically
normal neurodevelopmental outcomes, though in
research outcomes assessments there may be an
association between low glucose concentrations
and impaired neurodevelopment.
there is no evidence yet that treatment prevents
103
Furthermore,
UNIT THREE Metabolic and Nutritional Care of the Neonate448
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such abnormal outcomes. Symptomatic hypoglycemic
infants (primarily those with severe, protracted, and
recurrent neurologic abnormalities such as seizures
and coma associated with plasma glucose concentrations below 20 to 25 mg/dL for several hours or
more) have a poorer prognosis, with abnormalities
ranging from learning disabilities to cerebral palsy
and persistent or recurrent seizure disorders, as
well as mental retardation of varying degrees.50
Prompt initiation of treatment is thought to be associated with a more positive outcome, although this
has not been well documented.
In preterm infants, data indicate that hypo-
glycemia may adversely affect long-term out-
47,80,96
come.
A follow-up study of more than 600
former preterm infants found significantly lower
mental and motor indices in those with five or
more documented episodes of moderate hypoglycemia (defined as a blood glucose concentration
less than 45 mg/dL) during the neonatal period.
This difference remained significant even when
confounding factors such as intraventricular hemorrhage (IVH), need for ventilator support, and
asphyxia were considered. However, not all comorbidities can be controlled for in this type of study.
Furthermore, differences in cognitive function
were less apparent at school-age follow-up in the
same cohort of patients, and newer studies have
not confirmed any adverse outcomes associated
with hypoglycemia in preterm infants.
61,157
It
may be that because nearly all preterm infants
receive early IV dextrose infusions separately or
as part of parenteral nutrition, low glucose concentrations—particularly repeated low values—are
less likely to occur.
69,166
These discrepant results
indicate the need for further long-term studies in
preterm infants.
The incidence of neurodevelopmental abnormalities in IDMs ranges from 0% to 35%; the
lower figures are from more recent studies and
may represent improvement in obstetric and
neonatal care. Some studies have been able to
detect causes other than hypoglycemia that may
have contributed to the overall outcomes.
67,129
These causes include such factors as prematurity,
presence of congenital anomalies, congenital iron
deficiency, and degree of control of maternal disease. However, Stenninger and colleagues
139
found
that IDMs who were hypoglycemic as newborns
(glucose less than 27 mg/dL) had an increased
frequency of deficits in attention, motor control,
and perception at 8 years of age compared with
both IDMs without hypoglycemia and normal
newborn controls. This association was also doc-
umented in a more recent study.
103
A number of
other neonatal complications are associated with
maternal diabetes, including polycythemia, which
may add to disturbances of glucose homeostasis;
hypocalcemia secondary to maternal hypoparathyroidism; dystocia secondary to macrosomia; and
congenital anomalies. Infants of mothers with severe
diabetic vasculopathy, in contrast to most IDMs,
may have IUGR caused in part by decreased placental blood flow, with hypoglycemia resulting from
inadequate glycogen and fat stores as occurs in all
cases of IUGR rather than hyperinsulinemia alone.
Adverse neurologic outcomes have been reported
in as many as 40% to 50% of infants with PHIHG,
possibly because these infants cannot effectively
generate ketone bodies, which could serve as an
alternative source of energy for cerebral metabolism
during periods of hypoglycemia.
105-107
In addition,
infants with PHIHG who require a greater than
95% pancreatectomy often develop glucose intolerance or even frank diabetes mellitus later in life.94
Hypoglycemia secondary to hypopituitarism also is
associated with a poor outcome; often this results
from other CNS or endocrine dysfunction rather
than from the hypoglycemia itself.
PARENT TEACHING
Parent teaching should begin before delivery, with
emphasis placed on good nutrition and early and
regular prenatal care. Teaching also should include
information about those conditions that increase
the risk for hypoglycemia (e.g., IUGR associated
with maternal cigarette smoking and poor maternal
nutrition). Regular prenatal care ensures the early
detection of potentially serious problems, including
preeclampsia, gestational diabetes, and abnormal
fetal growth.
Prenatal teaching is especially important
in the woman with known diabetes mellitus,
because overall outcome (although not necessarily the incidence of hypoglycemia) is directly
related to the degree of control before and
during pregnancy. Breastfeeding information and
encouragement to breastfeed must be included
in the prenatal education. In addition, the possi-
bility of neonatal hypoglycemia and requirement for
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