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CHAPTER 14 Fluid and Electrolyte Management
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429
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35. Khan MA, Upadhyay A, Chikanna S, et al. Efficacy of prophylactic intravenous calcium administration in first 5 days
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38. Leick-Rude MK, Haney B. Midline catheter use in the intensive care nursery. Neonatal Netw. 2006;25(3):189.
39. Milstone AM, Reich NG, Advani S, et al. Catheter dwell time
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40. Modi N. Management of fluid balance in the very immature
neonate. Arch Dis Child Fetal Neonatal Ed. 2004;89(2):F108.
41. Moffet HL, Allan D, Williams T. Survival and dissemination
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43. Moyses HE, Johnson MJ, Leaf AA, et al. Early parenteral
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44. Nydegger A, Walsh A, Penny DJ, et al. Changes in resting
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46. Oh W. Fluid and electrolyte management of very low birth
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47. Pacifici GM. Clinical pharmacology of furosemide in neonates;
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48. Pierro A, Eaton S. Metabolism and nutrition in the surgical
neonate. Semin Pediatr Surg. 2008;17(4):276.
49. Prempunpong C, Efanov I, Sant’anna G. The effect of the
implementation of therapeutic hypothermia on fluid balance
and incidence of hyponatremia in neonates with moderate
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50. Ramasethu J. Complications of vascular catheters in the neonatal intensive care unit. Clin Perinatol. 2008;35(1):199.
51. Samedi VM, Yusuf K, Yee W, Obaid H, Al Awad EH. Neonatal
hypercalcemia secondary to subcutaneous fat necrosis successfully treated with pamidronate: a case series and literature
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53. Selewski DT, Chariton JR, Jetton JG, et al. Neonatal acute
kidney injury. Pediatrics. 2015;136(2):e463.
54. Shah PS, Shah VS. Continuous heparin infusion to prevent
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55. Sharpe E, Pettit J, Ellsbury DL. A national survey of neonatal
peripherally inserted central catheter (PICC) practices. Adv
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balance in the neonate. Neonatal Netw. 2008;27(4):261.
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albuterol inhalation in treatment of hyperkalemia in premature
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73. Wrightson DD. Peripherally inserted central catheter complications in neonates with upper versus lower extremity insertion
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74. Wu J, Mu D. Vascular catheter-related complications in newborns. J Paediatr Child Health. 2012;48(2):E91.
75. Zazzeron L, Ottolina D, Scott E, et al. Real-time electrolyte monitoring after furosemide administration in surgical ICU patients
with normal renal function. Ann Intensive Care. 2016;6(1):72.
GLUCOSE HOMEOSTASIS
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15
uring intrauterine life, the fetus depends
on the constant transfer of glucose across
D
requirements. After birth, neonates must maintain
glucose homeostasis by producing and regulating
their own glucose supply. This requires activation
of a number of metabolic processes, including gluconeogenesis (synthesis of glucose from nonglucose
precursor substrates) and glycogenolysis (release of
glucose via breakdown of glycogen stores) and intact
regulatory mechanisms for glucose metabolism and
an adequate supply of metabolic substrates.
the placenta to meet his or her glucose
PAUL J. ROZANCE, JANE E. MCGOWAN, WEBRA PRICE-DOUGLAS, AND WILLIAM W. HAY JR.
FETAL PHYSIOLOGY
Throughout gestation, maternal glucose provides
the principal source of energy for the fetus via
facilitated diffusion across the placenta. Fetal
glucose uptake varies directly with maternal glucose
concentration; fetal glucose concentration usually
is about 70% of the maternal value. Changes in
maternal metabolism, including increased carbohydrate and lipid intake and decreased sensitivity of the
maternal tissues to insulin, augment maternal glucose
production and provide the additional glucose necessary to meet fetal energy demands.9 With normal
maternal glucose concentrations and rates of
glucose supply to the fetus, the fetus produces
little, if any, glucose, although the enzymes for
gluconeogenesis are present by the third month of
gestation.
supply, however, the fetus is capable of adapting by using alternate substrates provided from
the maternal circulation, such as ketone bodies,
for energy production. This may be the case when
124
If fetal demand exceeds maternal
maternal fasting or even starvation is severe enough
to produce maternal and fetal hypoglycemia. In addition, data from animal models suggest that there may
be fetal glucose production under these conditions.92
Even in the basal state, the fetus relies on fuels such
as lactate and amino acids to meet up to 25% to 30%
of his or her energy demands, whereas lipids are used
primarily for fat production.
Fetal glycogen synthesis begins as early as the
ninth week of gestation, but the majority of fetal
glycogen is produced in the third trimester. The
major sites of glycogen deposition are skeletal
muscle (greater than 90% of body glycogen),
liver (the only organ whose glycogen can be
released for use by other organs), lung, and
131
heart.
etal muscle glycogen contents are several times adult
levels. By contrast, lung and cardiac muscle glycogen
stores decrease as the fetus approaches term, although
these stores are still sufficiently large to be of physiologic significance. Survival in animals exposed to
anoxia and human infants after asphyxia, for example,
is directly related to cardiac glycogen content. The
decrease in lung glycogen, which begins at 34 to 36
weeks’ gestation, may be related to ongoing developmental processes, such as the synthesis of surfactant.
stores energy as fat in adipose tissue.
glyceride synthesis occurs during the third trimester.
By 40 weeks’ gestation, the human fetus has a
body fat content of about 16%, making it the fat-
test of all terrestrial newborn mammals. The human
placenta transports some free fatty acids, although
the amount transported to the fetus is not sufficient
to account for the amount of adipose tissue present;
therefore the fetus also must synthesize triglycerides,
By 40 weeks of gestation, hepatic and skel-
In addition to glycogen, the human fetus also
128
Most tri-
BLUE type highlights content that is particularly applicable to clinical settings.
431
UNIT THREE Metabolic and Nutritional Care of the Neonate432
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using glycerol derived from glucose, as well as fatty
acids transported across the placenta. Conditions in
which fetal glucose supply is reduced will result
in less adipose tissue accumulation and reduced
glycogen stores.
In addition to increasing glucose utilization,
insulin also stimulates cellular hypertrophy and
hyperplasia and thus is an important stimulus for
fetal growth.52 Fetal pancreatic insulin content and
glucose-stimulated insulin secretion increase over
the second half of gestation to levels comparable to
those found in neonates.85 Fetal insulin secretion
is augmented by higher glucose concentrations;
increased concentrations of amino acids add to this
effect.53 Increased concentrations of insulin increase
fetal glucose and amino acid utilization and glucose
oxidation rates without increasing total fetal oxygen
consumption.
45,68
This implies that other substrates,
primarily amino acids, become available for nonoxidative metabolism when glucose and insulin are
plentiful; such conditions promote tissue accretion
and growth.
Fetuses of diabetic mothers who have very
unstable plasma glucose concentrations during late
gestation have an increased islet cell response to
hyperglycemia compared with normal fetuses of
nondiabetic mothers, releasing more insulin than
normal fetuses at any given blood glucose concentration. The higher insulin levels in turn lead to
increased growth consisting primarily of adipose
tissue, producing the macrosomia typically seen
in infants of diabetic mothers (IDMs).
In contrast, fetuses with intrauterine growth
restriction (IUGR) have reduced numbers of
pancreatic islets and beta cells and produce lessthan-normal amounts of insulin in response to
glucose and amino acid stimulation.
21,112,160
In
IUGR fetal sheep, hepatic insulin resistance devel-
153
ops,
augmenting hepatic glucose production. Such
conditions can lead to postnatal hyperglycemia. In
some neonates this propensity for postnatal hyperglycemia may be counterbalanced by other factors.
Recent studies in IUGR fetal sheep show increased
insulin sensitivity in peripheral tissues (e.g., heart
and skeletal muscle) that persists into the neonatal
12,25,123,153
period.
Furthermore, islet cells obtained
from IUGR fetal sheep when removed from the
environment with elevated catecholamines and
adrenergic signaling in response to placental insufficiency and reduced fetal oxygen supply and blood
oxygen content show insulin secretion at greater
than normal levels.
25,30,93,98
These observations may
account for the apparent hyperinsulinemia that
occasionally occurs in such IUGR infants several
days after birth when oxygenation is restored and
norepinephrine concentrations diminish, contributing to their common risk of hypoglycemia.
8,91
Not surprisingly, therefore, glucose homeostasis in
IUGR neonates is highly variable.
It also is important to note that although correction of acute insulin deficiency promotes growth,
exogenous insulin appears to have little effect on
growth in human newborns or animal models with
chronic insulin deficiency, suggesting that insulin
infusion to promote growth in growth-restricted
infants is unlikely to be beneficial and may lead
to additional complications.
The related pancreatic hormone glucagon,
which, like insulin, does not cross the placenta,
has been detected as early as 9 to 16 weeks of
gestation.
117
In postnatal life, glucagon is a potent
inducer of gluconeogenic enzymes, the opposite
of insulin, which suppresses gluconeogenesis.
124
In fetal life, glucagon plays a much less important
role in regulating glucose metabolism than insulin,
reflecting the developmental insensitivity of fetal
glucagon receptors. As a result, the insulin-to-glucagon effectiveness ratio in the fetus is high, which
is important in preferentially maintaining glycogen
synthesis and suppressing gluconeogenesis.
NEONATAL PHYSIOLOGY
At birth, the newborn infant is removed abruptly
from his or her placental glucose supply, and
blood glucose concentration falls. Several hor-
monal and metabolic changes occur at birth that
facilitate the adaptation necessary to maintain glucose homeostasis. Catecholamine levels increase
markedly right after birth, possibly as a response
to the decrease in environmental temperature and
to the loss of the placenta, which is responsible
for as much as 50% of the clearance of circulating
fetal epinephrine.
receptor sensitivity also increase, reversing the
relatively high insulin/glucagon effectiveness ratio
characteristic of fetal life.
gon and norepinephrine concentrations activate
hepatic glycogen phosphorylase, which induces
glycogenolysis. Simultaneously, the decreasing glu-
cose concentration and perinatal surge in fetal cortisol
152
Glucagon concentrations and
136
The increased gluca-
CHAPTER 15 Glucose Homeostasis
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433
secretion stimulate hepatic glucose-6-phosphatase
activity. Together these changes lead to an increase
in hepatic glucose release.40 Increased catecholamines also stimulate lipolysis, releasing fatty acids
that can be metabolized to provide precursors
for gluconeogenesis and providing energy in the
form of adenosine triphosphate (ATP) and cofactors
such as nicotinamide adenine dinucleotide phosphate
that enhance the activity of gluconeogenic enzymes.
Catecholamine release also activates brown fat
triglyceride turnover, producing heat necessary for postnatal thermoregulation. The normal
postnatal decrease in insulin, augmented by the
acute postnatal increase in catecholamines, combined
with the increase in glucagon, induce synthesis of
phosphoenolpyruvate carboxykinase (PEPCK), which
is considered the rate-limiting enzyme in hepatic
gluconeogenesis. The concentrations of PEPCK and
other gluconeogenic enzymes continue to increase
over the first 2 weeks of life, regardless of gestational
age. These changes act in concert to provide glucose
produced by the neonatal liver to replace the supply
previously received via the placenta.
Maintenance of glucose homeostasis in the
newborn infant depends on the balance between
hepatic glucose output and glucose utilization by
the brain and peripheral tissues. Hepatic glucose
output is a function of rates of glycogenolysis
and gluconeogenesis. Peripheral glucose utilization varies with the tissue- and organ-specific
metabolic demands in the neonate. Studies in
normal human newborn infants using several
different methods have estimated that the steadystate glucose production/utilization rate in a term
neonate ranges from 3 to 5 mg/kg/min, approx-
imately twice the weight-specific rate measured in
adults.43 As in the fetus, approximately half of this
glucose is oxidized to CO2 during normal metabolic
processes, whereas the remainder is used in nonoxidative pathways, such as glycogen and fat synthesis.
Neonatal glucose utilization increases (1) during
hypoxia, because of the inherent inefficiency
of anaerobic glycolysis97; (2) in the presence of
hyperinsulinemia, which increases glucose uptake
by insulin-sensitive tissues82; (3) in newborns
with respiratory distress, because of increased
respiratory muscle activity
116
; and (4) during cold
stress, which leads to increased sympathetic nervous system activity with subsequent release of
norepinephrine, epinephrine, and thyroid hormone, which increase metabolic rate.32 If rates of
glycogenolysis and gluconeogenesis do not match the
rate of glucose utilization because of insufficient or
excessive hormonal control mechanisms or variability
of substrate supply, disturbances of glucose homeostasis
occur. These disturbances are recognized clinically by
the presence of hypoglycemia or hyperglycemia.
Data Collection
HISTORY
The history of any neonate must include a detailed
prenatal and family history. The most important
information to be obtained from the infant’s history
is gestational age, fetal growth, 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.
BOX
15.1
INDICATIONS FOR ROUTINE
MONITORING OF BLOOD GLUCOSE
FOR PREVENTION OF NEONATAL
HYPOGLYCEMIA
Maternal Conditions
• Presence of diabetes or abnormal result of glucose tolerance test
• Preeclampsia and pregnancy-induced or essential hypertension
• Previous macrosomic infants
• Substance abuse
• Treatment with beta-agonist tocolytics
• Treatment with oral hypoglycemic agents
• Late antepartum to intrapartum administration of intravenous glucose
Neonatal Conditions
• Prematurity
• Intrauterine growth restriction
• Perinatal hypoxia-ischemia
• Sepsis
• Hypothermia
• Polycythemia-hyperviscosity
• Erythroblastosis fetalis
• Iatrogenic administration of insulin
• Congenital cardiac malformations
• Persistent hyperinsulinemia
• Endocrine disorders
• Inborn errors of metabolism
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TABLE
15.1
MECHANISM CLINICAL SETTING EXPECTED DURATION
Decreased substrate availability Intrauterine growth restriction Transient
Endocrine disturbances
Other endocrine disorders Immaturity of hepatic enzymes necessary for glucose production Transient
NEONATAL HYPOGLYCEMIA: ETIOLOGY AND TIME COURSE
Prematurity Transient
Reduced glycogen stores Transient
Reduced fat stores Transient
Reduced ketogenesis
Glycogen storage disease Prolonged
Inborn errors Prolonged
Carbohydrate metabolism defects
• Fructose 1,6-diphosphatase deficiency
• Pyruvate carboxylase deficiency
• Phosphoenolpyruvate carboxykinase (PEPCK) deficiency
• Galactosemia
Amino acid metabolism defects
• Propionic acidemia
• Methylmalonic academia
• Glutaric aciduria
• Maple syrup urine disease (branched-chain alpha-keto acid dehydrogenase deficiency)
Fatty acid metabolism defects
Hyperinsulinemia Infant of diabetic mother Transient
Persistent hyperinsulinism of infancy Transient
Congenital hyperinsulinism (HI)
• Recessive K
• Focal K
• Dominant K
• Dominant glucokinase (GCK) HI
• Dominant glutamate dehydrogenase (GDH) HI
• Short-chain 3-hyroxyacyl-CoA dehydrogenase (SCHAD) HI
Beckwith-Wiedemann syndrome Prolonged
Erythroblastosis fetalis Transient
Exchange transfusion Transient
Islet cell dysplasias Prolonged
Maternal beta-agonist tocolytics Transient
Improperly placed umbilical artery catheter Transient
Inadvertent insulin administration Transient
Reduced or failed counterregulation Prolonged
Hypopituitarism Prolonged
HI
ATP
(focal adenomatosis) HI
ATP
HI
ATP
Transient
Prolonged
CHAPTER 15 Glucose Homeostasis
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TABLE
15.1
MECHANISM CLINICAL SETTING EXPECTED DURATION
Increased utilization Increased brain weight to body weight and liver weight ratio with increased
Miscellaneous/multiple mechanisms Sepsis Transient
NEONATAL HYPOGLYCEMIA: ETIOLOGY AND TIME COURSE—CONT’D
Growth hormone deficiency Prolonged
Hypothyroidism Prolonged
Adrenal and cortisol insufficiency Variable
brain consumption of glucose
Perinatal asphyxia
Hypothermia Transient
Congenital heart disease Transient
Central nervous system abnormalities Prolonged
Prolonged
Transient
435
HYPOGLYCEMIA
Definition
The absolute blood or plasma glucose concentration that defines hypoglycemia as a pathologic condition remains difficult to establish and
has not been determined. Furthermore, there
is no absolute correlation between blood or
plasma glucose concentrations, clinical signs or
symptoms, and either short-term or long-term
outcomes. Instead, “reference” glucose concentrations generally reflect the lower limit of the
normal range in a specific population of newborn infants, determined by statistical analysis
of data collected in that population. Thus there
is no consensus about threshold glucose concentrations below which diagnostic evaluation
or treatment is mandated or that identify those
infants likely to have adverse neurodevelopmental outcome.
Published definitions of hypoglycemia range
from a blood glucose concentration of less than 20
mg/dL in preterm infants and less than 30 mg/dL
in term infants to a plasma concentration of less
than 45 mg/dL.
suggested raising the lower limit of normal to
50 to 70 mg/dL, although others have empha-
sized that such higher concentrations should be
used primarily as target values during treatment
for relatively severe and symptomatic hypoglycemia
rather than thresholds for instituting treatment.33
33-35
Some sources have even
Published reports fail to distinguish between threshold glucose concentrations below which physiologic responses may occur (and below which
clinical monitoring may be indicated) and those
below which pathologic consequences are likely
to develop (thus requiring aggressive treatment). In
1992 the majority of pediatricians in one survey in
the United Kingdom defined a safe glucose concentration to be at least 36 mg/dL in blood or 45
mg/dL in plasma.
83,84
Fig. 15.1 shows that 95% of
normal term infants have a blood glucose concentration of more than 30 mg/dL in the first 24 hours
after birth and more than 45 mg/dL after 24 hours
137
of age.
A number of current references use
40 to 45 mg/dL as the lower limit of “normal”
plasma glucose concentrations in the first 72
hours of life. By 72 to 96 hours of age mean
plasma glucose concentrations in normal infants
are very similar to those seen in older children
and adults.*
Using these definitions of hypoglycemia, the
overall incidence has been estimated at 1.3 to
4.4 per 1000 live births. Differences in incidence
figures probably reflect variable inclusion of data
from symptomatic versus asymptomatic infants. In
preterm infants, the incidence of hypoglycemia is increased; estimates range from 1.5%
to 5.5% (Fig. 15.2) . The incidence of hypogly-
cemia in term infants with IUGR may be as
* References 3,33,76,101,102,134,146.
l
200
180
Age (hr)
Plasma glucose (mg/dL)
Grams
Weeks of gestation
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160
140
120
(52)
100
80
60
40
20
FIGURE 15.1 Plasma glucose concentrations during the first week of life in
healthy appropriate-for-gestational-age term infants. (From Srinivasan G, Pildes
RS, Cattamanchi G, et al. Plasma glucose values in normal neonates: a new
look, J Pediatr. 1986;109:114.)
4500
3500
2500
1500
500
FIGURE 15.2 Incidence of neonatal hypoglycemia (blood glucose less than
30 mg/dL) by birth weight and gestational age. (From Lubchenco LO, Bard
H. Incidence of hypoglycemia in newborn infants classified by birth weight and
gestational age, Pediatrics. 1971;47:831.)
UNIT THREE Metabolic and Nutritional Care of the Neonate436
*
(51)
(51)
(52)
012346
90%
10%
(69)
(49) (40)
( ) Number of samples
*
Mean and 95% confidence interva
26 30
(35)
(55)
73-96
49-72
4%
(2/48)
10%
(12/126)
25%
(11/44)
34 38 42 46
12-24
(55)
25-48
38%
(6/16)
15%
(9/60)
67%
(10/15)
(26)
97-168
7%
(1/14)
5%
(2/40)
18%
(2/11)
high as 25% to 50%, with an even higher rate
seen in preterm small-for-gestational-age (SGA)
62,95
infants.
Hypoglycemia also may be defined clinically
as the glucose concentration in a neonate that is
associated with clinical signs that resolve when
glucose is administered (“symptomatic” hypoglycemia), fulfilling Whipple’s triad: (1) low
blood glucose concentration; (2) signs consistent
with neonatal hypoglycemia; and (3) resolution of
signs and symptoms after restoring the blood glucose concentrations to normal values. This value is
difficult to determine, however, because the clinical
signs of hypoglycemia are nonspecific and may not
be noticed initially. From a physiologic point of
view, an infant may be said to be hypoglycemic when glucose supply is inadequate to meet
demand. Unfortunately, no method is available to
establish this value in a given infant. Infants with
increased glucose utilization demand or limited
capability to alter glucose delivery (which is a
function of both blood supply and glucose concentration) are at increased risk for impaired organ
function at low blood glucose concentrations.
Specifically, animal studies have shown that insufficient glucose supply for relatively long durations
(hours rather than a few minutes) may contribute
to neuronal death, augment functional deficits, and
increase the risk for long-term neurologic injury
in the presence of cerebral hypoxia and/or ischemia. Clinical studies suggest that this may be true
also in newborn infants. However, it is not clear
whether the low glucose concentrations in cases
of hypoxia and ischemia contributed directly to
worse outcomes or were simply a marker for those
infants with more severe and prolonged metabolic
compromise during hypoxia-ischemia who were,
therefore, more likely to have worse outcomes.
Furthermore, it remains unclear whether earlier
detection of hypoglycemia, such as in the delivery
room, in this population could improve subsequent
neurologic outcome.
Rather than defining hypoglycemia as an
absolute blood glucose value, some investigators
have suggested using specific glucose concentrations as an indicator that further management of low glucose concentrations is warranted.
Threshold values are based on evidence available
in the literature (see further discussion under
Treatment later in this chapter).33 This approach
considers the overall metabolic and physiologic
CHAPTER 15 Glucose Homeostasis
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437
status of the infant when determining what
constitutes an acceptable blood glucose concentration. Some infants may undergo metabolic
derangements at glucose concentrations above the
hypoglycemic threshold, whereas others may be
able to tolerate lower concentrations of blood
glucose without developing metabolic stress. An
infant with polycythemia, for example, may have a
normal blood glucose concentration but decreased
cerebral delivery of glucose because of reduced
brain plasma flow. In contrast, breastfed infants have
normal substrate delivery to the brain even with
“hypoglycemic” blood glucose values, because they
have increased plasma concentrations of ketone
bodies compared with formula-fed infants, though
these concentrations are still lower than what is
observed in fasting children.
65,79
Concentrations of
ketones are even lower in preterm and IUGR/
SGA infants than in term infants who are feeding normally, suggesting that preterm birth
and IUGR are associated with less capacity to
generate alternate brain energy substrates. This
decreased capacity might increase the vulnerability
of such infants to cerebral energy deficits when
plasma glucose concentrations are decreased.
65,66
In summary, the definition of the blood glucose
concentration at which intervention is indicated
must be tailored to the clinical situation and
the particular characteristics of a given infant.
Further investigation and treatment should be
instituted in the symptomatic infant at blood
glucose concentrations of less than 45 mg/dL,
whereas asymptomatic term infants with known
risk factors should be treated if their blood glucose concentration is less than 36 mg/dL.
76,77
Several authors suggest that these thresholds for
intervention should be higher in preterm infants
and lower in breastfed full-term infants.
33,64
The
American Academy of Pediatrics’ Committee on
the Fetus and Newborn has recommended different guidelines for late preterm infants and term
SGA, large-for-gestational-age (LGA), and IDM
infants, emphasizing initial screening, feeding if
tolerated, and prompt (within 1 hour) reassessment for clinical signs and repeat measurement of
glucose concentrations.1 The Pediatric Endocrine
Society also has issued a set of guidelines that
focus on targets for glucose concentrations once
an infant has been identified as having hypogly-
155
cemia.
However, it is important to recognize that
there have been no systematic studies to demonstrate
the risks or benefits of using any specific blood glucose concentration as a threshold for intervention
in neonatal hypoglycemia. Given the apparently
wide range of glucose values associated with normal
neonatal outcomes and the inherent inaccuracies in
measuring glucose concentrations and the absence of
a specific level below which injury inevitably occurs,
any individual blood glucose measurement should be
considered a one-point-in-time-only representation
of the balance between glucose supply and utilization
rather than as an absolute indicator of glucose sufficiency or insufficiency.
Hypoglycemic Neuronal Injury and
Neuropathology
A schema of how hypoglycemia can contribute to neu-
ronal injury is presented in Fig. 15.3. Hypoglycemic
brain damage in the newborn infant occurs predominantly in gray matter structures, although
severe hypoglycemia in newborn infants may also
be associated with white matter injury, particularly
when the hypoglycemia occurs simultaneously
with hypoxic-ischemic injury.
125,162
Pathologic
studies of such severely hypoglycemic newborn infants
have shown widespread neuronal injury in the cerebral
cortex, hippocampus, basal ganglia, thalamus, brainstem, and spinal cord. Late neuropathologic lesions
associated with severe and prolonged low glucose
concentrations include microcephaly associated with
cortical atrophy and diffuse neuronal loss, as well as
astrogliosis. Abnormalities may also be seen in white
matter, whereas the cerebellum is generally spared.
Such severe outcomes are extremely uncommon and
are very seldom seen in normal clinical practice.
Neuroimaging of Hypoglycemic
Injury
Magnetic resonance imaging (MRI) performed 2
to 3 weeks after such severe but very infrequent
hypoglycemia demonstrates abnormal signals in
the cortex, often most apparent in the occipital
lobes.10 More recent neuroradiologic investigations have shown a much wider variety in the
pattern of injury involving both white matter
and gray matter as a consequence of severe
neonatal hypoglycemia.
after severe hypoglycemia in the newborn period
23,148
MRI-defined lesions
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Decreased glucose
availability
↑ Mitochondrial
free radicals
Change in membrane
structure
↑ Mitochondrial
DNA damage
Change in gene
expression
Altered
synaptogenesis
↑ Apoptosis
↑ Free fatty
acid release
↑ Glutamate
receptor activity
↑ Activation of proteases
and lipases
↑ Free radical generation
↑ Neuronal
necrosis
↑ Glutamate
↑ Cell swelling
↓ Glutamate
uptake
↑ Na
, Ca
Change in membrane
FIGURE 15.3 Proposed mechanism for the pathogenesis of hypoglycemic brain injury in the newborn. ATP, Adenosine 5′-triphosphate;
DNA, deoxyribonucleic acid; PCr, phosphocreatine. (McGowan JE: Role of glucose in cerebral function. In Hay WW Jr, editor: Semin Neonat
Nutr Metab 1997; 4:2-3. Columbus, OH: Ross Products.)
↓ ATP/PCr
↓ ATP-dependent
ion transport
2
potential
can be transient and not associated with long-term
neurologic consequences, indicating that follow-up
MRI scans should be considered to determine the
permanency of the lesions.
Etiology of Hypoglycemia
The causes of hypoglycemia can be grouped into
several broad categories based on the mechanisms
producing the hypoglycemia (see Box 15.1
15.1). These categories include inadequate substrate
supply, abnormal endocrine regulation of glucose
metabolism, and increased rate of glucose utilization.
There also are several proposed causes for which
mechanisms are not well defined.
121
; Table
INADEQUATE SUBSTRATE SUPPLY
If substrate availability is inadequate, hepatic glucose output will not meet metabolic demands.
Most often this results from subnormal fat and glycogen stores that consequently do not provide sufficient energy to maintain glucose homeostasis until
gluconeogenesis reaches adequate levels. Because
most hepatic glycogen is accumulated during the
third trimester, infants born preterm have diminished glycogen stores. In the past, infants with
IUGR secondary to placental insufficiency also were
considered to be at risk for decreased glycogen accumulation, presumably because of diminished transfer
of glycogen precursors (e.g., glucose, lactate) across
the placenta. In these infants, relative hypoxemia
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