Pathophysiology

The body normally defends against hypoglycemia by decreasing insulin secretion and
increasing glucagon, epinephrine, growth hormone, and cortisol secretion. These
hormonal changes combine to increase hepatic glucose output, to increase alternative fuel
availability, and to decrease glucose use (see image below). The increase in hepatic
glucose production is initially caused by the breakdown of liver glycogen stores due to
lower insulin levels and increased glucagon levels. When glycogen stores become
depleted and protein breakdown increases because of increased cortisol levels, hepatic
gluconeogenesis replaces glycogenolysis as the primary source of glucose production.
This breakdown of protein is reflected by increased plasma levels of the gluconeogenic
amino acids, alanine, and glutamine.

 Normal hypoglycemic counterregulation.

 Glucose levels increase transiently after meals to 120-140 mg/dL (6.6-7.7 mmol/L).
Feedback systems return the glucose concentration rapidly back to the preprandial level,
usually within 2 hours after the last absorption of carbohydrates.
 Insulin and glucagon are the important hormones in the immediate feedback control
system of glucose. When blood glucose increases after a meal, the rate of insulin
secretion increases and stimulates the liver to store glucose as glycogen. When cells
(primarily liver and muscle) are saturated with glycogen, additional glucose is stored as
fat.
 When blood glucose levels fall, glucagon secretion functions to increase blood
glucose levels by stimulating the liver to undergo glycogenolysis and release glucose
back into the blood.
 In starvation, the liver maintains the glucose level via gluconeogenesis.
Gluconeogenesis is the formation of glucose from amino acids and the glycerol portion of
fat. Muscle provides a store of glycogen and muscle protein breaks down to amino acids,
which are substrates utilized in gluconeogenesis in the liver. Circulating fatty acids are
catabolized to ketones, acetoacetate, and B-hydroxybutyrate and can be used as auxiliary
fuel by most tissues, including the brain.
 The hypothalamus stimulates the sympathetic nervous system, and epinephrine is
secreted by the adrenals causing the further release of glucose from the liver. Over a
period of hours to days of prolonged hypoglycemia, growth hormone and cortisol are
secreted and decrease the rate of glucose utilization by most cells of the body.
 In the newborn, serum glucose levels decline after birth until age 1-3 hours, then they
spontaneously increase. Liver glycogen stores become rapidly depleted within hours of
birth, and gluconeogenesis, primarily from alanine, can account for 10% of glucose
turnover in the newborn infant by several hours of age.

Physical

Clinical manifestations are broad and can be from a combination of adrenergic

stimulation or from decreased availability of glucose for the CNS. Unlike older children,
infants are not able to verbalize their symptoms and are particularly vulnerable to
hypoglycemia.

• Infants in the first or second day of life may be asymptomatic or have life-
threatening CNS and cardiopulmonary disturbances.
o Hypotonia
o Lethargy, apathy
o Poor feeding
o Jitteriness, seizures
o Congestive heart failure
o Cyanosis
o Apnea
o Hypothermia
• Clinical manifestations associated with activation of the autonomic nervous
system
o Anxiety, tremulousness
o Diaphoresis
o Tachycardia
o Pallor
o Hunger, nausea, and vomiting
• Clinical manifestations of hypoglycorrhachia or neuroglycopenia
o Headache
o Mental confusion, staring, behavioral changes, difficulty concentrating
 o Visual disturbances (eg, decreased acuity, diplopia)
o Dysarthria
o Seizures
o Ataxia, somnolence, coma
o Stroke (hemiplegia, aphasia), paresthesias, dizziness, amnesia, decerebrate
or decorticate posturing

Causes

• Cause of neonatal hypoglycemia

o Hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy
(PHHI)
o Limited glycogen stores (eg, prematurity, intrauterine growth retardation)
o Depleted glycogen stores (eg, asphyxia-perinatal stress, starvation): In
ketotic hypoglycemia, easily depleted glycogen stores, in combination
with inadequate production of glucose through gluconeogenesis,
contribute to hypoglycemia. Thus, fatty acid oxygenation is required to
provide substrate for gluconeogenesis and ketogenesis. Ketones, the
byproduct of fatty acid metabolism, are found in urine and represent the
starved state.
o Increased glucose use (eg, hyperthermia, polycythemia, sepsis, growth
hormone deficiency)
o Decreased glycogenolysis, gluconeogenesis, or use of alternate fuels (eg,
inborn errors of metabolism, adrenal insufficiency)

Differential Diagnoses
Glycogen-Storage Disease Type 0 Infant of Diabetic Mother
Glycogen-Storage Disease Type I Malnutrition
Glycogen-Storage Disease Type IVMaple Syrup Urine Disease
Glycogen-Storage Disease Type V Panhypopituitarism
Glycogen-Storage Disease Type VIPrematurity
Growth Hormone Deficiency Toxicity, Ethanol
Hyperinsulinemia Toxicity, Oral Hypoglycemic Agents
Hyperthyroidism Toxicity, Salicylate
Hypopituitarism

Other Problems to Be Considered

Addison disease
Adrenal crisis
Exogenous insulin administration
Medium chain acyl-CoA dehydrogenase deficiencies
Sepsis
Differential Diagnoses
Adrenal Insufficiency and Adrenal CrisisPlant Poisoning, Hypoglycemics
Hypopituitarism Shock, Septic
Hypothyroidism and Myxedema Coma Toxicity, Alcohols
Munchausen Syndrome Toxicity, Salicylate
Pediatrics, Reye Syndrome

Other Problems to Be Considered

Fasting
Malnutrition
Diarrhea
Enzymatic defects of glycogen synthetic pathways
Enzymatic defects of glycogenolytic pathways
Enzymatic defects of gluconeogenic pathways
Glucagon deficiency
Congenital hyperinsulinism (eg, nesidioblastosis, leucine sensitive hypoglycemia)
Defects of beta cell regulation
Large tumors
Decreased or absent fat stores
Enzymatic defects in fatty acid oxidation

Workup

Laboratory Studies

Fingerstick glucose levels or bedside testing may lead to overtreatment of hypoglycemia

because the primary error with the chemically treated strips is an underestimation of the
serum glucose value.
Interpretation of the critical sample.
[ CLOSE WINDOW ]

Interpretation of the critical sample.

• Serum or plasma glucose levels

o Serum glucose level is higher than whole blood glucose level. Whole
blood measurements of glucose may underestimate the plasma glucose
concentration by approximately 10-15% because RBCs contain relatively
low concentrations of glucose. Arterial and capillary samples may
overestimate the plasma glucose concentration by 10% in nonfasting
patients.
o Hold an extra tube of serum or plasma and refrigerate until laboratory
glucose is known.
• Serum insulin: When blood glucose is less than 40 mg/dL, plasma insulin
concentration should be less than 5 and no higher than 10 microunits/mL.
• Urine
o Obtain first voided urine dipstick for ketones.
 o Failure to find large ketones with hypoglycemia suggests that fat is not
being metabolized from adipose tissue (hyperinsulinism) or that fat cannot
be used for ketone body formation (enzymatic defects in fatty acid
oxidation).
o Send urine for organic acid analysis.
• Newborn screening: Electrospray ionization-tandem mass spectrometry in
asymptomatic persons allows earlier identification of clearly defined inborn errors
of metabolism. These include aminoacidemias, urea cycle disorders, organic
acidurias, and fatty acid oxidation disorders. Earlier recognition of these inborn
errors of metabolism has the potential to reduce morbidity and mortality rates in
these infants.

Imaging Studies

• The detection of adenomas by celiac angiography has limited success.

• The chance of detecting a tumor blush must be balanced by the potential risk of
causing vascular trauma in infants younger than 2 years.

Treatment

Prehospital Care

• Stabilize acute life-threatening conditions and initiate supportive therapy in

patients with hypoglycemia.
• If a patient is alert and has intact airway protective reflexes, oral liquids
containing sugar (eg, orange juice) can be administered.

Emergency Department Care

Supportive therapy includes oxygen, establishing an intravenous (IV) line, and

monitoring.

• Seizures unresponsive to correction of hypoglycemia should be managed with

appropriate anticonvulsants.
• Marked acidosis (pH <7.1) suggests shock or serious underlying disease and
should be treated appropriately.
• Treatment goal is to maintain a blood glucose level of at least 45 mg/dL (2.5
mmol/L).
• For the infant or child who does not drink but has intact airway protective
reflexes, orogastric or nasogastric administration of oral liquids containing sugar
may be performed.

Consultations

• If hypoglycemia is diagnosed in an infant younger than 3 months, surgical

intervention may be necessary. Surgical exploration usually is undertaken in
 severely affected neonates who are unresponsive to glucose and somatostatin
therapy.
o Near total resection of 85-90% of the pancreas is recommended.
o Risks include the development of diabetes.
o If hypoglycemia first becomes manifest in infants aged 3-6 months, a
therapeutic trial of octreotide, diazoxide, steroids, and frequent feedings
can be attempted for as long as 2-4 weeks.

Medication

Hypoglycemia should be treated as soon as possible to prevent complications of

neurologic damage. Early feeding of the newborn with breast milk or formula is
encouraged. For those unable to drink, a nasogastric tube can be used. The mainstay of
therapy for children that are alert with intact airway protection includes orange juice at 20
mL/kg. For those who cannot protect their airway or are unable to drink, nasogastric,
intramuscular, intraosseous, or intravenous (IV) routes can be used for the following
drugs used to raise glucose levels: dextrose, glucagon, diazoxide, and octreotide.

Case reports have shown that nifedipine may help maintain normoglycemia in children
with persistent hyperinsulinemic hypoglycemia of infancy (PHHI).

Cortisol should not be used because it has minimal acute benefit and may delay the
diagnosis of the cause of hypoglycemia. Cortisol stimulates gluconeogenesis and causes
decreased use of glucose, which leads to overall elevated blood glucose and may mask
the true cause of hypoglycemia.

Anti-hypoglycemic agents

These agents elevate blood glucose levels.

Dextrose

Treatment of choice. Absorbed from the intestine resulting in rapid increase in blood
glucose concentration when administered PO. Give IV dextrose to infants of diabetic
mothers with transient neonatal hyperinsulinemia for several days until hyperinsulinemia
abates. Avoid hyperglycemia evoking prompt insulin release, which may produce
rebound hypoglycemia. SGA infants and those with maternal toxemia or perinatal
asphyxia require dextrose IV infusion rates >20 mg/kg/min to control levels. Treatment
may be necessary for 2-4 wk.

• Dosing
• Interactions
• Contraindications
• Precautions
Diazoxide (Hyperstat)

Increases blood glucose by inhibiting pancreatic insulin release, and possibly through an
extrapancreatic effect. Hyperglycemic effect starts within an hour and usually lasts a
maximum of 8 h with normal renal function. Reportedly effective in SGA infants and
those with maternal toxemia or perinatal asphyxia.

Octreotide (Sandostatin)

Long-acting analog of somatostatin that suppresses insulin secretion for short-term

management of hypoglycemia.

Glucagon (Glucagon Emergency Kit)

May be used to treat hypoglycemia secondary to hyperinsulinemia and administered to

patients without initial IV access. Each mL contains 1 mg (ie, 1 unit). Maximal glucose
concentration occurs between 5-20 min for IV administration and about 30 min for IM
administration.
Neonatal HypoglycemiaAka: Hypoglycemia in Infants

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1. Causes
1. Decreased Glucose stores
1. Prematurity
2. Intrauterine Growth Retardation (IUGR)
3. Hypoxia or asphyxia
4. Sepsis
5. Hypothermia
6. Congenital Heart Disease
7. Glycogen Storage Disease
8. Glucagon deficiency
9. Adrenal Insufficiency
10. Galactosemia
11. Fructose intollerance
2. Hyperinsulinism
1. Mother with Diabetes Mellitus
2. Erythroblastosis Fetalis
3. Exchange Transfusions
4. Beckwith-Wiedemann Syndrome
5. Nesidioblastosis
6. Islet Cell adenoma
7. Leucine sensitivity
3. Maternal Medications
1. Salicylates
2. Beta-Sympathomimetics
3. Chlorpropamide
4. Benzothiadiazide
2. Associated Conditions in children of diabetic mothers
1. Perinatal asphyxia
2. Birth Trauma (Shoulder dystochia)
3. Congenital anomalies
4. Hypocalcemia
5. Hyperbilirubinemia
6. Respiratory distress syndrome
7. Polycythemia
8. Feeding problems
9. Renal vein thrombosis
3. Symptoms
1. Jittery or Tremors
2. Lethargic
3. Hypotonia
4. Apnea
 5. Hypothermia
6. Cyanosis
7. Seizures
8. Weak or high pitched cry
9. Poor feeding
4. Labs
1. Blood Glucose Monitoring
1. Hours of life: 1, 2, 3, 6, 12, 24, and 48 hours
2. Increase frequency of checks for symptoms
2. Serum Calcium
1. Check if lethargic or jittery despite normal glucose
3. Hematocrit
1. For signs of Polycythemia
4. Neonatal Bilirubin (as indicated)
5. Arterial Blood Gas
1. Indicated for signs of respiratory distress
5. Radiology
1. Chest XRay indicated for respiratory distress
6. Management: General Approach
1. Monitor Blood Sugar closely at above intervals
2. Glucose 35 to 45 mg/dl
1. Oral glucose replacement (see below)
2. Parenteral glucose replacement if symptomatic
3. Glucose 25-34 mg/dl
1. Attempt oral glucose replacement (see below)
2. Parenteral glucose replacement usually indicated
4. Glucose <25 mg/dl
1. Parenteral Glucose Replacement (initially with bolus)
2. Strongly consider NICU Admission
3. Glucagon if Intravenous Access delayed
1. Dose: 0.1 mg/kg/dose to 1 mg max IM or SQ q30 min
2. Not effective in SGA infants
7. Oral Glucose Replacement
1. Gavage or oral feedings hourly until glucose normal
2. Use 5% Dextrose in Water (D5W) or Infant Formula
8. Parenteral Glucose Replacement
1. Preparation of Glucose Solutions
1. D10W = 1:4 Dilution of D50W in sterile water
2. Do NOT use >12.5% glucose solutions in newborns
2. Intravenous Glucose Maintenance
1. Load: 2 ml/kg D10W at 2 ml/min
2. Maintenance: 80 ml/kg/day D10W
3. Emergent Glucose replacement
1. Dose: 0.5-1.0 g/kg (5-10 ml/kg D10W) IV over 20 min