eMedicine Specialties > Emergency Medicine > Pediatric

Pediatrics, Hypoglycemia

Author: Hilarie Cranmer, MD, MPH, FACEP, Director, Global Women's Health Fellowship, Associate Director, Harvard International Emergency Medicine Fellowship, Department of Emergency Medicine, Brigham and Women's Hospital; Director, Humanitarian Studies Initiative for Residents, Harvard Humanitarian Initiative; Assistant Professor, Harvard University School of Medicine
Coauthor(s): Michael Shannon, MD, MPH, Professor, Department of Pediatrics, Harvard Medical School; Chief and CHB Chair, Division of Emergency Medicine, Children's Hospital
Contributor Information and Disclosures

Updated: Oct 11, 2007

Introduction

Background

Hypoglycemia is the most common metabolic problem in neonates. In children, a blood glucose value below 40 mg/dL (2.2 mmol/L) represents 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.  

Patients with hypoglycemia may be asymptomatic or may present with severe central nervous system (CNS) and cardiopulmonary disturbances. The most common clinical manifestations can include altered level of consciousness, seizure, vomiting, unresponsiveness, and lethargy. Any acutely ill child should be evaluated for hypoglycemia, especially when history reveals diminished oral intake.

Sustained or repetitive hypoglycemia in infants and children has a major impact on normal brain development and function. There is evidence that hypoxemia and ischemia potentiate hypoglycemia, causing brain damage that may permanently impair neurologic development.

Causes of hypoglycemia in neonates differ slightly from the causes of hypoglycemia in older infants and children. Hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (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.

Excluding insulin therapy, almost all hypoglycemia in childhood occurs during fasting. Postprandial hypoglycemia is rare in children in the absence of prior gastrointestinal (GI) surgery. Management efforts are directed to immediate normalization of glucose levels and identification and treatment of the various causes.

Pathophysiology

Normal blood glucose is regulated very narrowly, usually from 80-90 mg/dL (4.4-5 mmol/L).

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.

Neonatal hypoglycemia

• Inappropriate changes in hormone secretion
• Inadequate substrate reserve in the form of hepatic glycogen
• Inadequate muscle stores as a source of amino acids for gluconeogenesis
• Inadequate lipid stores for the release of fatty acids

Hypoglycemia in older infants and children

• The pathophysiology of hypoglycemia is analogous to that in adults.
• Glucose homeostasis is maintained by glycogenolysis in the immediate postfeeding periods and by gluconeogenesis several hours after meals.

Frequency

United States

The overall incidence of symptomatic hypoglycemia in newborns varies from 1.3-3 per 1000 live births. Incidence varies with the definition, population, method and timing of feeding, and the type 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. Prematurity, hypothermia, hypoxia, maternal diabetes (1 in 1000 pregnant women has insulin-dependent diabetes), maternal glucose infusion in labor (gestational diabetes occurs in 2% of pregnant women), and intrauterine growth retardation increase the incidence of hypoglycemia. The incidence of inborn errors of metabolism that lead to neonatal hypoglycemia are rare but can be screened in infancy:

• Carbohydrate metabolism disorders (>1:10,000)
• Fatty acid oxidation disorders (1:10,000)
• 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)

Mortality/Morbidity

Hypoglycemia is the most common metabolic problem in neonates. Still, 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, recurrent seizure activity, developmental delay, and personality disorders. Some evidence suggests that severe hypoglycemia may impair cardiovascular function.

Clinical

History

• The clinical presentation of hypoglycemia reflects decreased availability of glucose for the CNS as well as adrenergic stimulation caused by a decreasing or low blood sugar level.
• During the first or second day of life, symptoms vary from asymptomatic to CNS and cardiopulmonary disturbances.
• Hyperinsulinemia
  • The onset is from birth to 18 months.
  • Insulin concentrations are inappropriately elevated at the time of documented hypoglycemia.
  • Transient neonatal hyperinsulinism occurs in macrosomic infants of diabetic mothers (who have diminished glucagon secretion and endogenous glucose production is significantly inhibited). Clinically, these infants are macrosomic and have increasing demands for feeding, intermittent lethargy, jitteriness, and frank seizures.
  • Infants with prolonged neonatal hyperinsulinism can be described by the following:
    • Small for gestational age (SGA)
    • Patients with perinatal asphyxia
    • Neonates born to mothers with toxemia
    • Have high rates of glucose utilization and often require dextrose infusion for a prolonged period of time
• Ketotic hypoglycemia is an uncommon but dramatic illness. It is observed in children younger than 5 years who usually become symptomatic after an overnight or prolonged fast, especially with illness and poor oral intake. Children often present inexplicably lethargic or frankly comatose, having only marked hypoglycemia with ketonuria.

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

Causes

• Cause of neonatal hypoglycemia
  • Hyperinsulinism, or PHHI
  • Limited glycogen stores (eg, prematurity, intrauterine growth retardation)
  • 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.
  • Increased glucose utilization (eg, hyperthermia, polycythemia, sepsis, growth hormone deficiency)
  • Decreased glycogenolysis, gluconeogenesis, or utilization of alternate fuels (eg, inborn errors of metabolism, adrenal insufficiency)
• Causes of hypoglycemia in older infants, children, and teenagers
  • Poisonings/drugs (eg, ethanol, isoniazid, insulin, propranolol, salicylates, oral hypoglycemics, pentamidine, quinine, disopyramide, unripe ackee fruit, Vacor [rat poison]).
  • Liver disease (eg, Reye syndrome, hepatitis, cirrhosis, hepatoma)
  • Amino acid and organic acid disorders (eg, maple syrup urine disease, propionic acidemia, methylmalonic acidemia, tyrosinosis, glutaric aciduria, 3-hydroxy-3-methylglutaric aciduria)
  • Systemic disease (eg, sepsis, burns, cardiogenic shock, respiratory distress syndrome)
• Causes of hyperinsulinemia
  • Congenital hyperinsulinism most commonly is associated with an abnormality of beta-cell regulation throughout the pancreas. A focal disease, such as isolated islet adenoma, occasionally causes congenital hyperinsulinism.
  • Recently identified genetic defects have been delineated and now replace the older terms, such as nesidioblastosis, leucine-sensitive hypoglycemia, persistent hyperinsulinemic hypoglycemia of infancy, and islet dysregulation syndrome. These defects are in the sulfonylurea receptor (SUR) and the beta-cell potassium adenosine triphosphate (ATP) channel gene located on the short arm of chromosome 11.
  • Drug-induced hyperinsulinism is secondary to surreptitious insulin administration or oral hypoglycemic drugs. Exogenous administration of insulin is diagnosed with low serum levels of C-peptide. The sulfonylureas are commonly prescribed for adults, thus, are available to children as unintentional ingestions. In these cases, hypoglycemia may persist for more than 24 hours. Diazoxide administration may be helpful by suppressing insulin secretion in severe cases.

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