AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Hypoglycemia may be considered a biochemical symptom, indicating the presence of an underlying cause. Because glucose is the fundamental energy currency of the cell, disorders that affect its availability or its use can cause hypoglycemia. Hypoglycemia is a common clinical problem in neonates, although it is less common in infants and toddlers and is rare in older children. It can be caused by various conditions. The most common cause of mild or severe hypoglycemia in childhood is insulin-treated type 1 diabetes and a mismatch among food, exercise, and insulin.

Clinical symptoms of hypoglycemia may be subtle or overt but are not specific to hypoglycemia and are frequently attributed to other disorders. This is particularly true if the patient has had another neurologic insult, such as head trauma or hypoxia.

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 utilization (see Image 1). 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.

Decreased peripheral glucose use again occurs initially because of a fall in insulin levels and later because of increases in epinephrine, cortisol, and growth hormone levels. All 3 events increase lipolysis and plasma free fatty acid levels, which are available as an alternative fuel and competitively inhibit glucose use. Increased plasma and urinary ketone levels indicate the use of fat as an energy source. Plasma free fatty acids also stimulate glucose production.

Hypoglycemia occurs when one or more of these counterregulatory mechanisms fail because of the overuse of glucose (as in hyperinsulinism), the underproduction of glucose (as in the glycogen-storage diseases), or both (as in growth hormone or cortisol deficiency).

Mortality/Morbidity

Hypoglycemia has both acute and long-term consequences (see Clinical). Infants and children with asymptomatic hypoglycemia have been shown to have neurocognitive defects at the time of hypoglycemia, including impaired auditory and sensory evoked responses and impaired test performance. Many etiologies of hypoglycemia may have the same consequences, complicating the causal distinction.

Long-term consequences of hypoglycemia include decreased head size, lowered intelligence quotient (IQ), and specific regional brain abnormalities revealed by MRI. As many as 50% of patients who survive hyperinsulinemic hypoglycemia of infancy have long-term neurologic complications; this rate has changed little over the last 20 years. This emphasizes the need for early recognition and treatment of these children.

Age

Hypoglycemia is most common in the immediate postneonatal period. The incidence of new cases decreases with increasing age, and true hypoglycemia is extremely rare in adolescents. The age is also helpful in assessing the probable diagnosis of hypoglycemia. Hyperinsulinemia, hypopituitarism, and inborn errors of metabolism are frequent causes of hypoglycemia in infancy. In toddlers, ketotic hypoglycemia is most common. In adolescents, insulin-producing pancreatic tumors are the most common cause of true hypoglycemia.

CLINICAL

Section 3 of 11  

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History

Glucose is normally the primary source for brain energy. The brain can also use ketones, but this transition is gradual. Symptoms of hypoglycemia reflect 2 major clinical pathways. The first pathway is caused by activation of the autonomic nervous system, which causes symptoms such as sweating, trembling, flushing, anxiety, heart pounding, and hunger. The second group of symptoms is due to neuroglycopenia and includes inability to concentrate, confusion, tiredness, feeling tearful, difficulty speaking, behavioral changes, incoordination, weakness, and drowsiness. Nonspecific symptoms include mouth tingling, dry mouth, blurred vision, headache, and nausea. These symptoms, of course, vary according to the age of the patient, as follows:

• Neonates
  
  
  • Tremulousness
  • Brisk Moro reflex
  • Lethargy
  • Poor feeding
  • Irritability
  • Hypothermia
  • Respiratory distress
  • Apnea
  • Bradycardia
  • Seizure
  • Coma
  • Sudden death
• Older children
  
  
  • Dizziness
  • Sweating
  • Hunger
  • Anxiousness
  • Confusion
  • Lethargy
  • Poor feeding
  • Irritability
  • Seizure
  • Coma
  • Sudden death

Physical

• Hypoglycemic reactions are usually, but not always, accompanied by an increased heart rate with bounding pulse due to increased epinephrine secretion. Infants, if awake, may be irritable, tremulous, and cranky.
• If the brain energy supply is severely impaired, the patient's mental status is likely to be impaired with extreme inappropriate affect and mood, lethargy, seizure, or coma.
• Large body size for age in the neonate or older child suggests hyperinsulinism, although some children with hyperinsulinism are born prematurely and are small for gestational age. Decreased subcutaneous fat suggests inadequate glucose stores. Poor linear growth may point to growth hormone deficiency, and midline facial and cranial abnormalities suggest pituitary hormone deficiencies. Liver size should be assessed for evidence of glycogen-storage diseases.

Causes

• Disorders of excessive glucose use
• • Hyperinsulinemia
  • • Possible causes of hyperinsulinism in children include maternal diabetes in pregnancy, persistent hyperinsulinemic hypoglycemia of infancy, insulin-producing tumors, and child abuse. Hyperinsulinism causes excess glucose use primarily by stimulating skeletal muscle to uptake glucose. This is aggravated by insulin-induced suppression of hepatic glycogenolysis and gluconeogenesis.
    • In infants, hyperinsulinemia may be due to various genetic defects that cause a loss of glucose regulation of insulin secretion. This disorder is known as endogenous-persistent hyperinsulinemic hypoglycemia of infancy (previously termed nesidioblastosis). The most common of these disorders is associated with an inactive or only partially active potassium channel. This channel is composed of 2 parts: the sulfonylurea receptor (SUR1) and the potassium pore (Kir6.2). The former is encoded by the ABCC8 gene and the latter by the KCNJ11 gene. Other rarer genetic defects associated with hyperinsulinism include activating defects of the GCK gene for the enzyme glucokinase, which serves as the primary glucose sensor in the cell. Most of these defects are autosomal recessive, but some are autosomal dominant.
    • Other genetic defects associated with hyperinsulinemia include increased glucokinase activity, which is associated with an increased intracellular ATP/ADP ratio and closure of the potassium-ATP channel. Defects in GLUD1,  which encodes the enzyme glutamate dehydrogenase, are usually associated with hyperammonemia and cause hyperinsulinism; however, the relationship is not entirely understood. Recently, a genetic defect in the enzyme short-chain L-3-hydroxyacyl-CoA dehydrogenase was described in patients with hypoketotic hyperinsulinemic hypoglycemia, although this causal relationship is not clear either. No genetic defect has been identified in 50-80% of patients with hyperinsulinism.
    • Infants of mothers with diabetes also have high insulin levels after birth due to the high glucose exposure in utero; the poorer the glucose control during pregnancy, the greater the likelihood of hyperinsulinism in the infant.
    • In older children, hyperinsulinemia is rare, but an insulin-producing tumor is the most common cause. Exogenous administration of insulin or oral hypoglycemic agents, either accidental or due to abuse, must be considered. 
• Glucose-processing defects (Krebs cycle defects, respiratory chain defects): These defects are rare; they interfere with the ability to appropriately generate ATP from glucose oxidation. Lactate levels are high.
• Defects in alternative fuel production (carnitine acyl transferase deficiency, hepatic hydroxymethyl glutaryl coenzyme A [HMG CoA] lyase deficiency, long- and medium-chain acyl-coenzyme A dehydrogenase deficiency, variably in short-chain acyl-coenzyme A dehydrogenase deficiency): All of these defects interfere with the use of fat as an energy supply, meaning the body depends only on glucose. This becomes a problem during periods of prolonged fasting that frequently accompany gastrointestinal illness.
• Sepsis or other hypermetabolic states, such as hyperthyroidism
• Disorders of glucose underproduction
• • Inadequate glucose stores are associated with prematurity, infants who are small for gestational age, malnutrition, and ketotic hypoglycemia. After insulin treatment in diabetes, these disorders are the most common causes of hypoglycemia. These disorders are largely diagnoses of exclusion made after other causes of hypoglycemia are ruled out. Prematurity, infants who are small for gestational age, and malnutrition should be readily apparent based on the clinical situation. Ketotic hypoglycemia, which usually affects children who are thin and small and aged 18 months to 6 years, is usually due to disrupted food intake.
  • Glycogen synthase deficiency (glycogen-storage disease type 0) is associated with fasting hypoglycemia because of the liver’s inability to store glucose in the immediate postprandial state. Thus, the glucose load from the meal is anaerobically used rather than stored for later use. In this disorder, plasma glucose and lactate levels are high in the immediate postprandial state.
  • Disorders of hepatic glucose production include glucose-6-phosphatase deficiency (glycogen-storage disease type I), debrancher deficiency (glycogen-storage disease type III), and hepatic phosphorylase deficiency (glycogen-storage disease type VI, glycogen synthase deficiency, fructose 1,6 diphosphatase deficiency, phosphoenol pyruvate deficiency, pyruvate carboxylase deficiency, galactosemia, hereditary fructose intolerance, maple syrup urine disease). These disorders interfere in glucose production through various defects, including blockage of glucose release or synthesis or blockage or inhibition of gluconeogenesis. Children with these diseases may adapt to their hypoglycemia because of its chronicity.
  • Hormonal abnormalities include panhypopituitarism, growth hormone deficiency, and cortisol deficiency (primary or secondary). As described above, growth hormone and cortisol play important roles in generating alternative fuels and stimulating glucose production. Because they are easily treatable abnormalities, early recognition is important. 
• Toxins and other illnesses (ethanol, salicylates, propranolol, malaria): Ethanol inhibits gluconeogenesis in the liver and can thus cause hypoglycemia. This is particularly true in patients with insulin-treated diabetes who are unable to reduce insulin secretion in response to developing hypoglycemia. Salicylate intoxication causes both hyperglycemia and hypoglycemia. The latter is due to augmentation of insulin secretion and inhibition of gluconeogenesis.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Addison disease
Adrenal crisis
Exogenous insulin administration
Medium chain acyl-CoA dehydrogenase deficiencies
Sepsis

WORKUP

Section 5 of 11  

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Lab Studies

• Detection of hypoglycemia
  
  
  • Hypoglycemia should be suspected as a cause of a counterregulation abnormality or a lack of alternative substrate, prompting a thorough investigation. Plasma glucose concentrations should be measured in all neonates and children with the symptoms listed above (see History), with due consideration given to the temporal relationships of the test samples.  
  • The exact glucose level that constitutes hypoglycemia is debatable, particularly in neonates. Older literature suggests levels of more than 1.7 mmol/L are acceptable in this age group. Newer publications suggest levels of less than 2.5 mmol/L are inappropriate. The Whipple triad is used to support a diagnosis of hypoglycemia and its symptomatic consequences. The triad consists of (1) the presence of symptoms likely or known to be caused by hypoglycemia, (2) a low plasma glucose concentration when symptoms are present, and (3) subsequent relief of symptoms when the hypoglycemia is corrected.
  • The plasma glucose concentration should ideally be measured with a laboratory-based glucose analyzer. If this is unavailable, the home blood-glucose monitors may be used; however, their accuracy in the low range is questionable, and they have been shown to provide false-positive and false-negative results. 
• Screening
  
  
  • Screening for hypoglycemia in the asymptomatic neonate is controversial. More recent reviews suggest screening is appropriate in infants of mothers who are diabetic, infants who are large or small for their gestational age, and infants who are premature.
  • Screening should begin within the first 2-3 hours of life and continue through the first 24 hours of life.
  • Infants who are premature and those small for their gestational age should be given intravenous or oral feedings shortly after birth to prevent hypoglycemia.
• Critical sample
  
  
  • Sorting through the differential diagnoses of hypoglycemia depends on obtaining the critical sample at the time of hypoglycemia. This sample is used to measure the various metabolic precursors and hormones involved in glucose counterregulation, including glucose, insulin, growth hormone, cortisol, lactate, pyruvate, beta-hydroxybutyrate, free fatty acid, carnitine, branched-chain amino acid, and insulinlike growth factor-binding protein-1 (IGFB-1) levels.
  • A urine sample for organic acid analysis is also critical.
  • If the critical-sample measurements are not available at the time of initial presentation, the hypoglycemia must be reproduced. This is usually achieved using a closely monitored fast. This fast should be conducted in a center that can respond quickly and appropriately if significant hypoglycemic consequences develop. When the plasma glucose concentration falls to less than 2.5 mmol/L, the fast has ended, and the critical sample is drawn. The maximum length of the fast depends on the age of the child. Conservative recommendations for maximum lengths of fasting are as follows:
  • • Younger than 6 months - 8 hours
    • Aged 6-8 months - 12 hours
    • Aged 8-12 months - 16 hours
    • Aged 1-2 years - 18 hours
    • Aged 2-7 years - 20 hours
    • Older than 7 years - 24 hours
  • Interpretation of critical sample (Image 2) 
  • • Metabolically, plasma free fatty acid levels should increase to more than 0.5 mmol/L, and beta- hydroxybutyrate levels should increase to more than 1 mmol/L to provide alternative fuel. A failure of both to increase suggests hyperinsulinemic lipolytic suppression. An increase in free fatty acid levels to more than 3 mmol/L without an increase in beta-hydroxybutyrate levels suggests a defect in fatty acid metabolism.
    • High plasma lactate levels suggest gluconeogenesis, glycolysis, or respiratory-chain defects.
    • Plasma insulin levels should be suppressed.
    • Cortisol levels should increase (>550 nmol/L [20 mcg/dL]).
    • Growth hormone levels should increase (>6 mcg/L).
• Other laboratory studies
• • Some authors have suggested measuring free carnitine, total carnitine, and acyl carnitine levels before performing a fasting study in order to detect medium-chain acyl-CoA dehydrogenase deficiency; this may prevent life-threatening hypoglycemia and hyperammonemia during the fast. Many states now conduct neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency.
  • Measuring IGFBP-1 before and after the fast may also be useful. IGFBP-1 levels are suppressed by insulin and, therefore, increase during fasting in healthy individuals but decrease or remain stable in individuals who are hyperinsulinemic.
  • A glucagon stimulation test at the end of the fast may also be useful. In most individuals, the glucose level does not increase following hypoglycemia because the glycogen stores are significantly depleted before hypoglycemia develops. However, in hyperinsulinemia, endogenous glucagon secretion and glycogenolysis are suppressed, and the plasma glucose concentration increases more than 1.9 mmol/L (35 mg/dL) following glucagon administration. Glucagon does not increase the blood glucose concentration in patients with glycogen-storage disease type I. Cortisol and growth hormone levels can also be drawn 30 and 60 minutes into the test to determine if levels rise following hypoglycemia.
  • After the fast is completed and the patient has been fed glucose, lactate levels should be measured for evidence of glycogen synthase deficiency.
  • Measuring sulfonylurea, ethanol, or salicylate levels is appropriate if hypoglycemia is believed to be secondary to their ingestion. Presence of a low C-peptide level with a high insulin level suggests exogenous insulin administration.
  • Oral glucose tolerance tests do not aid in the diagnosis of hypoglycemia because many healthy patients have low plasma glucose concentrations following a large glucose bolus. In addition, a low plasma glucose concentration during an oral glucose tolerance test does not prove that the patient is hypoglycemic when symptoms occur.
  • Commercially available genetic analysis is now available to identify many of the genetic disorders associated with hyperinsulinism.

Imaging Studies

• Hyperinsulinism: Persistent hyperinsulinemic hypoglycemia of infancy can be focal or diffuse. Routine abdominal ultrasonography, CT scanning, and MRI are of little use in distinguishing between the forms. Positron emission tomography scanning with [¹⁸F] dihydroxyphenylalanine (DOPA) has been shown to effectively distinguish focal from diffuse disease. This study is easier to perform than invasive radiologic techniques such as transhepatic venous sampling or intra-arterial calcium stimulation with hepatic venous sampling. Positron emission tomography is also helpful in locating insulin-producing tumors in older children with acquired hyperinsulinism, which is rare.
• Hypopituitarism: Perform head MRI to identify pituitary or hypothalamic neoplasms or congenital abnormalities.

TREATMENT

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Medical Care

Short-term treatment of hypoglycemia consists of an intravenous bolus of dextrose 10% 2.5 mL/kg. The critical sample should be drawn before the glucose is administered. After the bolus is administered, an intravenous infusion that matches normal hepatic glucose production (approximately 5-8 mg/kg/min in an infant and about 3-5 mg/kg/min in an older child) should be continued. This should be adjusted to maintain the plasma glucose level at more than 3 mmol/L. Children with hyperinsulinemia may have much higher needs. Long-term care of children with hypoglycemia varies based on the etiology.

In infants with many disorders (eg, ketotic hypoglycemia, glycogen-storage disorders, free fatty acid metabolism defects, mild hyperinsulinism), hypoglycemia can be prevented with frequent feedings involving specifically designed diets and a rapid response with parenteral dextrose when feeding is inadequate because of gastrointestinal problems or other illnesses. Fructose must be avoided in children with fructose diphosphatase deficiency.

A hierarchical approach is used to treat hyperinsulinism. The first step is usually frequent feeding. The next step is usually diazoxide. Octreotide is usually the second-line medical therapy. The calcium channel blocker nifedipine is also useful. Surgery is recommended if these treatments fail or if an insulin-producing tumor is suspected. Surgery is a first-line option in infants with persistent hyperinsulinemic hypoglycemia of infancy with documented focal lesions that can be removed without complete pancreatectomy.

Growth hormone and cortisol replacement are specific treatments for children with hypoglycemia and hypopituitarism or adrenal insufficiency.

Infants who are born prematurely and those who are small for their gestational age should be given intravenous or oral feedings shortly after birth to prevent hypoglycemia.

For hypoglycemia in patients with diabetes, treatment depends on the patient's mental status. If the patient is awake and alert, 15 g of simple carbohydrate (4 oz of most fruit juices, 3 tsp of sugar, glucose tablets) by mouth should be sufficient. Wait at least 15 minutes after the initial treatment before retesting because overtreatment of low blood sugar levels in patients with diabetes is a common cause of hyperglycemia. If more than an hour will pass before the next regularly scheduled meal, an additional 15 g of complex carbohydrate with additional protein (bread, crackers, peanut butter) may be warranted. If the patient's mental status is altered and aspiration is a concern, treatment depends on the patient's setting.

At home, intramuscularly administered glucagon is the best choice and should be available to families or close associates of all insulin-treated patients with diabetes. In the hospital setting, intravenous dextrose 25% is appropriate treatment. Dextrose is not associated with the nausea and vomiting that may follow glucagon administration. Glucagon should be used if venous access is a problem. After the low-sugar–level reaction is treated, the patient's insulin, diet, and activity patterns should be examined to determine the cause. Adjustments should be made to prevent hypoglycemia from recurring.

Surgical Care

Surgery for hyperinsulinism is usually performed when medical therapy fails or when the patient is an older child with a possible insulin-producing tumor. If focal disease has been identified in an area of the pancreas that is amenable to removal without damage to the rest of the organ, surgery can be performed.

In diffuse disease, the usual initial operation in infants with persistent hyperinsulinemic hypoglycemia of infancy is to remove 95% of the pancreas. If this is unsuccessful, drug therapy may be added or a complete pancreatectomy may be performed. In the child with an insulin-producing tumor, only the tumor is removed. The surgeon locates the tumors intraoperatively using palpation or intraoperative ultrasonography.

Consultations

Evaluation and treatment of a child with hypoglycemia requires a team approach. Typical consultations include a pediatric endocrinologist for initial evaluation and treatment, depending on the results of the evaluation. Consultation with a geneticist familiar with various metabolic disorders is helpful. A nutritionist is necessary to provide input and instruction regarding treatment for various metabolic disorders and to ensure proper caloric intake in children with inadequate stores.

Diet

As mentioned above, the dietary treatment for acute hypoglycemia is the rapid administration of at least 15 g of simple carbohydrates (4 oz of juice or most other beverages with sugar). 

Dietary prevention of hypoglycemia depends on the underlying condition. In patients with metabolic diseases, avoidance of specific substances is usually necessary and is dependent on the specific condition. In patients with ketotic hypoglycemia, glycogen-storage diseases, or other disorders not amenable to specific dietary, medical, or surgical interventions, the key is to avoid prolonged fasting and to provide a ready supply of long-acting complex carbohydrates on a regular basis.

MEDICATION

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Most medications used to treat hypoglycemia are hormonal and either replace a hormonal deficiency (ie, cortisol or growth hormone deficiency) or suppress excess hormone production (octreotide). Diazoxide is an antihypertensive agent that also suppresses insulin secretion.

Drug Category: Insulin secretion inhibiting agents

Various mechanisms may alter insulin secretion. Diazoxide inhibits pancreatic secretion of insulin, stimulates glucose release from the liver, and stimulates catecholamine release, which elevates blood glucose levels. Octreotide is a peptide with pharmacologic action similar to that of somatostatin, which inhibits insulin secretion. ATP-sensitive potassium channels (composed of the sulfonylurea receptor [SUR] and the potassium channel pore protein [Kir6.2]) are believed to function abnormally in nesidioblastosis. These channels initiate depolarization of the beta-cell membrane and opening of calcium channels. The resultant increase in intracellular calcium triggers insulin secretion. Calcium channel blockers block the action of these calcium channels, decreasing insulin secretion. Nifedipine is the only calcium channel blocker that has been reported in clinical trials in humans.

Drug Category: Dextrose and glucose stimulators

Prompt acting gluconeogenesis is achieved with glucagon. Emergent elevation of blood glucose levels requires intravenous dextrose.

FOLLOW-UP

Section 8 of 11  

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Complications

• Many of the etiologies of hypoglycemia may carry the same consequences, complicating the causal distinction.
• Infants and children with asymptomatic hypoglycemia have been shown to have neurocognitive defects at the time of hypoglycemia, including impaired auditory and sensory-evoked responses and impaired test performance.
• Long-term consequences of hypoglycemia include decreased head size, lowered IQ, and specific regional brain abnormalities observed using MRI.

Prognosis

Prognosis clearly is dependent on the underlying condition. Inborn errors of metabolism and hormonal deficiencies are lifelong diseases that require lifelong treatment. On the other hand, ketotic hypoglycemia is generally outgrown when the child has adequate nutritional stores to prevent hypoglycemia, which is usually around age 5 years.

The prognosis of hyperinsulinism varies and depends on the severity of the disease, whether it is amenble to medical therapy, and whether the lesion is focal or diffuse. Focal lesions can frequently be surgical cured. Mild hyperinsulinism that is responsive to diazoxide may require long-term therapy but may allow the child to lead a normal life. Diffuse lesions that are not responsive to medical therapy are frequently not entirely cured by pancreatectomy and may present continued problems, including hypoglycemia and developmental delay or, on the opposite extreme, type 1 diabetes.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Many physicians may fail to recognize hypoglycemia in affected patients, either initially or over the long term. Plasma glucose levels should be tested in any patient who presents with neurologic deficits at the time the deficits are present. This may prevent prolonged, inappropriate, ineffective anticonvulsant therapy in children who initially present with seizures. Failure to recognize hypoglycemia can lead to permanent impairments or death if not treated. Hypoglycemia has been reported in individuals who were thought to be comatose secondary to head trauma.
• A second area of medicolegal concern involves children with hypoglycemia due to abuse or Münchhausen syndrome by proxy. The possibility of exogenous insulin administration must be considered and, if found, reported to the appropriate authorities.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Normal hypoglycemic counterregulation.
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Media type:  Graph

Media file 2:  Interpretation of the critical sample.
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Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
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• Stanley CA, Baker L. Hyperinsulinism in infancy: diagnosis by demonstration of abnormal response to fasting hypoglycemia. Pediatrics. May 1976;57(5):702-11. [Medline].
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Article Last Updated: Jun 1, 2007