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 use can cause hypoglycemia. Hypoglycemia is a common clinical problem in neonates,[1] 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, when there is a mismatch among food, exercise, and insulin. (See Etiology and Epidemiology.)
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. (See Prognosis, History, and Physical Examination.)
Long-term consequences of hypoglycemia include decreased head size, lowered IQ, and specific regional brain abnormalities observed using magnetic resonance imaging (MRI).
Physiologic defenses against hypoglycemia
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, increase alternative fuel availability, and decrease glucose use (see the diagram below).
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Normal hypoglycemic counterregulation.
The increase in hepatic glucose production is initially caused by the breakdown of liver glycogen stores resulting from 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. The breakdown of protein is reflected by increased plasma levels of the gluconeogenic amino acids alanine and glutamine. Decreased use of peripheral glucose 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 1 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). (See Etiology.)
Diagnosis and management
The ability to properly sort 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 (IGFBP-1) levels. (A urine sample for organic acid analysis is also critical.)
In hyperinsulinism, positron emission tomography (PET) scanning with [18F] dihydroxyphenylalanine (DOPA) has been shown to effectively distinguish focal from diffuse disease.
In hypopituitarism, head magnetic resonance imaging (MRI) should be performed to identify pituitary or hypothalamic neoplasms or congenital abnormalities.
Short-term treatment of hypoglycemia consists of an intravenous (IV) 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 IV 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. Glucagon infusion at rates of 0.005-0.02 mg/kg/h should be used as a temporary treatment in children with hyperinsulinism in whom adequate amounts of dextrose cannot be given. It can cause a rash and decreased appetite if used over the long term. Long-term care of children with hypoglycemia varies based on the etiology.
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. 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, IV dextrose 25% is appropriate treatment.
Surgery for hyperinsulinism is usually performed when medical therapy fails or when the patient is an older child with a possible insulin-producing tumor.
Dietary prevention of hypoglycemia depends on the underlying condition. In patients with a metabolic disease, avoidance of specific substances is usually necessary and is dependent on the specific condition.
Hyperinsulinemia is characterized by an excessive use of glucose. 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 take up glucose. This is aggravated by insulin-induced suppression of hepatic glycogenolysis and gluconeogenesis.[2]
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.[3]
No genetic defect is identified in 50% of patients with hyperinsulinism, although unusual single nucleotide polymorphisms defects have been found that may be responsible in some infants.[4]
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.
Hyperinsulinemia can also result from in utero or perinatal stress (eg, maternal hypertension, prematurity, small for gestational age, hypoxia, Caesarian delivery).[5] These infants have no genetic mutations. Hypoglycemia is temporary and resolves in 1-14 months. The mechanism is unclear.
Uncommon genetic causes of hyperinsulinism in infants
Activating defects of the GCK gene for the enzyme glucokinase, which serves as the primary glucose sensor in the β cell, are rare. Most of these defects are autosomal recessive, but some are autosomal dominant. This defect causes an increased intracellular ATP/adenosine diphosphate (ADP) ratio and closure of the potassium-ATP channel.
Defects in GLUD1, which encodes the enzyme glutamate dehydrogenase, are usually associated with asymptomatic hyperammonemia and cause hyperinsulinism; however, the relationship is not entirely understood. Noninfant children with these gene defects also have asymptomatic hyperammonemia.
Genetic defects in the enzyme short-chain L-3-hydroxyacyl-CoA dehydrogenase and the transcription factor hepatocyte nuclear factor 4 alpha have been described in patients with hypoketotic hyperinsulinemic hypoglycemia, although the causal mechanisms are unknown.
A defect in SLC16A1 (monocarboxylate transporter) may cause exercise-induced hyperinsulinemic hypoglycemia.
Metabolic defects
Glucose-processing defects (Krebs cycle defects, respiratory chain defects) are rare; they interfere with the ability to appropriately generate adenosine triphosphate (ATP) from glucose oxidation. Lactate levels are high.
Defects in alternative fuel production (eg, carnitine acyl transferase deficiency, hepatic hydroxymethyl glutaryl coenzyme A [HMG CoA] lyase deficiency, long-chain and medium-chain acyl-coenzyme A dehydrogenase deficiency, variably in short-chain acyl-coenzyme A dehydrogenase deficiency) interfere with the use of fat as an energy supply, meaning that the body depends only on glucose. This becomes a problem during periods of prolonged fasting that frequently accompany gastrointestinal (GI) illness. These defects are frequently tested for during neonatal screening. Sepsis or other hypermetabolic states, such as hyperthyroidism, may cause hypoglycemia.
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. The first three of these should be readily apparent based on the clinical situation. Ketotic hypoglycemia, which usually affects small, thin children aged 18 months to 6 years, is usually caused by disrupted food intake. Ketotic hypoglycemia is a diagnosis of exclusion, made after other causes of hypoglycemia are ruled out.
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 metabolized rather than stored for later use. In this disorder, plasma glucose and lactate levels are high in the immediate postprandial state. Glycogen synthase deficiency must be considered before the diagnosis of ketotic hypoglycemia is assigned.
Disorders of hepatic glucose production include glucose-6-phosphatase deficiency (glycogen-storage disease type Ia); glucose 6-phosphate translocase deficiency (glycogen storage disease type 1b); debrancher deficiency (glycogen-storage disease type III); hepatic phosphorylase deficiency (glycogen-storage disease type VI); glycogen synthase deficiency; fructose 1,6 diphosphatase deficiency; phosphoenolpyruvate deficiency; pyruvate carboxylase deficiency; galactosemia; hereditary fructose intolerance; and 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
Hypoglycemia can also be caused by toxins (including ethanol, salicylates, propranolol) and illnesses (eg, 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 hyperglycemia and hypoglycemia. The latter is due to augmentation of insulin secretion and inhibition of gluconeogenesis.
Large for gestational age in mother with type 1 diabetes
A retrospective cohort study by Yamamoto et al of 161 women with type 1 diabetes mellitus indicated that in women with type 1 diabetes, large-for-gestational-age infants have a 2.5-fold greater risk for neonatal hypoglycemia. The study suggested that being large for gestational age in neonates of mothers with type 1 diabetes may be better than maternal glycemic control in terms of predicting neonatal hypoglycemia.[6]
One study found hypoglycemic events in newborns weighing more than 2500 grams from term, singleton, nondiabetic pregnancies occurring at rate of 24.7 events per 1000 infant-days at risk.[7] Hypoglycemia is more common in neonates born at less than 37 weeks' gestation and in those born at more than 40 weeks' gestation, with incidence rates of 2.4% in neonates born at 37 weeks' gestation, 0.7% in neonates born at 38-40 weeks' gestation, and 1.6% and 1.8% in neonates born at 41 weeks' gestation and 42 weeks' gestation, respectively.[8] The incidence of hypoglycemia in children older than 6 months in a large urban emergency department was 0.034%.[9]
A study by Birkebaek et al found the rate of severe hypoglycemia among children with type 1 diabetes mellitus in Denmark, Iceland, Norway, and Sweden to be 6.0 per 100 patient-years, with the lowest incidence in Sweden.[10]
Age-related demographics
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. Patient 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.
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 in hyperinsulinism varies and depends on the severity of the disease, whether it is amenable to medical therapy, and whether the lesion is focal or diffuse. Focal lesions can frequently be surgically 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, at the opposite extreme, type 1 diabetes.
In a study of patients under age 20 years with type 1 diabetes, Pacaud et al found that in those who suffered an episode of severe hypoglycemia/hypoglycemic coma, the risk for another such episode remained higher than that in patients who never had an episode even 4 years after the episode occurred.[11]
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 since the end of the 20th century. This emphasizes the need for early recognition and treatment of these children.
A study by Mahajan et al indicated that mean motor development and mental development quotients at corrected ages 6 and 12 months tend to be lower in neonates with symptomatic or asymptomatic hypoglycemia than in neonates with euglycemia. Moreover, these quotients were found to be lower in symptomatic infants than in asymptomatic ones.[12]
However, a study by Goode et al indicated that neurodevelopmental outcomes in preterm infants with neonatal hypoglycemia do not significantly differ from those of preterm infants who are euglycemic. The study, which compared preterm infants with hypoglycemia with controls at ages 3, 8, and 18 years, found no significant differences in cognitive or academic skills at any age. In addition, no clinically meaningful difference in problem behaviors was found.[13]
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 an 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.
Neonates
Symptoms of hypoglycemia in neonates include the following:
Tremulousness
Brisk Moro reflex
Lethargy
Poor feeding
Irritability
Hypothermia
Respiratory distress
Apnea
Bradycardia
Seizure
Coma
Sudden death
Older children
Symptoms of hypoglycemia in older children include the following:
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’s 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, as does micropenis in a male. Liver size should be assessed for evidence of glycogen-storage diseases.
The presence of hypoglycemia should prompt a thorough investigation for counterregulation abnormalities or a lack of alternative substrate. 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.[14]
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.[15] If this is unavailable, 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 for hypoglycemia in the asymptomatic neonate is controversial. Studies suggest that screening is appropriate in infants of mothers with diabetes, 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.
Persistent hyperinsulinemic hypoglycemia of infancy can be focal or diffuse. Routine abdominal ultrasonography, computed tomography (CT) scanning, and MRI are of little use in distinguishing between the forms. Positron emission tomography (PET) 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. PET scanning 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.
The ability to properly sort 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 (IGFBP-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 is stopped, and the critical sample is drawn before any treatment is given. 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 age 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 age 7 years - 24 hours
Interpretation of the critical sample
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. (See the diagram below.)
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Interpretation of the critical sample.
High plasma lactate levels suggest gluconeogenesis, glycolysis, or respiratory-chain defects. Plasma insulin levels should be suppressed, and cortisol levels should be increased (>550 nmol/L [20 mcg/dL]). Growth hormone levels should also be increased (>6 mcg/L).
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 be useful as well. 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 even in the fed state. 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 and 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. The 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.
Short-term treatment of hypoglycemia consists of an intravenous (IV) 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 IV 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. Glucagon infusion at rates of 0.005-0.02 mg/kg/h should be used as a temporary treatment in children with hyperinsulinism in whom adequate amounts of dextrose cannot be given. It can cause a rash and decreased appetite if used over the long term.
Long-term care of children with hypoglycemia varies based on the etiology.
In infants with one of several disorders (eg, ketotic hypoglycemia, glycogen-storage disorder, free fatty acid metabolism defect, mild hyperinsulinism), hypoglycemia can be prevented with frequent feedings involving a specifically designed diet and a rapid response with parenteral dextrose when feeding is inadequate because of GI 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 typically the administration of 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. (See Pancreatic Surgery.)
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 IV or oral feedings shortly after birth to prevent hypoglycemia.
A study by LeBlanc et al reported that after implementation of a quality-improvement initiative for neonates with at least one risk factor for hypoglycemia, which included the promotion of early skin-to-skin care, early breastfeeding, and, at 90 minutes, measurement of blood glucose in asymptomatic infants, the transfer rate for at-risk infants to the neonatal intensive care unit fell from 17% to 3%. Infants in the study were born at or after 35 weeks’ gestation.[16]
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.
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, IV 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.
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.
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 a metabolic disease, avoidance of specific substances is usually necessary and is dependent on the specific condition. In patients with ketotic hypoglycemia, glycogen-storage disease, or another disorder that is 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.
Clinical practice guidelines regarding congenital hyperinsulinism (congenital hyperinsulinemic hypoglycemia), created through a collaboration between The Japanese Society for Pediatric Endocrinology and the Japanese Society of Pediatric Surgeons, were published in 2017. The recommendations, targeted at patients under age 18 years, include the following[17] :
When the diagnosis of hyperinsulinemic hypoglycemia is made, acquired hyperinsulinemia should be excluded by the following - History of gastric bypass, fundoplication for gastroesophageal reflux, and the use of insulin or oral hypoglycemia agents for diabetes mellitus, as well as through blood insulin/C-peptide ratio, anti-insulin antibody, imaging studies of the pancreas (contrast-enhanced computed tomography [CT] scanning, contrast-enhanced magnetic resonance imaging [MRI], endoscopic ultrasonography)
Treatment goals should be set at blood glucose over 70 mg/dL for congenital hyperinsulinism
The threshold of blood glucose to circumvent neurologic sequelae cannot be set because it is patient specific
Regarding first-line treatment, maintain blood glucose above the target range by continuous glucose infusion
When blood glucose is not maintained by continuous glucose infusion or when it is difficult to withdraw glucose infusion for an extended period, a 5-day trial of oral diazoxide, in 2-3 divided doses, at 5-15 mg/kg/d should be attempted unless contraindicated by cardiac failure or pulmonary hypertension
While on diazoxide, the patient should be on a glucose self-monitoring regimen to detect episodes of hypoglycemia; furthermore, a complete blood count (CBC), blood chemistry, and physical examination should be performed to detect frequent adverse events, such as hypertrichosis, tachycardia, or edema
When euglycemia is not achieved by the first-line treatment and continuous glucose infusion cannot be withdrawn, second-line treatment should be initiated
In patients unresponsive to diazoxide, subcutaneous octreotide, intravenous (IV) glucagon, and oral calcium antagonist should be sequentially attempted as second-line therapies
Glucocorticoid is not recommended as a second-line therapy
In patients unresponsive to diazoxide, etiologic diagnosis should be performed
In patients unresponsive to diazoxide, mutational analysis of the KATP channel genes (ABCC8, KCNJ11) should be performed
In patients unresponsive to diazoxide, a 18F-L-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scan should be performed
Partial pancreatectomy should be performed when a focal lesion in the body-tail of the pancreas is identified by 18F-DOPA-PET scan and blood glucose cannot be stabilized by nutritional support and diazoxide
Partial pancreatectomy should be considered when a focal lesion in the head of the pancreas is identified by 18F-DOPA-PET scan and blood glucose cannot be stabilized by nutritional support and diazoxide
Consider pancreatectomy for a diffuse lesion diagnosed by mutational analysis or by 18F-DOPA-PET scan that is resistant to medical treatment, including second-line treatments
It is desirable to avoid pancreatectomy of greater than 95%
When a focal lesion cannot be identified by visual inspection or palpation, intraoperative biopsies should be taken from multiple parts of the pancreas for rapid diagnosis by frozen section
Most medications used to treat hypoglycemia are hormonal and either replace a hormonal deficiency (ie, a cortisol or growth hormone deficiency) or suppress excess hormone production (octreotide). Diazoxide is an antihypertensive agent that also suppresses insulin secretion.
As previously mentioned, in infants with one of several disorders (eg, ketotic hypoglycemia, glycogen-storage disorder, free fatty acid metabolism defect, mild hyperinsulinism), hypoglycemia can be prevented with frequent feedings using a specifically designed diet, but when feeding is inadequate because of GI problems or other illnesses, parenteral dextrose can be used to obtain a rapid response. Fructose must be avoided in children with fructose diphosphatase deficiency.
Clinical Context:
Octreotide, a synthetic polypeptide, is usually the second-line therapy for hyperinsulinism. It inhibits the release of many biologically active substances, including insulin.
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]) function abnormally in persistent hyperinsulinemic hypoglycemia of infancy. 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 for which data have been reported in clinical trials in humans.
Clinical Context:
Dextrose is used to promptly elevate serum glucose levels. It is a monosaccharide that is absorbed from the intestine and is then distributed, stored, and used by the tissues.
Clinical Context:
This is the first-line home treatment for severe hypoglycemic reactions in patients with diabetes. Glucagon promotes glycogenolysis and gluconeogenesis, resulting in elevation of blood glucose levels. Glucagon may cause vomiting for 4-6 hours after administration.
Glucagon may be useful when intravenous (IV) access for dextrose administration is problematic. This agent may be administered as part of emergency medical services (EMS) protocol in patients with altered mental status and no IV access. It is also available as a ready-to-use subcutaneous (SC) solution in prefilled syringes or an autoinjector.
Clinical Context:
Glucagon intranasal activates hepatic glucagon receptors that stimulate cAMP synthesis. This action accelerates hepatic glycogenolysis and gluconeogenesis, causing an increase in blood glucose levels. Preexisting hepatic glycogen stores are necessary for the drug to be effective in treating hypoglycemia. It is indicated for severe hypoglycemic reactions in adults and children aged 4 y or older with diabetes.
What is pediatric hypoglycemia?What are the complications of pediatric hypoglycemia?What are the physiological defenses against pediatric hypoglycemia?How is pediatric hypoglycemia diagnosed and treated?What is the role of hyperinsulinemia in the etiology of pediatric hypoglycemia?What is the role of genetics in the etiology of pediatric hypoglycemia?What is the role of metabolic defects in the etiology of pediatric hypoglycemia?What is the role of glucose production in the pathogenesis of pediatric hypoglycemia?Which toxins have an etiologic role in pediatric hypoglycemia?What is the role of maternal diabetes in the etiology of pediatric hypoglycemia?What is the prevalence of pediatric hypoglycemia?Which age groups are at highest risk for pediatric hypoglycemia?What is the prognosis of pediatric hypoglycemia?What is the morbidity associated with pediatric hypoglycemia?Which clinical history findings are characteristic of pediatric hypoglycemia?What are the symptoms of hypoglycemia in neonates?What are the symptoms of hypoglycemia in older children?Which physical findings are characteristic of pediatric hypoglycemia?What are the challenges in recognizing pediatric hypoglycemia?Which conditions should be included in the differential diagnoses of pediatric hypoglycemia?What are the differential diagnoses for Pediatric Hypoglycemia?How is pediatric hypoglycemia diagnosed?What is the role of imaging studies in the evaluation of pediatric hypoglycemia?What is the role of critical sampling in the diagnosis of pediatric hypoglycemia?What is the role of fasting in the diagnosis of pediatric hypoglycemia?How are critical sample findings interpreted for the diagnosis of pediatric hypoglycemia?What is the role of lab testing in the diagnosis of pediatric hypoglycemia?How is pediatric hypoglycemia treated?Which specialist consultations are beneficial for patients with pediatric hypoglycemia?How is pediatric hypoglycemia treated in patients with diabetes?What is the role of pancreatic surgery in the treatment of pediatric hypoglycemia?Which dietary modifications are used in the treatment of pediatric hypoglycemia?What are the Japanese Society for Pediatric Endocrinology and the Japanese Society of Pediatric Surgeons guidelines for the diagnosis and treatment of pediatric hypoglycemia?Which medications are used in the treatment of pediatric hypoglycemia?Which medications in the drug class Dextrose and glucose stimulators are used in the treatment of Pediatric Hypoglycemia?Which medications in the drug class Insulin secretion inhibiting agents are used in the treatment of Pediatric Hypoglycemia?
Robert P Hoffman, MD, Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children's Hospital
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London), Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece
Disclosure: Nothing to disclose.
Chief Editor
Sasigarn A Bowden, MD, Associate Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Associate Fellowship Program Director, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital
Disclosure: Nothing to disclose.
Additional Contributors
Karl S Roth, MD, Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
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