Approach To Hypoglycemia in Infants and Children

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Approach to hypoglycemia in infants and children
Authors: Agneta Sunehag, MD, PhD, Morey W Haymond, MD

Section Editor: Joseph I Wolfsdorf, MB, BCh
Deputy Editor: Alison G Hoppin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Oct 18, 2016.
INTRODUCTION — In healthy individuals, maintenance of a normal plasma glucose concentration depends upon:
● A normal endocrine system for integrating and modulating substrate mobilization, interconversion, and utilization.
● Functionally intact enzymes for glycogen synthesis, glycogenolysis, glycolysis, gluconeogenesis, and utilization of other metabolic fuels for oxidation and storage.
● An adequate supply of endogenous fat, glycogen, and potential gluconeogenic substrates (eg, amino acids, glycerol, and lactate).
Adults are capable of maintaining a near-normal plasma glucose concentration, even when fasting for weeks or, in the case of obese subjects, months [1]. In contrast,
healthy neonates and young children are unable to maintain normal plasma glucose concentrations after even a short fast (24 to 36 hours) and exhibit a progressive
decline in plasma glucose concentration to hypoglycemic values [2,3].
Congenital or acquired abnormalities in hormone secretion, substrate interconversion, and mobilization of metabolic fuels contribute to abnormalities in glucose
production and utilization that ultimately result in hypoglycemia in children. The evaluation and treatment of the child with hypoglycemia require an understanding of
the factors that regulate glucose metabolism and the unique aspects of glucose metabolism in infants and young children.
Glucose homeostasis and the diagnostic approach to hypoglycemia in infants and children will be discussed here. Other topics with related content include:
● (See "Causes of hypoglycemia in infants and children".)
● (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)
● (See "Management and outcome of neonatal hypoglycemia".)
● (See "Hypoglycemia in children and adolescents with type 1 diabetes mellitus".)
GLUCOSE HOMEOSTASIS IN NORMAL INFANTS AND CHILDREN — Throughout gestation, maternal glucose is transported across the placenta to meet a
substantial proportion of the energy needs of the fetus. The enzymes necessary for glycogen synthesis and glycogenolysis are present in the fetal liver long before
the accumulation of glycogen can be demonstrated. During the last three to four weeks of gestation, hepatic glycogen stores increase to reach around 5 percent of
liver weight at birth, a proportion that is higher than at any other time in the life cycle [4]. In animals, the activity of one or more important rate-limiting enzymes of
gluconeogenesis (pyruvate carboxylase, phosphoenol-pyruvate carboxykinase, glucose-6-phosphatase, and fructose 1,6 diphosphatase) is absent or very low in the
fetus, does not increase until the perinatal period, and reaches adult levels only after several hours to days of extrauterine life [4]. Similarly, in humans, hepatic
glucose production and gluconeogenesis are absent during fetal life [5], but rapidly increase within the first few hours of life, even in very premature infants [6].
At birth, the interruption of placental blood flow as a result of the clamping of the umbilical cord requires the infant to utilize his or her own endogenous substrates and
challenges the newborn with his or her first fast. With the clamping of the cord, there is an immediate release of glucagon [7]. However, despite the glucagon surge,
plasma glucose decreases over the first two hours of life. This is accompanied by a decrease in insulin and an increase in free fatty acids (FFAs) and ketone bodies
[8]. By four to six hours of life, the plasma glucose concentration is stabilized or is increasing in most infants. Much of this early glucose production probably comes
from the mobilization of hepatic glycogen, since hepatic glycogen content decreases during the first several days of extrauterine life. This release of hepatic glycogen
facilitates a smooth transition from the continuously fed (intrauterine) to the fasted or relatively fasted condition of the first hours to days of extrauterine life. However,
hepatic glycogen stores are quickly depleted, and gluconeogenesis must begin within hours of birth to meet an ever-increasing proportion of endogenous glucose
production [6,8].
In the premature and term infant, more than 90 percent of the glucose is utilized by the brain. This value decreases to approximately 40 percent of glucose turnover in
overnight-fasted adults (figure 1) [9]. The higher rates of glucose turnover per kilogram of body weight in infants and children when compared with adults are
consistent with the relatively higher proportion of brain mass to body size, which places infants and children at higher risk of hypoglycemia [10,11].
Fatty acid mobilization and oxidation play a crucial role in the maintenance of glucose homeostasis in infants and children. Plasma FFAs and ketone bodies can be
used by a variety of body tissues and, thus, decrease the demands of these tissues for glucose as an energy source. The brain is unique in that it uses glucose at a
rate 20 times that of other body tissues (per gram) and cannot use FFAs directly since they are not transported across the blood-brain barrier. However, ketone
bodies (beta-hydroxybutyric acid and acetoacetic acid) are transported across the blood-brain barrier, and their metabolism by the brain can partially supplant the
need for glucose [1]. The metabolic response to fasting in children is similar to that in adults, except that children have a more rapid decline in plasma glucose
concentration and a more rapid increase in the plasma concentration of ketone bodies than do adults. These findings suggest the relatively high glucose requirement
in children may accelerate the normal adaptive mechanism(s) of fasting observed in adults [3].
During the first 8 to 10 years of life, the rate of total body glucose utilization (and production) increases, followed by a plateau during the next five to seven years, after
which the normal adult rate (833 to 944 micromol/min [150 to 170 mg/min]) is achieved (figure 2) [9]. Studies utilizing isotopically-labeled glucose indicate that, by
weight, rates of glucose flux (production and utilization) in adults are approximately 11 to 13 micromol/kg per min (2 to 2.3 mg/kg per min) in the overnight
postabsorptive state (14-hour fast) and decrease to 9.8 micromol/kg per min (1.8 mg/kg per min) by 30 hours of fasting [10]. The rate of glucose flux in infants and
children after 4 to 14 hours of fasting is nearly three times higher (35 micromol/kg per min [6 mg/kg per min]) than that of adults, and decreases to 23 micromol/kg per
min (4 mg/kg per min) after a 30- to 40-hour fast [10,11].
The mobilization, use, and storage of nutrients is primarily orchestrated by the classical actions of hormones (eg, insulin, glucagon, catecholamines, cortisol, and
growth hormone), although more subtle interactions of other factors (eg, cytokines, neuronal input, ghrelin, leptin, glucagon-like peptide 1 [GLP1] post-receptor
activation mechanism) are now being recognized. Insulin secretion plays a central role in glucose homeostasis and is affected by a number of factors, the most
important of which is the plasma glucose concentration. A more detailed description of the secretion and actions of insulin is presented separately. However, we
provide a brief description here. (See "Pancreatic beta cell function" and "Insulin action".)
When the plasma glucose concentration increases after a meal in normal individuals, glucose is transported into the pancreatic beta-cell via the
glucose transporter 2 (GLUT2), is phosphorylated by glucokinase, and metabolized via the glycolytic pathway. This results in an increase in the adenosine
triphosphate/adenosine diphosphate (ATP/ADP) ratio, which closes the KATP channels, depolarizes the cell membrane, opening the Ca++ channels, resulting in fusion
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of the insulin granule with the plasma membrane causing insulin secretion. Conversely, a decrease in plasma glucose concentration results in decreased glucose
metabolism in the beta-cell, which leads to a reduced ATP/ADP ratio, opening of the KATP channels, hyperpolarization of the cell membrane, and closure of Ca++
channels, thus blocking Ca++ influx and reducing insulin secretion. Fundamental problems in these processes can lead to profound hypoglycemia in children [12].
(See "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy".)
During controlled insulin-induced hypoglycemia, children typically mount a greater counterregulatory hormone response (eg, with cortisol, epinephrine, and glucagon)
than do adults [13,14]. However, with repeated episodes of hypoglycemia, secretion of counterregulatory hormones wanes, leading to defective counterregulation and
"hypoglycemia unawareness" in an individual with diabetes. In the absence of classical symptoms of hypoglycemia, perhaps as a result of this process, the diagnosis
of hypoglycemia can be missed in some children for months.
DEFINITION OF HYPOGLYCEMIA — For diagnostic purposes, we define hypoglycemia as a plasma glucose value of ≤40 mg /dL (2.22 mM) at any age (except
during the first 48 to 72 hours of life). This concentration should trigger a formal evaluation to identify the cause of the hypoglycemia and to prevent its recurrence.
This concentration should not be construed as ideal or necessarily safe over time, and should only be used in identifying an individual at risk for and/or diagnosing
hypoglycemia.
In newborns, a plasma glucose value of ≤50 mg/dL is an appropriate threshold to distinguish infants who warrant further diagnostic testing. This threshold was
suggested by a consensus conference that focused primarily on the newborn period [15]. This is a relatively conservative threshold, intended to avoid discharging
newborns who may be at risk for recurrent and severe hypoglycemia. Similarly, when using a point-of-care (bedside) glucometer, it is reasonable to use a threshold of
≤50 mg/dL to identify a child who requires further evaluation, including laboratory measurement of plasma glucose. (See 'Critical samples' below.)
By tradition, laboratories measure plasma glucose (from sodium fluoride, heparin, or ethylenediaminetetraacetic acid [EDTA]-containing tubes). Even point-of-care
glucose values are adjusted in their calibration to "plasma concentrations." Alternatively, whole blood glucose can be measured on a number of glucose analyzers.
However, whole blood glucose concentrations are about 15 percent lower than plasma glucose measurements, and this difference should be recognized when
interpreting the results [16,17].
The precise definition of hypoglycemia in infants and children continues to be controversial. This is because normal distributions of glucose values depend on
conditions of feeding and fasting, and also vary with clinical factors such as age, gestation, and/or weight (small, average, or large for gestational age). Despite this
natural variation, we use a single threshold to define hypoglycemia for diagnostic purposes because the overall goal of identifying children with hypoglycemia is to
protect their central nervous systems from irreparable damage from hypoglycemia. There is no a priori reason that some individuals (eg, a premature or low birth
weight infant) should tolerate a low glucose concentration better than others (eg, an older child); in fact, quite the opposite might be argued.
ETIOLOGY OF HYPOGLYCEMIA — Hypoglycemia occurs when the rate of appearance of glucose into the plasma space is less than its rate of utilization. This can
be caused by defective glucose production, increased glucose utilization, or some combination of the two. For many hypoglycemic conditions, the mechanism is
incompletely understood.
In infants and children, important causes of hypoglycemia include (table 1):
● Inborn errors of metabolism – Most of the disorders of carbohydrate metabolism and several disorders of amino acid and fat metabolism are characterized by
defective glucose production. Because of the interactions of carbohydrate, and amino acid and fat metabolism in the maintenance of normal fuel homeostasis,
abnormalities in the metabolism of a single substrate can have secondary effects on other metabolic pathways.
● Hyperinsulinism
• Endogenous – Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or insulinoma. Ingestion of oral hypoglycemic agents (sulfonylureas) also
stimulates insulin secretion.
• Exogenous – Due to the administration of insulin or drugs that stimulate insulin secretion.
● Other – Miscellaneous causes of hypoglycemia include ketotic hypoglycemia, various toxic ingestions (including sulfonylureas, ethanol, and salicylates),
hormone deficiencies, and medical conditions that either increase glucose requirements (eg, sepsis, shock, burns, tumors) or affect the liver's ability to produce
glucose (eg, Reye syndrome, hepatitis, or other causes of liver dysfunction).
These and other causes of hypoglycemia in children are discussed elsewhere. (See "Causes of hypoglycemia in infants and children".)
CLINICAL FEATURES
Children and adults — In children and adults, the symptoms of hypoglycemia can be divided into two categories: those caused by the autonomic response to
hypoglycemia and those caused by neuroglycopenia [14].
Neurogenic (autonomic) symptoms — The early manifestations of hypoglycemia are caused by the autonomic response to hypoglycemia and include sweating,
weakness, tachycardia, tremor, and feelings of nervousness and/or hunger. These symptoms and signs usually occur at plasma glucose concentrations between 40
and 70 mg/dL (2.2 and 3.9 mM), which are higher than the plasma glucose concentrations that trigger neuroglycopenic signs and symptoms. Therefore, the
autonomic symptoms function as a "warning system." However, with repeated or prolonged episodes of hypoglycemia, the threshold for autonomic symptoms
decreases to that for neuroglycopenic symptoms. This can result in the appearance of severe symptoms of hypoglycemia with little or no warning, termed
"hypoglycemia unawareness." (See 'Glucose homeostasis in normal infants and children' above.)
Neuroglycopenic symptoms — Symptoms and signs that develop with prolonged or profound hypoglycemia are caused by insufficient supply of glucose to the
brain (neuroglycopenia), and include lethargy, irritability, confusion, uncharacteristic behavior, and hypothermia. In extreme hypoglycemia, loss of consciousness,
seizure, or coma may occur. These symptoms and signs occur at plasma glucose concentrations between 10 and 50 mg/dL (0.5 to 2.8 mM). Severe and repeated
episodes of hypoglycemia can result in permanent central nervous system damage, and occasionally in death.
Infants — In infants, the signs of hypoglycemia are frequently nonspecific and may include jitteriness, irritability, feeding problems, lethargy, cyanosis, tachypnea, and
hypothermia, as well as the signs of severe neuroglycopenia described above. These symptoms are not specific for hypoglycemia and may be early manifestations of
a number of other disorders, including septicemia, congenital heart disease, ventricular hemorrhage, and respiratory distress syndrome. Infants are at greatest risk for
hypoglycemia during the first few days of life. Neonatal hypoglycemia is discussed separately. (See "Pathogenesis, screening, and diagnosis of neonatal
hypoglycemia".)
IMMEDIATE MANAGEMENT — The immediate management of the infant or child with hypoglycemia involves obtaining critical samples and administering parenteral
glucose. These steps are summarized in a rapid overview (table 2).
Critical samples — When the diagnosis of hypoglycemia is suspected and supported by a rapid measurement of the plasma glucose concentration (and beta-
hydroxybutyrate, if available as a point-of-care measurement), a sample of blood should be obtained before therapeutic intervention. This sample is used to confirm
the diagnosis of hypoglycemia and assess for related electrolyte abnormalities. If the cause of the hypoglycemia is unknown, this critical sample is used for additional
biochemical tests to investigate its cause, as discussed below. (See 'Laboratory testing' below.)
Blood — During the period of hypoglycemia, collect a 5 to 10 mL sample of blood before therapeutic intervention. The blood should be drawn in the appropriate
tubes according to the requirements of individual clinical laboratories. However, most of the studies can be performed on blood treated with heparin or
ethylenediaminetetraacetic acid (EDTA). Blood samples should be transported on ice to the laboratory. Excess plasma should be stored at -70ºC until all the ordered
results are available.
Urine — If the cause of hypoglycemia is unknown, then the first urine voided during or after the hypoglycemic episode should be collected. A urine sample should
be tested for ketones (if plasma beta-hydroxybutyrate is not available) and reducing substances. The presence of non-glucose reducing substances in the urine
suggests galactosemia or hereditary fructose intolerance if other reducing substances (eg, streptomycin) are excluded. (See "Galactosemia: Clinical features and
diagnosis" and "Causes of hypoglycemia in infants and children".)
The remaining urine should be frozen and saved for toxicology studies, organic acids, dicarboxylic acids, and/or acylglycines, if indicated by subsequent evaluation.
(See 'Evaluation for the cause of hypoglycemia' below and "Approach to the child with occult toxic exposure".)
Treatment
Glucose therapy
Conscious patient — If the patient is conscious and able to drink and swallow safely, a rapidly-absorbed carbohydrate (eg, glucose tablets, glucose gel, table
sugar, fruit juice, or honey) should be given by mouth. An appropriate dose for a child is 10 to 20 grams (or 0.3 grams/kg). Fifteen grams can be supplied by 3
glucose tablets, a tube of dextrose gel with 15 grams; 4 oz (120 mL) fruit juice; 6 ounces of non-diet soda; or a tablespoon (15 mL) of honey or table sugar. This
process may be repeated in 10 to 15 minutes. However, if the hypoglycemia does not improve within 15 to 30 minutes, parenteral glucose is recommended.
Patient with altered consciousness — Infants and children with altered consciousness and/or who are unable to safely swallow rapidly-absorbed
carbohydrates should be treated with intravenous (IV) dextrose. If IV access is not readily available, then subcutaneous or intramuscular glucagon should be given.
(See 'Glucagon' below.)
● Initial bolus – Give dextrose, 0.20 to 0.25 grams/kg of body weight (maximum single dose, 25 grams). This is usually achieved with 2.5 mL/kg of 10 percent
dextrose solution, higher concentrations of glucose will lead to severe local tissue damage if extravasation occurs. The bolus should be administered slowly (2 to
3 mL/min), regardless of the patient's age. The dextrose is given slowly to avoid acute hyperglycemia, which can cause rebound hypoglycemia. Somewhat lower
concentration of dextrose solution is often used for management of hypoglycemia in neonates. (See "Pathogenesis, screening, and diagnosis of neonatal
hypoglycemia".)
● Subsequent infusion – After the bolus, plasma glucose should be maintained by an infusion of dextrose at 6 to 9 mg/kg per minute. The rate of glucose infusion
(mg/kg per minute) can be calculated as follows:
Rate of infusion (mg/kg per min) = (Percent dextrose in solution x 10 x rate of infusion [mL per hr]) ÷ (60 x weight [kg])
Thus, for an infusion of 10 percent dextrose solution:
● 3 mL/kg/hour provides 5 mg/kg per minute
● 5 mL/kg/hour provides approximately 8 mg/kg per minute
Higher doses of dextrose (eg, 0.5 to 1.0 g/kg) are sometimes recommended for the initial bolus. However, our clinical experience in children and infants, and studies
in adults, suggest that such doses are excessive and are likely to cause hyperosmolarity and hyperglycemia, which can result in rebound hyperinsulinemia and
recurrence of hypoglycemia [18,19].
Symptomatic hypoglycemia caused by sulfonylurea overdose is managed with boluses of dextrose as described above, with close monitoring for recurrent
hypoglycemia. If hypoglycemia recurs or becomes more severe, octreotide has been used [20] but use of glucagon as an infusion or mini-dose glucagon might also
be considered [21]. (See "Sulfonylurea agent poisoning".)
Glucagon — If IV access is not readily available and the patient is unable to safely swallow a rapidly-absorbed carbohydrate, hypoglycemia may be treated with
glucagon, given intramuscularly or subcutaneously (0.03 mg/kg up to a maximum of 1 mg).
Glucagon is generally effective for initial treatment of hypoglycemia caused by hyperinsulinemia (eg, in a patient with diabetes treated with exogenous insulin), but
may not be effective for other causes of hypoglycemia. Moreover, the response is frequently transient. Thus, if the hyperinsulinemia persists, repeated administration
of glucose and/or glucagon may be required. The response to glucagon also may provide diagnostic information for patients in whom the etiology of hypoglycemia is
unknown. (See 'Glucagon stimulation test' below.)
Monitoring — During the initial treatment phase, the plasma glucose should be monitored every 30 to 60 minutes and the dextrose infusion adjusted accordingly,
until a stable plasma glucose concentration between 70 and 120 mg/dL (3.9 to 6.7 mmol/L) is attained [15]. Thereafter, plasma glucose should be monitored every
two to four hours. If rates of glucose infusion greater than 6 to 10 mg/kg per minute are necessary to maintain normal plasma glucose concentrations, the patient's
hypoglycemia is likely to be caused by hyperinsulinemia (eg, due to persistent hyperinsulinemic hypoglycemia of infancy [PHHI], also known as congenital
hyperinsulinism [CHI]). (See "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy".)
EVALUATION FOR THE CAUSE OF HYPOGLYCEMIA — The results obtained from the history, physical examination, and initial plasma samples should guide
further testing.
History — The history in a hypoglycemic child should include a thorough exploration of the past medical history (including perinatal history), details of the acute event
as well as previous episodes, and family history [22].
Age at onset — Although there is considerable overlap, the age of onset of symptoms suggests diagnostic categories:
● Neonatal period or the first two years of life – Most inborn errors of metabolism (including causes of hyperinsulinism) and congenital hormone deficiencies. (See
"Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy" and "Overview of inherited disorders of glucose and
glycogen metabolism".)
● One year to early childhood – Ketotic hypoglycemia, isolated growth hormone deficiency, and cortisol deficiency. (See "Causes of hypoglycemia in infants and
children", section on 'Ketotic hypoglycemia' and "Causes of hypoglycemia in infants and children", section on 'Hormone deficiencies'.)
● Toddlers and young children – Ingestion should always be considered in this age group. (See "Approach to the child with occult toxic exposure" and "Causes of
hypoglycemia in infants and children", section on 'Ingestions'.)
Triggers — The details of the acute event should include information about the child's dietary intake before the event and helps to narrow the differential diagnosis
[23]. (See "Causes of hypoglycemia in infants and children".)
● Fasting state – Determine whether the child was in the fed or fasting condition at the time of hypoglycemia, or whether an acute illness prevented the child from
achieving adequate carbohydrate intake. The degree of fasting that is tolerated before hypoglycemia develops varies with age in healthy infants and children,
and varies among different inborn errors of metabolism. Patients with critical illnesses, especially sepsis, liver failure, or renal failure, are at greater risk for
developing hypoglycemia.
● Ingestion – Specifically inquire about the possibility that the child might have ingested substances that can cause hypoglycemia, including alcohol, oral
hypoglycemic agents (sulfonylureas or meglitinides), aspirin, beta-blockers, quinine, or unripe ackee fruit (a staple in Jamaican diets). (See "Approach to the
child with occult toxic exposure".)
● Specific foods
• Symptoms after ingestion of milk products or fructose may indicate galactosemia or hereditary fructose intolerance, respectively.
• Children who have hereditary defects of amino acid or organic acid metabolism may develop hypoglycemia shortly after the ingestion of protein. (See
"Organic acidemias".)
Past medical history — The perinatal history should include the birth weight, gestational age, and whether the child had hypoglycemic symptoms at birth or in the
neonatal period. It is important to explore the child's past medical history and to review available medical records, to determine whether the child had other episodes
suggestive of hypoglycemia that may have been missed or diagnosed as other conditions (eg, seizure disorder, etc).
Family history — A family history of Reye syndrome, unexplained infant deaths, or other affected family members suggests an inborn error of metabolism,
particularly a fatty acid oxidation defect [4,12,13]. Hormonal deficiencies and hyperinsulinism also may run in families [24]. (See "Causes of hypoglycemia in infants
and children", section on 'Disorders of fatty acid oxidation'.)
Physical examination — The examination may provide important clues to the diagnosis [15].
● The child's weight and length or height should be measured and plotted on an appropriate growth chart, and the child's growth trajectory should be evaluated.
Short stature may indicate hypopituitarism or growth hormone deficiency. Disorders of amino acid, organic acid, and carbohydrate metabolism are usually
associated with failure to thrive, whereas children with fatty acid oxidation disorders typically have normal growth. Children who are underweight for age may be
at risk for ketotic hypoglycemia. Poor weight gain also may be caused by hypopituitarism and adrenocorticotropic hormone (ACTH) deficiency or
unresponsiveness, and primary adrenal insufficiency [25,26].
● Fever suggests sepsis or another infectious trigger, while hypothermia is consistent with prolonged hypoglycemia (neuroglycopenia), sepsis, alcohol toxicity, and
some inborn errors of metabolism that impair energy utilization.
● Midline facial defects (eg, a single central incisor, optic nerve hypoplasia, cleft lip or palate) and microphallus or small normal penis or undescended testicles in
boys may indicate hypopituitarism and/or growth hormone deficiency. (See "Diagnosis of growth hormone deficiency in children".)
● Hepatomegaly and/or hypotonia suggest an inborn error of metabolism, such as a glycogen storage disease, defects in gluconeogenesis, galactosemia, or
hereditary fructose intolerance [25]. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
● Macrosomia, hepatosplenomegaly, and umbilical hernia may indicate Beckwith-Wiedemann syndrome. Hypoglycemia in affected patients usually is limited to the
neonatal period (ie, the first month of life). (See "Beckwith-Wiedemann syndrome".)
● Hyperventilation may be a clue to metabolic acidosis from an inborn error of metabolism. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and
clinical features" and "Inborn errors of metabolism: Metabolic emergencies".)
● Hyperpigmentation may be a clue to adrenal insufficiency. (See "Causes and clinical manifestations of primary adrenal insufficiency in children".)
Laboratory testing — For patients with unexplained hypoglycemia, the history and physical examination are used to develop clinical suspicions and the evaluation is
tailored accordingly (algorithm 1). As examples, clinical features suggesting an accidental or toxic ingestion or a specific inborn error of metabolism should prompt
specific testing for the suspected disorder.
If the cause of the hypoglycemia is unknown, the following tests should be performed on "critical samples" collected during a period of hypoglycemia (either at the
initial presentation or during an elective fast) [15]:
● Plasma glucose
● Insulin
● C-peptide
● Beta-hydroxybutyrate
● Free fatty acids (FFAs)
● Acylcarnitine profile
● Lactate
● Ammonia
● Urine organic acids
Also measure blood electrolytes, blood urea nitrogen (BUN), creatinine, aspartate aminotransferase (AST), and alanine aminotransferase (ALT), if not already done.
Measurements of both growth hormone and cortisol at the time of hypoglycemia seldom provide diagnostic information. However, should the child have any
indications of hypopituitarism (microphallus, central facial anomalies, growth failure) or if the diagnosis remains unclear following the initial evaluation, consideration
should be given to evaluating the child for hypothalamic or pituitary deficiencies. Evaluation would include brain magnetic resonance imaging (MRI) and laboratory
testing for growth hormone, cortisol, and thyroid function (T4 and TSH) (algorithm 1).
Subsequent testing for unexplained hypoglycemia — If the cause of the hypoglycemia remains unclear after reviewing the critical sample results, we perform
further testing to narrow the diagnostic possibilities. These steps must be performed during a period of hypoglycemia, either arising spontaneously or induced by a
diagnostic fast under carefully established conditions. If the fast induces a hypoglycemic episode, the critical samples must be obtained prior to therapeutic
intervention and a glucagon stimulation carried out as described below (algorithm 1). The glucagon stimulation test will narrow the diagnostic possibilities by
identifying or excluding hyperinsulinemia.
Elective fast — If the cause of the hypoglycemia remains unclear and the critical diagnostic samples were not obtained during a spontaneous episode of
hypoglycemia (see 'Critical samples' above), then an elective fast usually should be performed to determine the cause of the hypoglycemia. Prior to performing an
elective fast, the plasma carnitine and acylcarnitine concentrations should be proven to be normal, to exclude the possibility of a defect in fatty acid or carnitine
metabolism. This is because hypoglycemia can cause severe encephalopathy in children with these disorders. (See "Causes of hypoglycemia in infants and
children", section on 'Disorders of fatty acid oxidation' and "Overview of fatty acid oxidation disorders".)
The duration of the fast depends upon the child's age and normal feeding pattern. For infants and very young children who are normally fed every three to six hours,
the fast may consist of omitting one or more feedings [27]. For an older child, who by history typically fasts overnight, a 24- to 30-hour fast should be initiated after the
evening meal (ie, starting around 6 PM). Children who fasted according to such a protocol tend to develop hypoglycemia after 16 to 24 hours of fasting (ie, between
10:00 AM and 6:00 PM), a time during which they should be awake and alert, and the availability of the physician and laboratory staff is optimal.
During the fast, plasma concentrations of glucose, insulin, beta-hydroxybutyrate, and lactate should be serially monitored and compared with published values for a
fasting study. The timing of sampling is dependent on the plasma glucose value. We typically sample every two to three hours while the plasma glucose remains
above 70 mg/dL. As the plasma glucose decreases below this threshold, we sample more frequently (eg, hourly) to avoid prolonged hypoglycemia.
If hypoglycemia develops (plasma glucose <40 mg/dL [2.2 mM] for children and infants other than newborns):
● Repeat measurement of glucose, insulin, C-peptide, beta-hydroxybutyrate, and lactate concentrations.
● Measure free fatty acids, ammonia, acylcarnitine profile, and urine organic acids
● Measure plasma growth hormone, cortisol, and insulin-like growth factor binding protein 1 (IGFBP1) (although their interpretation is not always clear).
● Perform a glucagon stimulation test, as described below.
If ketotic hypoglycemia is suspected, the clinician may consider obtaining a plasma alanine concentration at the time of hypoglycemia; this disorder is characterized
by low plasma alanine with normal lactate concentration.
If hypoglycemia cannot be induced with a fast of reasonable duration, the child should be discharged after the family is instructed in home glucose monitoring, to
ensure safety and to provide further diagnostic information. Should the child experience an additional episode of hypoglycemia, it is imperative that the critical
samples be obtained immediately to confirm the hypoglycemia and also to obtain the critical samples as described above.
Glucagon stimulation test — In the case of a child with hypoglycemia of unknown cause, a glucagon stimulation test (or glucagon challenge test) at the time of
hypoglycemia can provide very useful diagnostic information about glycogen stores.
The test is performed as follows: While the child is hypoglycemic, glucagon (0.03 mg per kg) is infused or given by subcutaneous or intramuscular injection. It is
critically important that plasma glucose concentration is measured within minutes prior to giving the glucagon. Subsequently, we measure plasma glucose at 10, 20,
and 30 minutes. The initial samples are primarily to make sure that the plasma glucose concentration is not continuing to decrease. A clear glycemic response
(plasma glucose rises by >30 mg/dL [2 mmol/L] within the first 30 minutes after glucagon administration) in a hypoglycemic child suggests hyperinsulinemia.
Hyperinsulinemia causes inappropriate sequestration of hepatic glycogen at the time of hypoglycemia, which is then released in response to the pharmacologic dose
of glucagon. (See 'Hyperinsulinism' below.)
Interpretation of results — For patients with unexplained hypoglycemia, the tests on the "critical samples" obtained during an episode of hypoglycemia (either at
the time of initial presentation or during an elective fast) and glucagon stimulation test are used to identify the type of disorder causing hypoglycemia.
We narrow the diagnostic possibilities in the following sequence, as summarized in the algorithm (algorithm 1).
● Hyperinsulinism
● Fatty acid oxidation disorders
● Disorders of gluconeogenesis and/or glycogen metabolism
We then confirm or refine the diagnostic category established by these tests by considering the degree of ketosis.
Hyperinsulinism — First, we determine whether one or both of the following characteristics of hyperinsulinism are present (algorithm 1):
● Positive glucagon stimulation test – A glycemic response (plasma glucose rises >30 mg/dL) to glucagon stimulation is caused by inappropriate hepatic glycogen
stores, and suggests hyperinsulinemia.
● Inappropriately elevated plasma concentrations of insulin – Plasma insulin concentration for a normal child who has become hypoglycemic due to fasting is
usually <15 pmol/L (2 microIU/mL) and rarely greater than 35 pmol/L (5 microIU /mL), except in markedly obese children. Plasma insulin concentrations greater
than 35 pmol/L (5 microIU/mL) with concomitant plasma glucose value less than 2.8 mM (50 mg/dL) are distinctly abnormal, regardless of the period of fasting.
If hyperinsulinemia is suggested by one or both of the above measures, the next step is to determine if it is of endogenous or exogenous origin. A low C-peptide
concentration in a patient with a positive glycemic response to a glucagon stimulation test indicates that the source of the insulin is exogenous because the beta cell
co-secretes C-peptide in equimolar amounts with insulin.
If the glucagon stimulation test is clearly positive but the plasma insulin concentrations are low (and the C-peptide level is also low), the possibility of exogenous
insulin administration should be further investigated [28]. This is because recombinant modified human insulins may not be detected in the new monoclonal sandwich
assays used by many commercial laboratories to measure specifically unmodified human insulin. In this case, polyclonal insulin assays must be sought to detect
exogenous insulin. (See "Causes of hypoglycemia in infants and children", section on 'Hyperinsulinism'.)
In addition, low concentrations of IGFBP1 (if measured), provides supportive evidence of inappropriate hyperinsulinemia because insulin potently inhibits IGFBP1
production [29]. (See "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy", section on 'Biochemical tests'.)
Fatty acid oxidation disorders — If hyperinsulinemia is excluded, we determine whether the following characteristics are present, which suggest a fatty acid
oxidation disorder (algorithm 1):
● Elevated FFA and acyl carnitine concentrations. FFA concentrations may be very high (>1.8 mmol/L) in fatty acid oxidation disorders, but also may be moderately
elevated in disorders of gluconeogenesis or glycogen metabolism. The specific acyl carnitine profile helps to identify the specific fatty acid oxidation disorder
(table 3).
● Mild or moderate ketosis (beta-hydroxybutyrate <2.5 mmol/L) because FFAs cannot be used for ketone body formation (table 4); this low level of ketosis is
sometimes termed "inappropriate" for the degree of hypoglycemia.
● In contrast to hyperinsulinism, there is minimal glycemic response to glucagon stimulation, and plasma concentrations of insulin and C-peptide are normal. An
exception is that some disorders of fatty acid oxidation (eg, hydroxyacyl-coenzyme A dehydrogenase, HADH, previously known as short-chain L-3-hydroxyacyl
CoA dehydrogenase deficiency, SCHAD) can cause disturbance of adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratios in the beta cell and have
been associated with hyperinsulinemia [30]. As a result, this disorder is grouped with the mutations causing persistent hyperinsulinemic hypoglycemia of infancy
(PHHI). (See "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy".)
Defects in gluconeogenesis or glycogen metabolism — Next, we determine whether the following characteristics are present, which suggest defective
gluconeogenesis or glycogen metabolism (algorithm 1):
● Normal acyl carnitine profile, usually with mild or moderately elevated FFA concentrations.
● In children with severe glucose-6-phosphatase deficiency, the baseline plasma lactate concentration will be significantly elevated and may increase further during
a glucagon stimulation test, with no concomitant rise in glucose. For children with milder disease, the baseline lactate concentration may be only mildly elevated
but could increase dramatically during a glucagon stimulation test.
● Mild or moderate ketosis (beta-hydroxybutyrate <2.5 mmol/L) because ketones are not being synthesized appropriately in glycogen storage disease type 1 (von
Gierke disease) and other conditions in which defective gluconeogenesis exist (table 5). (See "Overview of inherited disorders of glucose and glycogen
metabolism".)
● In contrast to hyperinsulinism, there is minimal glycemic response to glucagon stimulation, and plasma concentrations of insulin and C-peptide are normal or low.
Most but not all of the disorders of glycogenolysis and gluconeogenesis are associated with hepatomegaly; they can be further distinguished by their clinical features
(table 6 and table 7), and by specific genetic testing. (See "Causes of hypoglycemia in infants and children", section on 'Disorders of carbohydrate metabolism'.)
Ketosis — Last, we determine whether the patient had a robust ("appropriate") ketotic response to the episode of hypoglycemia, ideally measured by plasma
beta-hydroxybutyrate concentration (algorithm 1). This serves to confirm or refine the diagnostic category established by the other tests:
● Minimal ketosis – Consistent with hyperinsulinemia. Because this lack of a ketotic response to hypoglycemia is abnormal, it is sometimes termed "inappropriate."
● Mild or moderate ketosis (beta-hydroxybutyrate <2.5 mmol/L) – Consistent with disorders of gluconeogenesis or glycogen metabolism including glycogen storage
disease type I [31,32], and with most fatty acid oxidation disorders. The mild ketosis seen in these disorders is also considered abnormal or "inappropriate" for
the degree of hypoglycemia.
● Marked ketosis (beta-hydroxybutyrate >2.5 mmol/L) – This finding is a normal (appropriate) response to fasting, and is consistent with starvation or prolonged
fasting in an individual without an inborn error of metabolism. This degree of ketosis is also consistent with ketotic hypoglycemia, a disorder of unknown cause,
certain glycogen storage diseases (types 0, III, VI, and IX), or with deficiencies of growth hormone or cortisol [33]. (See "Causes of hypoglycemia in infants and
children", section on 'Ketotic hypoglycemia' and "Overview of inherited disorders of glucose and glycogen metabolism".)
Disorders of amino acid or organic acid metabolism also tend to have ketosis during hypoglycemia. The presence or absence of hepatomegaly and
measurement of qualitative urine organic acids can help to distinguish among these possibilities. (See "Organic acidemias".)
Markedly elevated ketones with relatively mild hypoglycemia may be seen in disorders of ketolysis. These disorders are rare and can be screened for by the
finding of elevated beta-hydroxybutyrate after an overnight fast and indeed even in the fed state (>0.2 mmol/L). They include succinyl-CoA:3-ketoacid CoA
transferase (SCOT) deficiency (MIM #245050), alpha-methylacetoacetic aciduria (MIM #203750), and monocarboxylase transporter 1 (MCT1) deficiency (MIM
#616095) [34].
Additional testing — Once the general category of disorder is identified, further diagnostic testing can be performed to identify the specific disorder. A variety of
disorders are diagnosed with DNA analyses (eg, defects in glycogen and fatty acid metabolism, hyperinsulinemia, defects in gluconeogenesis or glycogenolysis,
defects in mitochondrial function). (See "Inborn errors of metabolism: Identifying the specific disorder".)
Further information about identifying the specific order within each category is available in separate topic reviews:
● Endogenous hyperinsulinism – (See "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy" and "Insulinoma".)
● Fatty acid oxidation disorders – (See "Causes of hypoglycemia in infants and children", section on 'Disorders of fatty acid oxidation' and "Overview of fatty acid
oxidation disorders" and "Specific fatty acid oxidation disorders".)
● Disorders of gluconeogenesis or glycogen metabolism – (See "Causes of hypoglycemia in infants and children", section on 'Disorders of carbohydrate
metabolism'.)
● Appropriate ketosis – (See "Causes of hypoglycemia in infants and children", section on 'Ketotic hypoglycemia' and "Causes of hypoglycemia in infants and
children", section on 'Hormone deficiencies'.)
If such targeted testing does not establish the diagnosis, then other provocative tests may be considered. As examples, galactose, fructose, and alanine tolerance
tests may be performed in children with suspected defects in gluconeogenesis (see "Causes of hypoglycemia in infants and children"), or leucine tolerance tests for
suspected hyperinsulinism-hyperammonemia (HIHA) syndrome (see "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of
infancy", section on 'Glutamate dehydrogenase defects'). However, as a general rule, these tests should be performed only in selected circumstances and by
individuals who are experienced in their performance and interpretation.
If the diagnosis and appropriate therapy cannot be reasonably determined, the child should be transferred to a center prepared and experienced to make an even
more thorough evaluation of the child's and/or families' deoxyribonucleic acid (DNA). Using total exome sequencing new and previously unrecognized disorders may
be identified. Rarely, a liver biopsy may be necessary to measure deficiencies of hepatic enzymes when all else has been exhausted. (See "Inborn errors of
metabolism: Identifying the specific disorder".)
SUMMARY AND RECOMMENDATIONS — Hypoglycemia in infants and children requires prompt recognition and treatment to prevent permanent neurologic
sequelae.
Clinical presentation and diagnosis
● Symptoms of hypoglycemia include neurogenic (autonomic) symptoms and neuroglycopenic symptoms. The severity of symptoms may or may not predict the
severity of the hypoglycemia. Neuroglycopenic symptoms typically occur at lower plasma glucose levels than autonomic symptoms. However, with repeated
episodes of hypoglycemia, the threshold glucose concentration for adrenergic symptoms decreases, such that they may not appear before the onset of
neuroglycopenic symptoms. (See 'Clinical features' above.)
• Autonomic symptoms of hypoglycemia in children and adults are due to increased adrenergic activity, and include sweating, weakness, tachycardia, tremor,
and feelings of nervousness, and/or hunger. (See 'Neurogenic (autonomic) symptoms' above.)
• Neuroglycopenic symptoms include lethargy, irritability, confusion, behavior that is out of character, and hypothermia. In extreme hypoglycemia, seizure and
coma may occur. (See 'Neuroglycopenic symptoms' above.)
● In infants, symptoms of hypoglycemia are nonspecific and include jitteriness, irritability, feeding problems, lethargy, cyanosis, and tachypnea. (See 'Infants'
above.)
● When hypoglycemia is suspected, a rapid (bedside) plasma glucose determination should be performed. If it is low (≤50 mg/dL [2.7 mmol/L] for this initial
bedside measurement), critical samples should be obtained before treatment, if this can be done without delaying treatment. Obtaining critical samples before
the initiation of therapy, and collecting the first voided urine sample, can dramatically improve the ability to diagnose the etiology of the hypoglycemia and simplify
the subsequent diagnostic evaluation. (See 'Critical samples' above.)
Treatment — Treatment of hypoglycemia varies with the degree of hypoglycemia and associated symptoms. The key steps for diagnosis and treatment are
summarized in a rapid overview (table 2). (See 'Immediate management' above.)
● If the patient is fully conscious and able to drink and swallow safely, a rapidly-absorbed carbohydrate (eg, glucose tablets, glucose gel, table sugar, or fruit juice)
should be given by mouth. If the hypoglycemia does not improve within 10 to 15 minutes, parenteral glucose must be administered. (See 'Glucose therapy'
above.)
● Individuals with altered consciousness and/or who are unable to safely swallow a rapidly-absorbed carbohydrate should be treated with intravenous (IV)
dextrose, at a dose of 0.2 to 0.25 g/kg of body weight (maximum single dose, 25 grams). This is usually achieved with 2.5 mL/kg of 10 percent dextrose solution,
given slowly (2 to 3 mL/min). (See 'Glucose therapy' above.)
● Subsequent management – The IV bolus described above should be followed by an infusion of dextrose. Plasma glucose should be monitored every 30 to 60
minutes and the dextrose infusion adjusted accordingly, until stable plasma glucose concentration between 70 and 120 mg/dL (3.9 to 6.7 mmol/L) is attained.
Thereafter, frequency of glucose monitoring should be decreased according to the patient's clinical and biochemical responses. (See 'Glucose therapy' above.)
● Sulfonylurea overdose – Symptomatic hypoglycemia caused by sulfonylurea overdose is managed with boluses of dextrose and sometimes also with octreotide.
(See "Sulfonylurea agent poisoning".)
Evaluation for the cause
● Causes of hypoglycemia include a variety of inborn errors of metabolism, hyperinsulinemia, toxic ingestions, and a variety of underlying illnesses (table 1). The
evaluation to determine the cause is guided by the findings of the history, examination, and preliminary laboratory results. As examples, clinical features to
suggesting an accidental or toxic ingestion or a specific inborn error of metabolism should prompt specific testing for the suspected disorder. (See 'Evaluation for
the cause of hypoglycemia' above.)
● If the cause of the hypoglycemia is unclear, the critical samples obtained during an episode of hypoglycemia are used to identify the type of disorder causing
hypoglycemia. A controlled elective fast may be necessary to collect the critical samples, but should be performed only after disorders of fatty acid oxidation have
been excluded by performing an acyl carnitine profile and urine organic acids in the well state. We narrow the diagnostic possibilities into categories in a stepwise
sequence, as summarized in the algorithm (algorithm 1). (See 'Subsequent testing for unexplained hypoglycemia' above and 'Interpretation of results' above.)
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REFERENCES
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4. Darmaun D, Haymond MW, Bier DM. Metabolic aspects of fuel homeostasis in the fetus and neonate. In: Endocrinology, 3rd ed, DeGroot LJ, Besser M, Burger
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6. Sunehag A, Ewald U, Gustafsson J. Extremely preterm infants (< 28 weeks) are capable of gluconeogenesis from glycerol on their first day of life. Pediatr Res
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7. Grajwer LA, Sperling MA, Sack J, Fisher DA. Possible mechanisms and significance of the neonatal surge in glucagon secretion: studies in newborn lambs.
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8. Cornblath M, Schwartz R. Disorders of Carbohydrate Metabolism in Infancy, Blackwell Publications, Cambridge, MA 1991.
9. Haymond MW, Sunehag A. Controlling the sugar bowl. Regulation of glucose homeostasis in children. Endocrinol Metab Clin North Am 1999; 28:663.
10. Haymond MW, Howard C, Ben-Galim E, DeVivo DC. Effects of ketosis on glucose flux in children and adults. Am J Physiol 1983; 245:E373.
11. Bier DM, Leake RD, Haymond MW, et al. Measurement of "true" glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 1977;
26:1016.
12. Huopio H, Shyng SL, Otonkoski T, Nichols CG. K(ATP) channels and insulin secretion disorders. Am J Physiol Endocrinol Metab 2002; 283:E207.
13. Amiel SA, Simonson DC, Sherwin RS, et al. Exaggerated epinephrine responses to hypoglycemia in normal and insulin-dependent diabetic children. J Pediatr
1987; 110:832.
14. Cryer PE. Banting Lecture. Hypoglycemia: the limiting factor in the management of IDDM. Diabetes 1994; 43:1378.
15. Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent
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16. Holtkamp HC, Verhoef NJ, Leijnse B. The difference between the glucose concentrations in plasma and whole blood. Clin Chim Acta 1975; 59:41.
17. Geeting DG, Suther CA, Sylbert P. Determination of glucose in serum and whole blood: statistical relationships between values obtained by different methods.
Clin Chem 1972; 18:976.
18. Collier A, Steedman DJ, Patrick AW, et al. Comparison of intravenous glucagon and dextrose in treatment of severe hypoglycemia in an accident and
emergency department. Diabetes Care 1987; 10:712.
19. Wiethop BV, Cryer PE. Alanine and terbutaline in treatment of hypoglycemia in IDDM. Diabetes Care 1993; 16:1131.
20. Llamado R, Czaja A, Stence N, Davidson J. Continuous octreotide infusion for sulfonylurea-induced hypoglycemia in a toddler. J Emerg Med 2013; 45:e209.
21. Chung ST, Haymond MW. Minimizing morbidity of hypoglycemia in diabetes: a review of mini-dose glucagon. J Diabetes Sci Technol 2015; 9:44.
22. Haymond MW. Hypoglycemia in infants and children. Endocrinol Metab Clin North Am 1989; 18:211.
23. Verrotti A, Fusilli P, Pallotta R, et al. Hypoglycemia in childhood: a clinical approach. J Pediatr Endocrinol Metab 1998; 11 Suppl 1:147.
24. Stanley CA, Lieu YK, Hsu BY, et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J
Med 1998; 338:1352.
25. Roe TF, Kogut MD. Hypopituitarism and ketotic hypoglycemia. Am J Dis Child 1971; 121:296.
26. Kershnar AK, Roe TF, Kogut MD. Adrenocorticotropic hormone unresponsiveness: report of a girl with excessive growth and review of 16 reported cases. J
Pediatr 1972; 80:610.
27. Morris AA, Thekekara A, Wilks Z, et al. Evaluation of fasts for investigating hypoglycaemia or suspected metabolic disease. Arch Dis Child 1996; 75:115.
28. Green RP, Hollander AS, Thevis M, et al. Detection of surreptitious administration of analog insulin to an 8-week-old infant. Pediatrics 2010; 125:e1236.
29. Ferrara C, Patel P, Becker S, et al. Biomarkers of Insulin for the Diagnosis of Hyperinsulinemic Hypoglycemia in Infants and Children. J Pediatr 2016; 168:212.
30. Clayton PT, Eaton S, Aynsley-Green A, et al. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-
oxidation in insulin secretion. J Clin Invest 2001; 108:457.
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32. Fernandes J, Pikaar NA. Ketosis in hepatic glycogenosis. Arch Dis Child 1972; 47:41.
33. Cornblath M, Pildes RS, Schwartz R. Hypoglycemia in infancy and childhood. J Pediatr 1973; 83:692.
34. van Hasselt PM, Ferdinandusse S, Monroe GR, et al. Monocarboxylate transporter 1 deficiency and ketone utilization. N Engl J Med 2014; 371:1900.
Topic 5805 Version 20.0
GRAPHICS
Glucose use by the brain versus other tissues
Estimated percentage of glucose rate of disappearance (Rd) used by brain and non-brain tissue
from infancy to adulthood (n=141). The tissue data points represent the mean values for
subjects with body weights, in kg, of 0.5-1.0, 1.1-2.0, 2.1-3.0, 3.1-4.0, 4.1-5.0, 5.1-10, 10.1-
15, 15.1-20.0, 20.1-30.0, 30.1-40.0, 40.1-50.0, 50.1-60.0, 60.1-70, and 70.1-95.0,
respectively.
Data from Haymond, MW, Sunehag, A, Endocrinol Metab Clin North Am 1999; 28:663.
Graphic 76157 Version 1.0
Glucose rate of disappearance (Rd)
Total glucose rate of disappearance (Rd) (mmol/min) as a function of body weight from infancy to
adulthood (n=141; body weights range from 0.6 to 94 kg).
Data from Haymond, MW, Sunehag, A. Controlling the sugar bowl. Regulation of glucose homeostasis in
children. Endocrinol Metab Clin North Am 1999; 28:663.
Causes of hypoglycemia in infants and children
Other names OMIM #
Disorders of carbohydrate metabolism

Disorders of glycogenolysis
Glycogen synthetase deficiency GSD type 0a 240600
Glucose-6-phosphatase deficiency GSD type Ia (von Gierke disase) or Ib 232200 or 232220
Debrancher deficiency GSD type III 232400
Hepatic phosphorylase deficiency GSD type VI 232700
Hepatic phosphorylase B kinase deficiency GSD IXa1, IXb-d 306000

Disorders of glycosylation
Phosphoglucomutase 1 deficiency Congenital disorder of glycosylation type It 614921
Phosphomannomutase 2 deficiency Congenital disorder of glycosylation type Ia 212065
Mannosephosphate isomerase deficiency Congenital disorder of glycosylation type Ib 602579

Disorders of gluconeogenesis
Fructose 1,6 bisphosphatase deficiency 229700
Pyruvate carboxylase deficiency 266150
PEPCK deficiency 261650
Galactosemia 230400; others
Hereditary fructose intolerance 229600
Disorders of amino acid metabolism
Propionic acidemia 606054
Methylmalonic aciduria 277400; others
Glutaric aciduria type 1 231670
Disorders of fatty acid metabolism
Medium-chain acyl-CoA dehydrogenase (MCAD) and 201450, others

others
Increased utilization of glucose

Hyperinsulinemia
Persistent hyperinsulinemic hypoglycemia of infancy Familial hyperinsulinemic hypoglycemia; congenital 256450; 601820; others
(PHHI) hyperinsulinism
Insulinoma (including in association with MEN1)
Exogenous administration of insulin (eg, in

Munchausen's syndrome by proxy or diabetes
mellitus)
Miscellaneous
Ketotic hypoglycemia
Hormone deficiencies
Growth hormone deficiency
Cortisol deficiency
± Hypothyroidism
Ingestions
Oral hypoglycemics (eg, sulfonylureas such as

glipizide or glyburide) - cause hyperinsulinemia
Ethanol
Salicylates
Beta blockers
Pentamidine
Trimethoprim-sulfamethoxazole (rare)
Refer to UpToDate table on drugs that cause

hypoglycemia
Other
Heart disease
Surgery
Critical illness (eg, sepsis)
Hepatic failure
OMIM: on-line Mendelian inheritance in man database; GSD: glycogen storage disease; PEPCK: phosphoenolpyruvate carboxykinase; PHHI: persistent hyperinsulinemic hypoglycemia of
infancy; MEN1: multiple endocrine neoplasia type 1; MCAD: medium-chain acyl-CoA dehydrogenase.
Courtesy of Drs. Morey Haymond and Agneta Sunehag.
Rapid overview for hypoglycemia in adolescents and children, other than neonates
Clinical features
Any patient with acute lethargy or coma should have an immediate measurement of blood glucose to determine if hypoglycemia is a possible cause
Other findings of hypoglycemia are nonspecific* and vary by age:
Infants
Irritability
Lethargy
Jitteriness
Feeding problems
Hypothermia
Hypotonia
Tachypnea
Cyanosis
Apnea
Seizures
Older children and adolescents
Autonomic response (tends to occur with blood glucose <50 to 65 mg/dL)
Sweating
Tachycardia
Palpitations
Tremor
Nervousness
Hunger
Paresthesias
Pallor
Neuroglycopenia
Irritability
Confusion
Uncharacteristic behavior
Weakness
Seizures
Coma
Occasionally, transient focal neurologic deficits
Diagnosis
Obtain rapid bedside blood glucose concentration (and β-hydroxybutyrate, if available as a point-of-care measurement)
Confirm the presence of hypoglycemia with a simultaneously drawn plasma glucose
Treat, as outlined below, if the bedside value is low (<70 mg/dL [3.89 mmol/L]) in symptomatic patients
Obtain a blood sample for additional diagnostic studies prior to glucose administration, if possible, and collect the first voided urine after the hypoglycemic event in all infants
and young children who are not being treated for diabetes mellitus or do not have a known cause for hypoglycemia ¶
Treatment
Do not delay treatment if symptomatic hypoglycemia is suspected. However, every reasonable effort should be made to obtain a rapid blood glucose measurement prior to
administering glucose.
Give glucose based upon the patients level of consciousness and ability to swallow safely (ie, alert enough to do so and with intact gag reflex) as follows:
Conscious and able to drink and swallow safely:
Administer 0.3 g/kg (10 to 20 g) of a rapidly-absorbed carbohydrate. 15 g is supplied by 3 glucose tablets, a tube of gel with 15 g, 4 oz (120 mL) sweetened fruit juice, 6
oz non-diet soda, or a tablespoon (15 mL) of honey or table sugar. May repeat in 10 to 15 minutes.
Altered mental status, unable to swallow, or does not respond to oral glucose administration within 15 minutes:
Give an initial IV bolus of glucose of 0.25 g/kg of dextrose (maximum single dose 25 g). Δ The volume and concentration of glucose bolus is infused slowly at 2 to 3 mL
per minute and based upon age:
2.5 mL/kg of 10% dextrose solution (D10W) in infants and children up to 12 years of age (10% dextrose is 100 mg/mL)
1 mL/kg of 25% dextrose (D25W) or 0.5 mL/kg of 50% dextrose (D50W) in adolescents (25% dextrose is 250 mg/mL; 50% dextrose is 500 mg/mL)
Unable to receive oral glucose and unable to obtain IV access:
Give glucagon 0.03 mg/kg IM or SQ (maximum dose 1 mg): ◊
Perform blood glucose monitoring every 10 to 15 minutes as the effects of glucagon may be transient
Establish vascular access as soon as possible
After initial hypoglycemia is reversed, provide additional glucose and treatment based upon suspected etiology:
Give children and adolescents with type I diabetes mellitus a normal diet
Give patients with an unknown cause of hypoglycemia intravenous infusion of dextrose 10% (6 to 9 mg/kg per minute) titrated to maintain blood glucose in a safe and
appropriate range (70 to 150 mg/dL [3.89 to 8.33 mmol/L])
Give patients, who have ingested a sulfonylurea and have recurrent hypoglycemia, octreotide (dose: 1 to 1.5 mcg/kg IM or SQ, maximum dose 150 mcg every 6 hours) in
addition to glucose. (Refer to UpToDate topic on sulfonylurea poisoning.)
Measure a rapid blood and plasma glucose 15 to 30 minutes after the initial IV glucose bolus and then monitor every 30 to 60 minutes until stable (minimum of four hours) to
ensure that plasma glucose concentration is maintained in the normal range (>70 to 100 mg/dL [>3.89 to 5.55 mmol/L])
Obtain pediatric endocrinology consultation for patients with hypoglycemia of unknown cause
Obtain medical toxicology consultation for patients with ingestion of oral hypoglycemic agents by calling the United States Poison Control Network at 1-800-222-1222 or
access the World Health Organization's list of international poison centers
Admit the following patients:
Cannot maintain normoglycemia with oral intake
Hypoglycemia of unknown cause
Ingestion of long-acting hypoglycemic agents
Recurrent hypoglycemia during the period of observation
IV: intravenous; IM: intramuscular; SQ: subcutaneous; D10W: 10% dextrose in water; D25W: 25% dextrose in water; D50W: 50% dextrose in water.
* These findings may also occur in infants with sepsis, congenital heart disease, respiratory distress syndrome, intraventricular hemorrhage, other metabolic disorders, and in children and
adolescents with a variety of underlying conditions.
¶ Specific laboratory studies to obtain in children include blood samples for glucose, insulin, C-peptide, beta-hydroxybutyrate, lactate (free flowing blood must be obtained without a
tourniquet), plasma acylcarnitines, free fatty acids, growth hormone, and cortisol.
Δ Higher doses of glucose (eg, 0.5 to 1 g/kg [5 to 10 mL/kg of 10% dextrose in water or 2 to 4 mL/kg of 25% dextrose in water]) may be needed to correct hypoglycemia caused by
sulfonylurea ingestion. (For more detail, refer to UpToDate topic on sulfonylurea agent poisoning.)
◊ Glucagon will reverse hypoglycemia caused by excess endogenous or exogenous insulin and will not be effective in patients with inadequate glycogen stores (prolonged fasting), ketotic
hypoglycemia, or are unable to mobilize glycogen (glycogen storage diseases). Of note, children may exhaust their glycogen stores in as little as 12 hours. Other conditions in which
glycogen cannot be effectively mobilized include ethanol intoxication in children, adrenal insufficiency, and certain inborn errors of metabolism (eg, a disorder of glycogen synthesis and
glycogen storage diseases).
Algorithm for evaluation of an infant or child with hypoglycemia
BUN: blood urea nitrogen; AST: aspartate aminotransferase; ALT: alanine aminotransferase; FFA: free fatty acids; PG: plasma glucose; ↑: elevated; ↓: decreased; ACTH: adrenocorticotropic hor
ammonia; IGF-I: insulin-like growth factor I; IGFBP3: insulin-like growth factor binding protein 3; T4: thyroxine; TSH: thyroid stimulating hormone (thyrotropin).
* Plasma insulin levels may be either low or high if exogenous insulin has been given (eg, in Munchausen syndrome by proxy). This is because recombinant modified human insulins may not be
monoclonal "sandwich" assays used by many commercial laboratories to measure unmodified human insulin. Thus, if the glucagon challenge test is positive (rise in BG), but measured plasma in
concentrations are low (and the C-peptide level is also low), polyclonal insulin assays must be sought to detect exogenous insulin.
¶ Acylcarnitine elevations will be for a specific fatty acid oxidation disorder.
Δ When the lactate is elevated without hepatomegaly, consider organic acidemia, ketolysis defect, or mitochondrial respiratory chain disorder. If the lactate is present with isolated hepatomegaly
storage disease or gluconeogenesis defects are suspected.
◊ Defects of ketolysis may cause markedly elevated ketones in the setting of mild hypoglycemia. These disorders are rare, and include SCOT deficiency (MIM #245050), alpha-methylacetoacetic
#203750), and monocarboxylase transporter 1 deficiency (MIM #616095).
§ Thyroid function tests are measured as part of the evaluation for panhypopituitarism. It is unlikely that isolated hypothyroidism causes hypoglycemia.
Summary of fatty acid oxidation disorders
Other Plasma
Enzyme Gene Prevalence Symptoms
complications acylcarnitines
VLCADD Very-long-chain acyl- ACADVL 1 in 42,500 to 120,000 G, L, C, M, R Elevated C14:1-, C14-,

CoA dehydrogenase C16:1-, C16-
deficiency
LCHADD Long-chain 3- HADHA 1 in 110,000 G, L, C, M, R Retinopathy, peripheral Elevated C16:1-OH-,

hydroxyacyl-CoA neuropathy C16-OH-, C18:1-OH-,
dehydrogenase C18-OH-
deficiency
TFPD Trifunctional protein HADHA, HADHB Rare G, L, C, M, R Retinopathy, peripheral Elevated C16:1-OH-,
deficiency neuropathy C16-OH-, C18:1-OH-,
C18-OH-
CTD Carnitine transporter SLC22A5 1 in 20,000 to 120,000 G, L, C, M, R NBS maternal CTD Low total and free
deficiency carnitine levels
CACTD Carnitine-acylcarnitine SLC25A20 G, L, C Elevated C16-, C16:1-,

translocase deficiency C18, C18:1-
CPT1D Carnitine palmitoyl- CPT1A 1 in 500,000 G, L Renal tubular acidosis, Elevated total and free
transferase 1A Arctic variant plasma carnitine levels
deficiency
CPT2D Carnitine palmitoyl- CPT2 G, L, C, M, R Renal cysts, facial Elevated C16-, C16:1-,
transferase 2 deficiency dysmorphism C18, C18:1-
MCADD Medium-chain acyl-CoA ACADM 1 in 20,000 G, L Elevated C6-, C8-,

dehydrogenase C10-, C10:1-
deficiency
MADD Multiple acyl-CoA ETFA, ETFB, ETFDH G, L, C, M Renal cysts, congenital Elevated C4-, C5-,
dehydrogenase malformations, facial C5DC-, C6-, C8-,
deficiency dysmorphism, sweaty C10:1-, C12-, C14-,
foot odor C14:1-, C16-, C16:1-,
C18-, C18:1-, C16-
OH-, C16:1-OH-, C18-
OH-, C18:1-OH-
SCADD Short-chain acyl-CoA ACADS 1 in 35,000 to 50,000 Asymptomatic Elevated C4-

dehydrogenase
deficiency
M/SCHAD Short-chain l-3- HADH Hyperinsulinism Elevated C4-OH-

hydroxyacyl-CoA
dehydrogenase
deficiency
ACADVL: acyl-CoA dehydrogenase, very long chain gene; G: hypoglycemia; L: liver dysfunction; C: cardiomyopathy; M: skeletal myopathy; R: rhabdomyolysis; HADHA: hydroxyacyl-CoA
dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit; HADHB: hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase
(trifunctional protein), beta subunit; SLC22A5: solute carrier family 22 member 5 gene; NBS: newborn screening; SLC25A20: solute carrier family 25 member 20 gene; CPT1A: carnitine
palmitoyltransferase 1A; CPT2: carnitine palmitoyltransferase 2; ACADM: acyl-CoA dehydrogenase, C-4 to C-12 straight chain; ETFA: electron transfer flavoprotein, alpha subunit; ETFB:
electron transfer flavoprotein, beta subunit; ETFDH: electron transfer flavoprotein dehydrogenase; ACADS: acyl-CoA dehydrogenase, C-2 to C-3 short chain; HADH: hydroxyacyl-CoA
dehydrogenase.
Adapted from: Sun A, Merritt JW II. Orphan drugs in development for long-chain fatty acid oxidation disorders: Challenges and progress. Orph Drug Res Rev 2015; 5:33.
Distinguishing biochemical findings of inborn errors of metabolism*
Urea Disorders of Fatty acid Lysosomal

Maple syrup Organic Mitochondrial Peroxisomal
Findings cycle carbohydrate oxidation storage
urine disease acidemias disorders disorders
defects metabolism disorders disorders
Metabolic acidosis ± ++ - ± ± ± - -
Respiratory - - + - - - - -
alkalosis
Hyperammonemia ± + ++ - ± - - -
Hypoglycemia ± ± - + + ± - -
Ketones A/H H A A/H A/L A/H A A
Lactic acidosis ± ± - + ± ++ - -
-: usually absent; ±: sometimes present; +: usually present; ++: always present; A: appropriate; H: inappropriately high; L: inappropriately low.
* Within disease categories, not all diseases have all findings; for disorders with episodic decompensation clinical and laboratory findings may be present only during acute crisis; for
progressive disorders, findings may not be present early in the course of disease.
Adapted from: Weiner DL. Metabolic Emergencies. In: Textbook of Pediatric Emergency Medicine, 5th ed, Fleisher GR, Ludwig S, Henretig FM (Eds), Lippincott, Williams & Wilkins,
Philadelphia 2006. p.1193.
Disorders of glycogen/glucose metabolism
Classification Key clinical findings Diagnosis Therapy
GSD 0a (MIM #240600, glycogen synthase 2 deficiency in liver) Ketotic hypoglycemia, no Liver biopsy and enzyme testing; Uncooked cornstarch,
hepatomegaly DNA testing commercial glucose polymers (eg,
Glycosade), liver transplantation
GSD 0b (MIM #611556, muscle glycogen synthase deficiency) Cardiomyopathy, exercise Muscle biopsy (glycogen No specific treatment
intolerance, weakness depletion), enzyme assay, DNA
testing
GSD I (MIM #232200; GSD Ia, von Gierke disease, glucose-6- Ketotic hypoglycemia, DNA testing, liver biopsy, and Cornstarch, allopurinol,
phosphatase deficiency; GSD Ib due to q transport defect) hepatomegaly enzyme assay granulocyte colony-stimulating
factor (G-CSF), commercial
glucose polymers (eg, Glycosade),
liver transplantation
Lysosomal acid maltase deficiency (MIM #232300, Pompe disease, Hypotonia, muscle weakness, Fibroblast, leukocyte, muscle, or Enzyme replacement therapy,
GSD II*) hypertrophic cardiomyopathy, liver enzyme assay; DNA testing commercial glucose polymers (eg,
rhabdomyolysis Glycosade), liver transplantation
Lysosome-associated membrane protein 2 (LAMP2) deficiency (MIM Hypotonia, hypertrophic Muscle biopsy, DNA testing No specific treatment
#300257, Danon disease, GSD IIb *) cardiomyopathy, rhabdomyolysis
GSD III (MIM #232400, glycogen debrancher deficiency) Ketotic hypoglycemia, Fibroblast or liver enzyme assay; Uncooked cornstarch,
hepatomegaly DNA testing commercial glucose polymers (eg,
Glycosade), liver transplantation
GSD IV (MIM #232500, glycogen branching enzyme deficiency) Hepatomegaly, cirrhosis, rare Fibroblast, muscle, or liver Commercial glucose polymers (eg,
neuromuscular presentations, biopsy; DNA testing Glycosade), liver transplantation
such as fetal akinesia sequence,
myopathy, axonal neuropathy,
adult polyglucosan body disease
GSD V (MIM #232600, McArdle disease, muscle phosphorylase Fatigability, myoglobinuria, Muscle biopsy, muscle enzyme Sucrose prior to exercise
deficiency) rhabdomyolysis assay, DNA testing
GSD VI (MIM #232700, Hers disease, liver phosphorylase deficiency) Hepatomegaly, mild hypoglycemia Liver biopsy and enzyme assay; Commercial glucose polymers (eg,
DNA testing Glycosade), liver transplantation
GSD VII (MIM #232800, Tarui disease, phosphofructokinase deficiency Fatigability, myoglobinuria, Muscle enzyme assay, DNA No specific treatment
in muscle) rhabdomyolysis testing
Phosphoglycerate kinase deficiency (MIM #311800) Hemolysis, fatigability, Muscle/RBC enzyme assay; DNA Bone marrow transplantation
myoglobinuria, CNS dysfunction, testing
rhabdomyolysis
GSD IX (phosphorylase kinase deficiency; IX a1, MIM #306000, Hepatomegaly, mild Liver/muscle biopsy; enzyme Commercial glucose polymers (eg,
formerly GSD VIII, alpha-2 subunit defect in liver; IXb, MIM #261750, hypoglycemia, fatigability, assay; DNA testing Glycosade), liver transplantation
beta subunit defect in liver; IXc, MIM #613027, gamma subunit defect exercise intolerance
in liver and muscle; IXd, MIM #300559, alpha subunit defect in
muscle)
GSD X (MIM #261670, phosphoglycerate mutase deficiency) Fatigability, myoglobinuria, Muscle biopsy and enzyme assay; No specific treatment
exercise intolerance, DNA testing
rhabdomyolysis
GSD XI (MIM #612933; lactate dehydrogenase A [LDHA, MIM Fatigability, myoglobinuria, Muscle or RBC enzyme assay; No specific treatment
#150000] deficiency and lactate dehydrogenase B deficiency [LDHB, rhabdomyolysis DNA testing
MIM #150100])
GLUT2 deficiency (MIM #138160; Fanconi-Bickel syndrome) Growth retardation, renal Fanconi Clinical features, DNA testing Small meals, cornstarch,
syndrome, galactosemia electrolytes as needed
GSD XII (MIM #611881, aldolase A deficiency) Hemolysis, jaundice, Muscle or RBC enzyme assay; No specific treatment
myoglobinuria, muscle weakness, DNA testing
fatigability, rhabdomyolysis
GSD XIII (MIM #612932, beta-enolase deficiency in muscle) Exercise intolerance, increased Muscle biopsy, enzyme assay, No specific treatment
CPK, rhabdomyolysis DNA testing
GSD XIV (MIM #612934, phosphoglucomutase 1 deficiency in muscle) Exercise intolerance, Muscle biopsy, enzyme assay, No specific treatment
myoglobinuria, increased CPK, DNA testing
rhabdomyolysis, myoglobinuria
GSD XV (MIM #613507, glycogenin 1 deficiency in muscle) Muscle weakness, arrhythmias Muscle biopsy (glycogen No specific treatment
depletion), DNA testing
GSD: glycogen storage disease; MIM: Mendelian inheritance in man; DNA: deoxyribonucleic acid; CNS: central nervous system; RBC: red blood cell; GLUT2: glucose transporter 2; CPK:
creatine phosphokinase.
* These diseases were originally classified as glycogen storages diseases. It was subsequently recognized that the accumulation of glycogen in lysosomes seen in these diseases is due to
defective lysosomal metabolism rather than energy deficiency from glycogen/glucose metabolism. Thus, they are considered both glycogen storage diseases and lysosomal storage
diseases.
Clinical and laboratory features of hepatic enzyme deficiencies of glycogen/glucose metabolism in children
Response
Enzyme Serum
Lactic acid Uric acid Ketosis to Clinical features
deficiency lipids
glucagon
Glycogen ↑* ↑ + ↑ ↓ Normal liver size

synthase (GSD
Neonatal onset
0)
Severe fasting hypoglycemia, but postprandial hyperglycemia and
lactic acidosis
Glucose-6- ↑ ↑ + ↑ ↓ Hepatomegaly
phosphatase
Neonatal onset
(GSD I)
Severe fasting hypoglycemia
Some patients have neutropenia, platelet dysfunction, renal disease or

hypertension
Glycogen Normal or ↑ Normal + Normal or ↑ Normal two Hepatomegaly

debrancher hours after
Onset in infancy
(GSD III) glucose meal,
but absent Mild fasting hypoglycemia
after fast May have cardiac or skeletal muscle manifestations (eg, elevated CK)
May have elevated RBC glycogen
Hepatic Normal Normal + Normal or ↑ Usually normal, Hepatomegaly

phosphorylase but variable
Onset in early childhood
(GSD VI)
Mild fasting hypoglycemia
Hepatic Normal Normal or ↑ + Normal or ↑ Normal Hepatomegaly

phosphorylase
Onset in early childhood
b kinase
Mild fasting hypoglycemia
X-linked inheritance
GSD: glycogen storage disease; CK: creatine kinase; RBC: red blood cell; +: present.
* Postprandial.
Clinical and laboratory features of hepatic enzyme deficiencies of gluconeogenesis in children
Enzyme Lactic Uric Serum Response to

Ketosis Comment
deficiency acid acid lipids glucagon
G6P ↑ ↑ ± ↑ ↓ Hepatomegaly
Neonatal onset
Severe fasting hypoglycemia
Some patients have neutropenia, platelet dysfunction, renal disease or

hypertension
F16DP ↑ ↑ + ↑ ↑ (when fed, not when Mild/moderate hepatomegaly

fasted)
Moderate hypoglycemia
Onset in infancy
Muscular weakness
Failure to thrive
Hyperalaninemia
PEPCK ↑ Normal ± ↑ ↓ Onset in infancy
Severe hypoglycemia
Elevated transaminases
Coagulation abnormalities
Fatty liver, fatty kidneys
PC ↑ Normal + Normal or ↑ ↓ Onset in infancy, with early death
Mild hypoglycemia
Severe mental retardation
Subacute necrotizing encephalopathy
G6P: glucose 6 phosphatase; F16DP: fructose 1, 6, diphosphatase; PEPCK: phospholenol pyruvate carboxykinase; PC: pyruvate carboxylase; ↑: increased; ↓: decreased; +: present; ±:
may or may not be present.
Contributor Disclosures
Agneta Sunehag, MD, PhD Nothing to disclose Morey W Haymond, MD Consultant/Advisory Boards: Aegerion Pharmaceuticals Inc [Review a registry
(Metreleptin)]; AstraZeneca [diabetes (Exenatide)]; Daiichi Sankyo [Wellkids Study (Colesevelam hydrochloride)]; National Institutes of Health [Data and safety
monitoring boards (Life Mom study)]; Xeris Pharmaceuticals, Inc [Glucagon and hypoglycemia (Non-aqueous glucagon formulation)]; Zealand Pharmaceutical
[Advisory council]. Joseph I Wolfsdorf, MB, BCh Nothing to disclose Alison G Hoppin, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process,
and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.
Conflict of interest policy

Approach To Hypoglycemia in Infants and Children - UpToDate

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Approach To Hypoglycemia in Infants and Children - UpToDate

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3/26/2018 Approach to hypoglycemia in infants and children - UpToDate

Official reprint from UpToDate®

Authors: Agneta Sunehag, MD, PhD, Morey W Haymond, MD

● (See "Causes of hypoglycemia in infants and children".)

● (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

● (See "Management and outcome of neonatal hypoglycemia".)

● (See "Hypoglycemia in children and adolescents with type 1 diabetes mellitus".)

In infants and children, important causes of hypoglycemia include (table 1):

Thus, for an infusion of 10 percent dextrose solution:

● 3 mL/kg/hour provides 5 mg/kg per minute

● 5 mL/kg/hour provides approximately 8 mg/kg per minute

● Free fatty acids (FFAs)

● Urine organic acids

● Repeat measurement of glucose, insulin, C-peptide, beta-hydroxybutyrate, and lactate concentrations.

● Perform a glucagon stimulation test, as described below.

● Fatty acid oxidation disorders

● Disorders of gluconeogenesis and/or glycogen metabolism

Clinical presentation and diagnosis

Evaluation for the cause

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Topic 5805 Version 20.0

Glucose use by the brain versus other tissues

Graphic 76157 Version 1.0

Glucose rate of disappearance (Rd)

Graphic 64790 Version 1.0

Causes of hypoglycemia in infants and children

Other names OMIM #

Disorders of carbohydrate metabolism

Glycogen synthetase deficiency GSD type 0a 240600

Glucose-6-phosphatase deficiency GSD type Ia (von Gierke disase) or Ib 232200 or 232220

Debrancher deficiency GSD type III 232400

Hepatic phosphorylase deficiency GSD type VI 232700

Hepatic phosphorylase B kinase deficiency GSD IXa1, IXb-d 306000

Phosphoglucomutase 1 deficiency Congenital disorder of glycosylation type It 614921

Phosphomannomutase 2 deficiency Congenital disorder of glycosylation type Ia 212065

Mannosephosphate isomerase deficiency Congenital disorder of glycosylation type Ib 602579

Fructose 1,6 bisphosphatase deficiency 229700

Pyruvate carboxylase deficiency 266150

PEPCK deficiency 261650

Galactosemia 230400; others

Hereditary fructose intolerance 229600

Disorders of amino acid metabolism

Propionic acidemia 606054

Methylmalonic aciduria 277400; others

Glutaric aciduria type 1 231670

Disorders of fatty acid metabolism

Medium-chain acyl-CoA dehydrogenase (MCAD) and 201450, others

Increased utilization of glucose

Insulinoma (including in association with MEN1)

Exogenous administration of insulin (eg, in

Growth hormone deficiency

Oral hypoglycemics (eg, sulfonylureas such as

Refer to UpToDate table on drugs that cause

Critical illness (eg, sepsis)

Courtesy of Drs. Morey Haymond and Agneta Sunehag.

Graphic 103015 Version 3.0

Other findings of hypoglycemia are nonspecific* and vary by age:

Older children and adolescents

Autonomic response (tends to occur with blood glucose <50 to 65 mg/dL)

Occasionally, transient focal neurologic deficits

Confirm the presence of hypoglycemia with a simultaneously drawn plasma glucose

Conscious and able to drink and swallow safely: