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: Jul 2015. | This topic last updated: Sep 11, 2013.

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 glycogenolysis, glycogen synthesis, 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 blood glucose concentration, even when totally

deprived of calories 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].

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 appropriate 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. The causes of hypoglycemia and hypoglycemia in neonates are discussed

separately. (See "Etiology of hypoglycemia in infants and children" and"Pathogenesis, screening,

and diagnosis of neonatal hypoglycemia".)

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. 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]. In keeping with these findings, there is no evidence of fetal glucose production at birth in

humans [5]. However, hepatic glucose production and gluconeogenesis are well established within

hours of birth, even in very premature infants [6]. The enzymes necessary for glycogen synthesis

and glycogenolysis are present in the fetal liver long before the accumulation of glycogen can be

demonstrated. It is only during the last three to four weeks of gestation in humans that hepatic

glycogen stores increase to reach values at birth seen only in children with glycogen storage

diseases [4].

The interruption of placental blood flow as a result of the clamping of the umbilical cord at birth

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, in most infants, the plasma glucose concentration is stabilized

or is increasing. It is presumed that much of the initial glucose production is 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 content is limited, and within hours of birth

gluconeogenesis must meet an ever-increasing proportion of endogenous glucose production [6,8].

Fatty acid mobilization and metabolism 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 (eg, ß-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. However, 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 relative increase in the

glucose requirement in children may result in an acceleration of the normal adaptive mechanism(s)

of fasting observed in adults [3].

During the first 8 to 10 years of life, the rate of 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 1) [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 9.8micromol/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 23micromol/kg per min (4 mg/kg per min) after a 30- to 40-hour fast [10,11].

In the premature and term infant, more than 90 percent of the glucose is utilized by the brain. Over

time, this value decreases to approximately 40 percent of glucose turnover in overnight-fasted

adults (figure 2) [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].

The primary orchestration of substrate mobilization (or storage) and utilization is the result of

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 "Insulin secretion and 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 GLUT2 transporter, is phosphorylated by

glucokinase, and metabolized via the glycolytic pathway. This results in an increase in

the ATP/ADP ratio, which closes the KATP channels, depolarizes the cell membrane, opening the

Ca++ channels, resulting in fusion of the insulin granule with the plasma membrane causing insulin

secretion. Conversely, a decrease in blood 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 what is called "hypoglycemic 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 — The overall goal of identifying children with hypoglycemia is

to protect their central nervous systems from irreparable damage as a result of severe,

prolonged and/or repeated episodes of hypoglycemia.

The precise definition of hypoglycemia in infants and children continues to be controversial.

Knowing the conditions preceding the collection of blood for a quantitative glucose determination is

critical to its interpretation. As an example, the normal distribution of glucose values following a

meal, an overnight fast, or a 30- to 40-hour fast, will be strikingly different. Creating different

definitions of hypoglycemia based upon the child's age, gestation and/or weight (small, average, or

large for gestational age), feeding or fasting will not resolve this controversy. There is no a priori

reason that a premature or low-birth-weight infant should tolerate a low glucose concentration better

than an older child; in fact, quite the opposite might be argued.

For diagnostic purposes, we define hypoglycemia as a plasma glucose value of ≤40 mg/dL (2.22

mM) regardless of age. As discussed above, the physiologic nadir of the plasma glucose occurs in

the first two to four hours of life, but normally increases to values >60mg/dL by six hours of life.

Other than this unique circumstance, a documented plasma glucose concentration of

≤40 mg/dL (2.22 mM) should trigger a formal evaluation. However, 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. An elective fast should be considered as a

diagnostic maneuver, under carefully controlled conditions. (See 'Elective fast' below.)

ETIOLOGY OF HYPOGLYCEMIA — The body maintains a delicate balance between the rate at

which glucose is produced or enters the circulation (appearance rate) and the rate at which it is

utilized (disappearance rate). When the rate of appearance of glucose into the plasma exceeds the

rate of disappearance, the plasma glucose concentration increases. Conversely, when the rate of

disappearance is greater than the rate of appearance, the plasma glucose concentration

decreases. In many hypoglycemic conditions, the understanding of glucose kinetics is insufficient to

assign a clear cause (eg, increased utilization or decreased production). In other conditions, a

combination of decreased production and increased utilization is thought to contribute to the

development of hypoglycemia. Specific causes of hypoglycemia in infants and children are

discussed elsewhere. (See "Etiology of hypoglycemia in infants and children".)

CLINICAL FEATURES — In infants, the signs of hypoglycemia are frequently nonspecific, but may

include the signs of severe neuroglycopenia discussed below. The signs of hypoglycemia include

jitteriness, irritability, feeding problems, lethargy, cyanosis, tachypnea, and hypothermia. These

signs 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".)

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].

Autonomic response — 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 higher blood glucose

concentrations (between 40 and 70 mg/dL [2.2 and 3.9 mM]) than the neuroglycopenic signs and

symptoms, and may 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: "hypoglycemic unawareness." (see 'Glucose homeostasis in normal infants and

children' above).

Neuroglycopenia — Symptoms and signs of neuroglycopenia occur with prolonged hypoglycemia

and at lower plasma concentrations of glucose (approximately 10 to 50 mg/dL [0.5 to 2.8 mM]).

These include lethargy, irritability, confusion, uncharacteristic behavior, hypothermia, and, in

extreme hypoglycemia, seizure and coma. Severe and repeated episodes of hypoglycemia can

result in permanent central nervous system damage, and occasionally, death.

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 1).

Critical samples — When the diagnosis of hypoglycemia is suspected and supported by a rapid

indicator of the blood glucose concentration (and β-hydroxybutyrate, if available as a point-of-care

measurement), a 5 to 10 mL sample of blood should be obtained beforetherapeutic intervention.

This sample is used to confirm the diagnosis by an established quantitative laboratory method and

to permit additional biochemical tests, as described below.

Blood — 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 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.

Blood tests that should be performed immediately include:

●Measurement of key substrates: plasma glucose, free fatty acids (FFAs), ß-hydroxybutyrate,

lactate, total and free carnitine, and acylcarnitines

●Measurement of glucoregulatory hormones: plasma insulin, C-peptide, cortisol, and growth

hormone

Other tests that are helpful include:

●Serum electrolytes (for calculation of the anion gap)

●Liver function tests

●Ammonia

●Toxicology studies (salicylate, ethanol, sulfonylurea)

●Metabolic screening for some disorders.

Urine — In addition to the critical blood sample, the first voided urine should be collected. A sample

should be tested for ketones (if plasma ketones are 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 "Etiology 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 "Approach to the child with

occult toxic exposure".)

Clinical management

Glucose therapy

Oral therapy — 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. Administer 0.3 grams/kg (10 to 20 grams) of a rapidly absorbed carbohydrate. This can be

supplied by 2 to 3 glucose tablets, a tube of gel with 15 grams, 4 oz (120 mL) sweetened fruit juice,

non-diet soda, or a teaspoon (5 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 must be seriously considered and is recommended.

Intravenous therapy — Infants and children with altered consciousness and/or who are unable to

safely swallow rapidly absorbed carbohydrate should be treated with intravenous (IV) dextrose.

While placing the intravenous lines, subcutaneous or intramuscularglucagon should be

considered.(See 'Glucagon' below.)

●Initial bolus of dextrose, 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, since extravasation of

higher concentrations of glucose will lead to severe tissue damage. The bolus should be

administered slowly (2 to 3 mL/min), regardless of age. Somewhat lower concentration of

dextrose solution is often used for management of hypoglycemia in neonates.

(See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".) The infusion is

given slowly to avoid acute hyperglycemia, which can cause rebound hypoglycemia.

●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])

Higher doses of dextrose (eg, 0.5 to 1.0 g/kg) have been 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 [15,16].

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 should be considered. (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). The response is frequently transient. Thus, if the hyperinsulinemia persists,

repeated administration of glucose and/orglucagon may be required. The response to glucagon

also may provide diagnostic information for patients in whom the etiology of hypoglycemia is

unknown. (See 'Glucagon challenge' 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. Thereafter, plasma

glucose should be monitored every two to four hours. Hyperinsulinemia is highly likely when rates of

glucose infusion greater than 6 to 10 mg/kg per minute are necessary to maintain normal plasma

glucose concentrations. (See "Pathogenesis, clinical features, and diagnosis of persistent

hyperinsulinemic hypoglycemia of infancy".)

DIAGNOSTIC EVALUATION

Overview — Numerous diagnostic procedures are available to clarify the pathogenesis of the

various hypoglycemic disorders, but a systematic approach will yield the most interpretable results.

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 [17].

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).

Age at onset — What was the age at the onset of symptoms? Although there is considerable

overlap, the age of onset suggests diagnostic categories:

●Neonatal period or the first two years of life – Most inborn errors of metabolism (including

causes of hyperinsulinemia) 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 "Etiology of hypoglycemia in infants and children", section on

'Ketotic hypoglycemia' and "Etiology 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 "Etiology of hypoglycemia in

infants and children", section on 'Ingestions'.)

Dietary factors — The details of the acute event should include information about the child's

dietary intake before the event. Did acute illness prevent the child from achieving adequate

carbohydrate intake? Was the child in the fed or fasting condition at the time of hypoglycemia? All

of this information can help to narrow the differential diagnosis [18]. (See "Etiology of hypoglycemia

in infants and children".)

●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".)

●Was there a history of ingestion, or opportunity for ingestion of alcohol, oral hypoglycemic

agents, aspirin, beta blockers, or quinine (all of which can cause hypoglycemia in children)?

Was there ingestion of foods containing toxins (eg, unripened ackee fruit, a staple in Jamaican

diets)? (see "Approach to the child with occult toxic exposure").

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 [19]. (See "Etiology of

hypoglycemia in infants and children", section on 'Disorders of fatty acid metabolism'.)

Physical examination — The examination may provide important clues to the diagnosis.

●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. (See "Causes of short stature".) 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 ACTH unresponsiveness [20,21].

●Midline facial defects (eg, a single central incisor, optic nerve hypoplasia, cleft lip or palate)

and microphallus or undescended testicles in boys may indicate hypopituitarism and/or growth

hormone deficiency. (See "Diagnosis of growth hormone deficiency in children".)

●Macrosomia, hepatosplenomegaly, and umbilical hernia may indicate Beckwith-Wiedemann

syndrome, whereas hepatomegaly and hypotonia may indicate a glycogen storage disease,

defects in gluconeogenesis, galactosemia, or hereditary fructose intolerance [20].

(See "Overview of inherited disorders of glucose and glycogen metabolism".)

●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".)

Elective fast — For most children with a history of hypoglycemia, a diagnostic fast under carefully

controlled conditions should be considered. Because of the potential risk of provoking an episode of

severe encephalopathy in a child with a defect in fatty acid orcarnitine metabolism, the plasma

carnitine concentration (and plasma concentrations of the acylcarnitines) should be proven to be

normal before initiating an elective fast. (See "Etiology of hypoglycemia in infants and children",

section on 'Disorders of fatty acid metabolism' and "Metabolic myopathies caused by disorders of

lipid and purine metabolism".)

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. For an older child, who by history, typically fasts overnight, a 24- to 30-hour

fast should be initiated after the evening meal. Children fasted according to such a protocol are at

risk to develop hypoglycemia 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, ketone bodies, lactate, alanine, and insulin

should be serially monitored and compared with normal standards. Plasma concentrations of

growth hormone and cortisol should be obtained at the time of hypoglycemia (although their

interpretation is not always clear).

Hypoglycemia without (or with only minimal) hepatomegaly and the absence of substantial

ketonuria or ketonemia should focus attention on abnormalities of insulin secretion, or disorders of

ketogenesis or fatty acid oxidation. Hyperinsulinism is best documented by obtaining a number of

plasma samples for simultaneous determination of the glucose and insulin levels at times of

hypoglycemia. The plasma insulin concentration after 24 hours of fasting in normal children,

depending upon the laboratory assay used, is usually <15pmol/L (2 mcU/mL) and rarely greater

than 35 pmol/L (5 mcU/mL), except in markedly obese children. Plasma insulin concentrations

greater than 35 pmol/L (5 mcU/mL) with concomitant blood glucose value less than 2.8 mM

(50 mg/dL), regardless of the period of fasting, are distinctly abnormal and are indications for further

studies to document potential hyperinsulinemia.

If the patient becomes hypoglycemic (plasma glucose <40 mg/dL [2.2 mM]), a glucagon challenge

test should be performed.

Glucagon challenge — In the case of a child with hypoglycemia of unknown cause,

a glucagon challenge test (or glucagon stimulation test) at the time of hypoglycemia can provide

very useful diagnostic information about glycogen stores. Following infusion (or IM injection) of

glucagon (0.03 mg per kg), the glycemic response should be measured at 10, 20, and 30 minutes.

A clear glycemic response (>20 to 30 mg/dL [1 to 2 mmol/L] during the first 10 to 20 minutes) in a

hypoglycemic child suggests inappropriate sequestration of hepatic glycogen caused by

hyperinsulinemia, which may be of endogenous or exogenous origin. Since the beta cell co-

secretes C-peptide in equimolar amounts with insulin, the plasma C-peptide concentrations reflect

endogenous insulin secretion. Therefore, a low C-peptide concentration in a patient with a positive

glycemic response to a glucagon challenge indicates that the source of the insulin is exogenous.

Plasma insulin levels may be either high or low in patients whose hypoglycemia is caused by covert

exogenous administration of insulin [22]. 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. Thus, if measured plasma insulin concentrations

are low (and the C-peptide level is also low), polyclonal insulin assays must be sought to detect

exogenous insulin. (See "Etiology of hypoglycemia in infants and children", section on

'Hyperinsulinism'.)

Additional testing — Today a variety of disorders are diagnosed with DNA analyses (eg, defects in

glycogen and free fatty acid [FFA] metabolism, hyperinsulinemia, defects in gluconeogenesis or

glycogenolysis). The clinical presentation and the critical blood samples serve to narrow the

diagnostic possibilities and guide further testing. 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 "Etiology 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 or families’ DNA. On occasion, 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".)

INTERPRETATION OF RESULTS — Whether the critical sample is obtained at the time of initial

presentation or after an elective fast, the results can help in determining the etiology of

hypoglycemia. Assuming that true hypoglycemia occurred, the first step in interpretation is to

determine whether the degree of ketosis is appropriate or inappropriate for the degree of

hypoglycemia. The degree of ketosis can only be determined by measurement of beta-

hydroxybutyrate in the serum.

Inappropriate ketosis — The presence of only mild or moderate ketosis (beta-hydroxybutyrate of

<2.5 mmol/L) at the time of hypoglycemia in a child indicates that FFAs are not being mobilized

appropriately or cannot be used for ketone body formation. These findings suggest hyperinsulinism

or fatty acid oxidation defects, respectively.

Hyperinsulinemia is the primary diagnostic consideration. A robust glycemic response (>20 to

30 mg/dL) to glucagon at the time of hypoglycemia would further strengthen this possibility.

Elevated plasma insulin concentration confirms hyperinsulinemia, but clear and unequivocal

elevation of the plasma insulin concentration is frequently not observed. (See 'Glucagon

challenge' above.)

In fatty acid oxidation defects, the plasma FFA concentrations may be very high (>1800 mM) in the

face of relatively modest ketonemia, and very low or undetectable plasma insulin concentrations.

However, some disorders of FFA oxidation (eg, hydroxyacyl-coenzyme A dehydrogenase, HADH,

previously known as short-chain L-3-hydroxyacly CoA dehydrogenase deficiency, SCHAD) can

cause disturbance of ADP/ATP ratios in the beta cell and have been associated with

hyperinsulinemia [23]. (See "Pathogenesis, clinical features, and diagnosis of persistent

hyperinsulinemic hypoglycemia of infancy".)

Children with glycogen storage disease type I (GSD I, glucose-6-phosphatase deficiency, von

Gierke disease) also have relative hypoketonemia. However, additional clinical features permit

differentiation of these patients from those with hyperinsulinemia or defects of fatty acid oxidation.

Clinical features of glucose-6-phosphatase deficiency include profound hepatomegaly (except in the

newborn), hypertriglyceridemia, and failure to generate a clear glycemic response, but dramatic

lactate response, following glucagon stimulation test. (See "Glucose-6-phosphatase deficiency

(glycogen storage disease I, von Gierke disease)".)

Appropriate ketosis — The presence of ketonemia (beta-hydroxybutyrate >2.5 mmol/L) indicates

that the child is able to mobilize FFAs and use them for ketone body formation. Diagnostic

considerations in these children include a normal fasting response, ketotic hypoglycemia, growth

hormone and/or cortisol deficiency [24], some disorders of fatty acid oxidation, and disorders of

amino and organic acids. The measurement of qualitative urine organic acids and the presence or

absence of hepatomegaly can help to distinguish among these possibilities. (See "Organic

acidemias".)

SUMMARY AND RECOMMENDATIONS — Hypoglycemia in infants and children requires prompt

recognition and treatment to prevent permanent neurologic sequelae.

Symptoms

●Symptoms of hypoglycemia include autonomic (adrenergic) symptoms, and neuroglycopenic

symptoms. The severity of symptoms may or may not predict the severity of the

hypoglycemia. Neuroglycopenic symptoms typically occur at lower blood 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 infants are nonspecific and include jitteriness,

irritability, feeding problems, lethargy, cyanosis, and tachypnea. Older children may have the

characteristic symptoms due to increased adrenergic activity (sweating, weakness,

tachycardia, tremor, and feelings of nervousness and/or hunger). (See 'Autonomic

response' above.)

●Symptoms of neuroglycopenia include lethargy, irritability, confusion, behavior that is out of

character, hypothermia, and, in extreme hypoglycemia, seizure and coma.

(See 'Neuroglycopenia' above.)

●When hypoglycemia is suspected, a rapid (bedside) blood glucose determination should be

performed. If it is low (≤40 mg/dL [2.2 mmol/L]), critical samples should be obtained and

subsequently treatment should be initiated. 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 greatly 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 1).

(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

0.25 g/kg of body weight. 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 intravenous 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".)

●Mild symptoms – If the hypoglycemia is mild and the patient is able to tolerate an oral

carbohydrate, oral glucose administration can be attempted. However, if the hypoglycemia

does not improve within 10 to 15 minutes, parenteral glucose must be administered.

Diagnosis

●The diagnostic evaluation depends upon the findings of the history, examination, and

preliminary laboratory results. A controlled elective fast may be necessary, but should be

performed only after disorders of fatty acid oxidation have been excluded. (See'Diagnostic

evaluation' above.)

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