Hypoglycemia in Infants and Children

Authors:

Robert A. Felter, MD, FAAP, CPE, FACPE, Professor of Clinical Pediatrics, Georgetown University School of Medicine; Assistant Director, Pediatric Inpatient and Emergency Service, Inova Loudoun Hospital, Leesburg, VA.

Ron D. Waldrop, MD, FACEP, CPE, FACPE, Assistant Professor of Clinical Pediatrics, Georgetown University School of Medicine; Director, Pediatric Inpatient and Emergency Services, Inova Loudoun Hospital, Leesburg, VA.

Peer Reviewer:

Ademola Adewale, MD, FAAEM, Assistant Professor of Emergency Medicine, Assistant Program Director, Florida Hospital Emergency Medicine Residency Program, Orlando, FL.

Hypoglycemia is the most common metabolic disorder in children. The causes for hypoglycemia are many and diverse.1 One of the most frequent causes of hypoglycemia is insulin/glucose imbalance in diabetic children; since the management of diabetes and its complications is a subject on its own, this topic will not be included in this issue. The authors focus on issues important to the emergency physician, with emphasis on the need to diagnose and treat hypoglycemia quickly. In the very young infant, failure to recognize and treat hypoglycemia may lead to permanent neurological sequelae. It is also important to remember that hypoglycemia is a symptom and not a diagnosis or a disease entity and always has an underlying etiology that must be ascertained. Sometimes the emergency department (ED) physician may determine the underlying cause, and sometimes the symptom must be treated without knowing the underlying cause. Because hypoglycemia can be rapidly and easily determined at the bedside, there is little reason not to obtain this important piece of clinical information. Recognition of hypoglycemia in the seriously ill child is so significant that it may be seen as important as a critical vital sign.

— The Editor

Hypoglycemia and Glucose Metabolism

Hypoglycemia is defined generally as a serum glucose < 50 mg/dL with neuroglycopenic symptoms, or < 40 mg/dL in the absence of symptoms. In the developing neonate, however, there is no agreed-upon absolute minimum, with the suggested range 30–45 mg/dL. Using < 30 mg/dL as a minimum in neonates, the estimated incidence of hypoglycemia varies from 0.4% to 11.4%.1

Glucose homeostasis in infants and children results from a complex interplay of glucose ingestion and storage as glycogen as well as synthesis of glucose from metabolic intermediates and the use of alternative metabolic fuels such as fats and amino acids, all under hormonal control and subject to exogenous factors such as stress and drugs. Beginning during gestation, glucose is transported across the placenta from the mother to meet the metabolic needs of the fetus. The developing brain utilizes glucose 20 times faster than any other organ and development is critically dependent on glucose availability. As a result, persistent hypoglycemia may result in permanent neurologic damage in the newborn. Near the end of gestation, however, the appearance of hepatic enzymes for glycogen synthesis and glycogenolysis as well as gluconeogenesis prepare the fetus and newborn to utilize and generate the high glucose levels needed in the perinatal and neonatal period. With the interruption of placental blood flow, a cascade of events enables glucose homeostasis in the newborn. Hormonal release results in mobilization of hepatic glycogen and adequate gluconeogenesis which must be coupled with ingestion of glucose, amino acid, and lipid-containing breast milk or formula. Due to the rapid utilization of glucose in the neonatal period, full-term, healthy infants have exuberant gluconeogenesis to compensate for rapid fluctuations. Such compensatory mechanisms are often less than adequate in the preterm infant, increasing the likelihood of hypoglycemia between feeds and during stress.

Glucose mobilization and storage is regulated by the hormones insulin, glucagon, catecholamines, cortisol, and growth hormone, as well as local cellular mediators. Insulin plays a primary role in serum glucose homeostasis beginning in the fetus. To summarize, when glucose levels increase, it is transported to the pancreas and results in insulin release, while decreasing serum glucose concentration results in decreased insulin concentration.

Decreased blood sugar also results in counterregulatory hormone release (cortisol, epinephrine, and glucagon), which stimulates gluconeogenesis and synthesis of glucose from precursors, utilization of fats and amino acids for energy sources, and the release of substrate through glycogenolysis in the liver. Metabolism of alternative fuels leads to ketotic waste products in the blood. In the absence of sufficient glycogen stores, as in the preterm infant, counter-regulatory hormones may not be able to maintain serum glucose in this way.

Symptoms

Table 1. Clinical Presentation of Hypoglycemia

Whipple's Triad

  • Altered mental status
  • Serum glucose less than 40 mg/dL
  • Relief with glucose administration

Adrenergic Symptoms

  • Tachypnea
  • Tachycardia
  • Vomiting
  • Weakness
  • Nervousness
  • Diaphoresis

Neuroglycopenic Symptoms

  • Headache
  • Irritability
  • Psychotic behavior
  • Lethargy
  • Altered mental status
  • Seizures
  • Coma

Neonatal Hypoglycemia

  • Hypotonia
  • Hypothermia
  • Feeding difficulties
  • Jitteriness
  • Hyperreflexia

Symptoms of hypoglycemia are multiple and varied. They may be very subtle, or part of a life-threatening presentation. Classic clinical manifestations of hypoglycemia include the triad of altered mental status, serum glucose < 40 mg/dL, and relief of symptoms with glucose administration. The clinical picture of a hypoglycemic patient may, however, be significantly clouded or exaggerated by age, recent diet, previous hypoglycemic episodes, current medications (including sedatives), and pre-existing illness. In general, hypoglycemic symptoms can be divided into two broad categories: adrenergic, which are those associated with activation of the autonomic nervous system; and neuroglycopenic, resulting from low brain glucose.2 (See Table 1.) Adrenergic symptoms usually occur early in the process and may be seen prior to arrival in the ED or be the reason for the ED visit. Typically, a rapid decline in the glucose level leads to these nonspecific symptoms that include tachycardia, tachypnea, vomiting, weakness, nervousness, and diaphoresis. All of these are common findings in infants and children in the ED.3

Neuroglycopenic symptoms occur late or with a more gradual decrease in the glucose level. Initially, symptoms include headache, irritability, psychotic behavior, poor feeding, lethargy, altered mental status, seizures, and coma. These symptoms may be obvious in the older child; however, newborns and infants may present with more subtle presentations, including hypotonia, hypothermia, feeding difficulties, jitteriness, and exaggerated reflexes.

If the hypoglycemic state is not corrected, transient or permanent cerebral dysfunction may occur. The mechanism of neurologic injury is incompletely understood and not solely due to an absence of substrate but may involve cytotoxic intermediate byproducts such as aspartic acid. The most common neurological damage caused by persistent hypoglycemia includes ischemia and hemorrhage in the posterior white matter areas, middle cerebral artery infarction, and basal ganglia/thalamic abnormalities.2 These injuries may lead to permanent cognitive and motor manifestations.

Hypoglycemia may be the underlying etiology for a diversity of critical illnesses such as acute respiratory failure, which can mimic pneumonia; sepsis; acute congestive heart failure; and status epilepticus.4-6 Altered level of consciousness in children is a clinical challenge, and of the many etiologies, hypoglycemia must be sought and treated immediately.7

It is essential to consider hypoglycemia as a potential cause of seizures in the newborn.8 Neonatal seizures may be very subtle. Clinical findings may include:

  • Ocular signs (tonic horizontal deviation of eyes or sustained eye opening with ocular fixation or cycled fluttering);
  • Oral-facial-lingual movements (chewing, tongue-thrusting, lip-smacking);
  • Limb movements (cycling, paddling, boxing jabs);
  • Autonomic phenomena (tachycardia or bradycardia);
  • Apnea.

Causes of Hypoglycemia

The myriad of causes for hypoglycemia can be best discussed along physiologic lines and are summarized in Tables 2 and 3.

Decreased production/availability of glucose. Small for gestational age (SGA) and premature infants. As soon as placental flow is interrupted, the newborn must depend on its own supply of glucose. Infants who are premature or SGA will have less stores of glucose, an immature glucose production system, or both.9 Add this to the fact that the brains of these infants are significantly larger per body mass than at any other time in life, and it is obvious why these children may be susceptible to hypoglycemia. Obtaining the history that the child presenting to the ED was premature or SGA will alert the ED physician to the possibility of hypoglycemia. These patients should be considered for bedside glucose testing immediately upon arrival. Correction of hypoglycemia should be a priority.

Malnutrition/fasting. Ketotic hypoglycemia is the most common cause of hypoglycemia in children from 1 year to 5 years of age.3 In normal fasted individuals, the maintenance of plasma glucose concentrations in the normal range is dependent upon:

1. A normal endocrine system;

2. Functionally intact hepatic glycogenolytic and gluconeogenic systems; and

3. An adequate supply of endogenous metabolic fuels.

Adults are capable of maintaining a normal glucose concentration even when totally deprived of calories for weeks or more. Children and neonates, in contrast, are unable to supply sufficient glucose to meet obligatory demands and exhibit progressive fall in plasma glucose concentration to hypoglycemic levels when fasted for even short periods of time (12 to 24 hours). For unknown reasons, children with ketotic hypoglycemia are less able to tolerate brief periods of fasting.

Table 2. Causes of Hypoglycemia (Decreased Production / Availability of Glucose)

Low glycogen stores

  • Small for gestational age, prematurity

Malnutrition / fasting

  • Ketotic hypoglycemia

Malabsorption / diarrhea

Hormone abnormalities

  • Growth hormone deficiency
  • Cortisol deficiency
  • Hypothyroidism

Inborn errors of metabolism

  • Carbohydrate

Glycogen storage diseases

Galactosemia

Hereditary fructose intolerance

  • Amino acid

Tyrosinemia

  • Fatty acid

Carnitine deficiency

Fatty acid transport deficiency

Beta oxidation deficiency

Increased use of insulin

  • Hyperinsulinism

Beta cell hyperplasia

Insulin dysregulation

  • Infant of diabetic mother
  • Beckwith-Weidemann Syndrome

Stressors associated with hypoglycemia

  • Specific infections

Shigella

Malaria

Meningococcus

  • Sepsis syndrome
  • Miscellaneous

Congenital heart disease Shock

Burns Tumors

Reye Syndrome Surgery

Hepatitis Alpha-1-antitrypsin deficiency

Pharmacologic causes of hypoglycemia

Methanol, ethanol Salicylates

Beta blockers Oral hypoglycemics

Pentamidine Insulin therapy

Adapted from: Kwon K, Tsai V. Metabolic emergencies. Emerg Med Clin North Am 2007;4:1041-1060.

Classically, this disorder presents between 18 months and 5 years of age, coinciding with the time children usually sleep through the night. Fortunately, there is usually spontaneous resolution by 8–9 years of age due to a relative decrease in glucose requirement per body mass, maturity of the autonomic nervous system, and maturation of the gluconeogenic pathways. Although the cause of the hypoglycemia remains undefined, it is often seen in children who are small for their age. Increased glucose requirements on a per kilogram body weight basis in the young child, when compared with adults, may result in a modest compromise in the supply of endogenous gluconeogenic substrates (e.g., amino acid from decreased muscle mass, independent of a specific enzyme or hormone defect), predisposing to the development of hypoglycemia and ketosis.

Ketotic hypoglycemia may constitute one end of a spectrum representing the normal distribution pattern of tolerance to fasting.8,10 As the child has longer sleep time and longer time between feedings, this problem may become evident and result in the clinical presentation of a previously healthy child who is brought to the ED in the morning for vomiting, weakness, headache, or jitteriness. Evaluation will reveal hypoglycemia, ketosis, and an elevated anion gap. Children normally develop ketosis faster than adults, and ketosis is associated with a drop in plasma concentrations of glucose and insulin. This tendency of children is accentuated in children with ketotic hypoglycemia. In children with a typical presentation of ketotic hypoglycemia, it is useful to obtain additional blood testing to exclude other causes and definitively make the diagnosis. Children with ketotic hypoglycemia have normal venous lactate and pyruvate concentrations, but have hypoalaninemia prior to and during fasting or ketogenic diet challenge. The low plasma insulin and high free-fatty acid and ketone body concentration virtually exclude hyperinsulinemia as the underlying cause.8 Children with ketogenic hypoglycemia are more prone to hypoglycemic episodes with intercurrent illness, especially if there is prolonged fasting. Parents are typically instructed to maintain frequent feedings of a high-protein, high-carbohydrate diet, and may check the child's urine for ketones.

Malabsorption/diarrhea. Hypoglycemia is a recognized complication of severe malnutrition and diarrhea.11 Although morbidity and mortality from diarrhea is low in the United States, it remains a significant problem in less-developed countries. Hypoglycemia has been shown to be a potentially fatal complication of infectious diarrhea in both well nourished and poorly nourished children.12 A recent study has shown that hypoglycemia is not just a problem in developing countries but must be considered even in patients in the United States with diarrhea.13 Approximately 10% of the children in this series with diarrhea had hypoglycemia. Although none of the children had significant clinical symptoms such as altered mental status or hypotension, it was noted that because of the signs and symptoms of dehydration, the signs and symptoms of hypoglycemia were masked. Also of clinical importance, children with hypoglycemia generally had a longer clinical course of vomiting and may remain symptomatic even after the vomiting has subsided. These children may remain in a fasting state, refusing feedings. Correction of the hypoglycemia often is associated with the child regaining the interest in oral feedings.

Hormone abnormalities. Hormone abnormalities that may cause hypoglycemia include growth hormone deficiency, cortisol deficiency, and hypothyroidism. The mechanism of hypoglycemia in these patients is incompletely understood but is characterized by blunted response to glucagon induced glycogenolysis as well as gluconeogenesis stimulated by hypoglycemia.

Inborn errors of metabolism. Inborn errors of metabolism associated with a specific enzyme deficiency are rare disorders but frequently associated with hypoglycemia. Disorders of carbohydrate metabolism leading to hypoglycemia involve deficiencies in hepatic enzymes used in the metabolism of glycogen, galactose, and fructose. The time course of hypoglycemia onset after the last meal may give a clue to the enzyme deficiency. For example, patients with galactosemia or heredity fructose intolerance may become hypoglycemic several hours after the ingestion of galactose or fructose. Galactosemia is the most common disorder of carbohydrate metabolism and is identified through neonatal screening programs. Galactosemia results in the inability to utilize lactose found in human breast milk and cow's-milk-based formulas as an energy source and results in hypoglycemia. Conversely, patients with deficiencies of glycogenolysis or gluconeogenesis may become symptomatic between two hours and 20 hours after the last meal. In addition, glycogenolysis-deficient patients may have mild to moderate ketosis. Finally, infants and children who have disorders of gluconeogenesis develop ketotic hypoglycemia and lactic acidosis after fasting long enough to deplete glycogen stores and do not respond to glucagon administration.

Disorders of amino acid metabolism causing hypoglycemia result in organic acidemias with an anion gap and typically become clinically apparent during the neonatal period after a short well-appearing period. These children may be mistaken for having sepsis and may eventually develop failure to thrive and developmental delay. The hypoglycemia associated with amino acid disorders may be due to associated liver disease (tyrosemia) or carnitine deficiency. These disorders become most evident during stress episodes with metabolic decompensation including illness, trauma, or surgery.

Disorders of fatty acid metabolism and ketone body formation are rare causes of hypoglycemia. The most common disorders are carnitine deficiency, fatty acid transportation defects, and beta oxidation enzyme defects. During fasting or periods of stress, free fatty acids are mobilized from adipose tissue and utilized for energy by various organs. Free fatty acids undergo beta oxidation in the liver to produce ketone bodies such as beta-hydroxybutyric acid and acetoacetic acid. The stimulus for this process is decreased serum glucose and insulin suppression. The cause of hypoglycemia in these disorders has been postulated to involve decreased hepatic glucose production or the rapid utilization of glucose in the absence of ketone body availability. Classically, these disorders are not ketotic. Symptoms of these disorders include profound hypoglycemia during prolonged fasting or exercise or a low-carbohydrate, high-fat diet. Clinically, these patients also have persisting CNS disturbance and hypotonia in the face of corrected blood glucose.

Increased use of glucose. Hyper-insulinism. Hyperinsulinism (HI) is the most common cause of both transient and persistent hypoglycemia in infants and is usually due to beta cell hyperplasia or nesidioblastosis.14 HI was first called "idiopathic hypoglycemia of infancy" and has had several other names. It is caused by dysregulated secretion of insulin. It consists of a group of clinically, genetically, and morphologically heterogeneous disorders. It occurs in 1 of 30,000 to 50,000 live births. It usually presents during the first few days of life but may occur later in infancy and childhood.14 Premature infants with the disorder may present with severe hypoglycemia that is difficult to control. For unclear reasons, some of these children will have hypertrophic cardiomyopathy.14 Newborns presenting with persistent and severe hypoglycemia, often with seizures, lethargy, and apnea, should have extra blood drawn at the time of treatment to evaluate for the critical diagnostic markers of disease entities. The ED physician may not be able to make the definitive diagnosis, and treatment should not be delayed, but obtaining critical blood samples during the acute phase is very useful in assisting with a timely, definitive diagnosis. Treatment is giving enough glucose to maintain euglycemia.

Infant of diabetic mother. While in utero, the infant of a diabetic mother is exposed to frequent episodes of hyperglycemia. Glucose crosses the placenta, but insulin does not. This stimulates the fetus to produce insulin. When the maternal blood supply and glucose is stopped at delivery, these infants, in addition to facing the regular problems of maintaining glucose levels, are faced with high levels of insulin. The persistence of elevated levels of insulin can cause prolonged hypoglycemia.15

Beckwith-Weidemann Syndrome. Patients with Beckwith-Weidemann syndrome have macrosomia, macroglossia, hemi hypertrophy, transverse creases of the ear lobes, hypoglycemia, and predisposition to childhood tumors. Up to 50% of the patients will have hypoglycemia that can be transient and mild to persistent and severe. The cause is unclear and spontaneous remission often occurs.13 Otherwise, they may be controlled by medical therapy or partial pancreatectomy.

Stressors. Children, especially toddlers and infants, have limited glycogen stores and rapidly develop hypoglycemia during periods of stress. Severe hypoglycemia with subsequent central nervous system damage may occur if hypoglycemia is not identified and treated.

Specific infections. Although not well studied, there are reports of the association of hypoglycemia with severe infection and sepsis. The association of hypoglycemia in patients with malaria and shigellosis was reported early on, but the association with other infections was not reported until more recently, when Halamek and colleagues described the presence of hypoglycemia in three children with severe meningococcemia and adrenal hemorrhage.16 Other authors have emphasized the importance of glucose testing in septic patients.17 A very recent study showed a prevalence of hypoglycemia in 8.6% of patients with bacteremic pneumococcal infection.18 A higher morbidity has also been substantiated in those patients presenting with hypoglycemia. The mechanism of hypoglycemia and severe sepsis is not well understood. In humans, endotoxin plays a crucial role in the pathogenesis of gram-negative shock, which leads to impairment of glucose homeostasis and lethal septic shock. A recently published study showed a greater frequency of hypoglycemia in previously malnourished children, hypothermic patients, and those with Shigella as a cause of their diarrhea.11 Also, hypoglycemia was more common in more severe infections. Morbidity was increased in patients with bacteremia and hypoglycemia. In their analysis, bacteremic children with clinical sepsis were four times more likely to be hypoglycemic. The authors recommended that a rapid bedside glucose test should be considered as an inexpensive way to help in management decisions for ill children with diarrheal illness and bacteremia.

Certain more unusual infections have been associated with hypoglycemia. Although not common in the United States, malaria is the most important parasitic disease in the world. It kills more people annually than any other disease except tuberculosis and HIV/AIDS. Annually, there are more than 515 million clinical cases of malaria worldwide. Many pediatric cases present with impaired consciousness, repeated seizures, severe anemia, respiratory distress, or shock. Deaths are particularly common with children who present with impaired consciousness, shock, or hypoglycemia.19 While most cases will occur in endemic areas, patients may return to the United States after a visit to one of these areas. Children with severe malaria present with hypoglycemia in 10% of cases. In patients with cerebral malaria, hypoglycemia is more common and occurs in up to 30% of cases.19 The clinical presentation of cerebral malaria may be mild with a one- to four-day history of fever, listlessness, anorexia, irritability, vomiting, and cough before seizures and coma appear.20 As with several other illnesses presenting with hypoglycemia, the treatment of severe malaria requires attention to multiple other problems. Hypoglycemia is associated with increased mortality and brain injury.

Sepsis. Sepsis is an uncommon but very serious condition that can occur at any time from the newborn period to adulthood. The incidence of sepsis is estimated to be 0.56/1,000 children. The highest incidence is in infancy at 5.6/1,000 children. The overall mortality is estimated at over 10%. The systemic inflammatory response syndrome (SIRS) for children requires presentation with hypo- or hyperthermia or elevated white blood cell count in the presence of one of the following findings: abnormal temperature, leukocytosis, tachypnea, or tachycardia. Sepsis is defined as proven or suspected infection with the diagnosis of SIRS. Patients most at risk include those not immunized and those with any form of immunocompromise. The presentation of sepsis varies by age and underlying etiology. The clinical presentation of sepsis is especially variable in the newborn period. The realities of current medical practice make it very clear that the treatment of sepsis needs to be aggressively initiated as soon as suspected. Hypoglycemia must be anticipated in the septicemic child. Children may present with sepsis in community hospitals and subsequently require transfer, or a bed in the intensive care unit (ICU) may be delayed by hours or longer. Consequently, ED physicians may need to provide ongoing critical care while awaiting transfer to an inpatient service. ED physicians must aggressively manage early sepsis and recognize concomitant issues such as hypoglycemia. Early, aggressive treatment may result in a significant decrease in mortality and morbidity.

Regardless of the age or the cause, immediate attention to many details is required to optimize the treatment of patients with sepsis. Early use of "goal-directed therapy" (EGDT) is recommended to organize an approach to sepsis. EGDT was formulated in 2001 at Henry Ford Hospital, and much like the algorithms in PALS, ACLS, and ATLS, the standardized approach to sepsis is useful. Of the many variables included in the management of sepsis are early antibiotics, corticosteroids, glucose control, and consideration of recombinant human activated protein C lung protective strategies. Much as the use of pulse oximetry in ED patients as a vital sign has increased the diagnosis of hypoxia, blood glucose levels obtained routinely on all sick children will alert the physician to elevated or low glucose levels. A recently published study used the monitoring of glucose levels as one of the parameters to evaluate the success of treatment. The goal in this study was to keep the glucose level above the lower limit of normal but below 150 mg/dL.21 Hyperglycemia is considered to be an early sign of sepsis, and management with insulin has been recommended.21 With aggressive insulin management of hyperglycemia, hypoglycemia can result.22 Hypoglycemia may also be a late sign of sepsis. Whether the glucose level is elevated or low, the management and monitoring of the glucose level aids in the management of sepsis and the response to interventions.

Miscellaneous. Children with heart disease are predisposed to hypoglycemia, thought to be due to under-perfusion of the liver. Similarly, numerous disease states increase the body glucose requirement (shock, burns, and tumors) or affect the liver's ability to produce glucose (Reye's syndrome, hepatitis, alpha-1-antitrypsin deficiency). Finally, surgery may result in hypoglycemia due to preoperative fasting without carbohydrate loading, intra-operative stress, and intra-operative medications.

Table 3. Etiology of Hypoglycemia in Neonates

Transient neonatal hypoglycemia

  • Day 1 of life: Developmental immaturity of fasting adaptation (mechanism: impaired ketogenesis and gluconeogenesis)
  • First two days of life: Transient hypoglycemia due to maternal factors

○ Maternal diabetes (mechanism: hyperinsulinism)

○ Intravenous glucose administration during labor and delivery (mechanism: hyperinsulinism)

○ Medications: oral hypoglycemics, terbutaline, propranolol (mechanism: hyperinsulinism)

Prolonged neonatal hypoglycemia

  • Perinatal stress-induced hyperinsulinism (low birth weight, birth asphyxia, maternal toxemia or pre eclampsia, prematurity)
  • Beckwith-Weidemann syndrome
  • Hypopituitarism

Permanent neonatal hypoglycemia (caused by congenital endocrine or metabolic disorders)

  • Congenital hyperinsulinism

○ ATP-sensitive potassium channel hyperinsulinism

○ Glutamate dehydrogenase hyperinsulinism

○ Glucokinase hyperinsulinism

○ Short-chain 3-hydroxyacyl-CoA dehydrogenase hyperinsulinism

○ Congenital disorders of glycosylation

  • Counter regulatory hormone deficiency

○ Hypopituitarism

○ Adrenal insufficiency

  • Gluconeogenesis or glycogenolysis enzyme defects
  • Fatty acid oxidation disorders

Adapted from Jan I, et al. Hypoglycemia associated with bacteremic pneumococcal infections. Int J Infect Dis 2009:13:570-576

Acute metabolic encephalopathy is a relatively common problem and may be the initial presentation or a complication of a metabolic disorder. A detailed history, examination and investigations performed during the acute illness (blood sugar, blood gases, plasma ammonia, blood lactate, plasma ketones, plasma amino acids, liver function tests, and urinary organic acids) should identify those patients in whom a metabolic disorder is likely. The differential diagnosis of acute metabolic encephalopathy can be divided into three broad categories: endocrine, metabolic, and hepatic.23 (See Table 4.)

Reye's syndrome was first described in 1963. An association with aspirin use was determined and since aspirin use has been discouraged the prevalence of Reye's syndrome has reduced greatly. Despite this, there are still a few cases of Reye's syndrome.24,25 It is an acute encephalopathy and hepatopathy. There is often an antecedent viral infection, frequently with influenza and varicella. With the recent pandemic of H1N1 influenza, the ED physician must be watchful for any cases of Reye's syndrome. To make the diagnosis of Reye's syndrome, it is necessary to exclude metabolic disorders that may also present with similar symptoms.25 The syndrome had a 42% mortality and another 11% residual neurologic damage. One of the most challenging aspects in the management of the child with Reye's syndrome is maintenance of normal glucose levels. Hypoglycemia is profound and persistent, often requiring a continuous infusion of 10% dextrose in addition to the other supportive care.

A recent discussion of three cases of infant botulism pointed out the difficulty in making this diagnosis. One patient presented with severe acidosis and hypoglycemia, suggesting an underlying metabolic disorder.26

Exogenous Pharmacologic Causes of Hypoglycemia

Ingestions associated with hypoglycemia include methanol, salicylates, beta blockers, oral hypoglycemics, and pentamidine.

Ethanol is found in alcoholic beverages and many other products (e.g., mouthwash, cold preparations) to which a child may have access. Ethanol ingestion results in hypoglycemia by inhibiting gluconeogenesis and decreasing uptake of gluconeogenesis substrates by the liver. The resulting hypoglycemia may be severe leading to seizures and death. The younger the child, the more at risk for hypoglycemia. The classic triad of acute ethanol overdose in children is hypothermia, hypoglycemia, and coma. These symptoms may occur with ethanol levels of 50–100 mg/dL. Development of hypoglycemia does not seem to be directly related to the seriousness of the ingestion, and may be accompanied by metabolic acidosis. Occasionally, these patients may present with seizures.28 Ethanol ingestion should be suspected in the presence of metabolic acidosis with an anion gap, elevated lactate, and blunted response to glucagon.

Table 4. Causes of Hypoglycemia and Acute Encephalopathy

Endocrine

  • Hypopituitary coma

Metabolic

  • Organic acidemias

- Maple syrup urine disease

- Methylmalonic acidemia

- Acetoacetyl-CoA thiolase

deficiency

- Propionic and isovaleric

acidemias

  • Fat oxidation defects

- Medium, long-chain, and

multiple acyl-CoA

dehydrogenase

deficiencies

- 3-Hydroxy-3-methylglutaryl-

CoA lyase deficiency

- Others not fully

characterized

Drugs and toxins

  • Alcohol
  • Oral hypoglycemic agents
  • Salicylates

Hepatic

  • Fulminant liver failure
  • Reye's syndrome

Adapted from: Surtees R, et al. Acute metabolic encephalopathy: A review of causes, mechanisms and treatment. J Inher Metab Dis 1989:12:42-54

Salicylates. Similarly, salicylates should be considered in the patient with hypoglycemia, metabolic acidosis, increased anion gap, delirium, and hyperventilation. Although there has been a great reduction in the number of salicylate poisonings, a timely diagnosis requires consideration of the disease process. Nausea, vomiting, fever, tinnitus, and hyperventilation occur with significant ingestions. Most patients will have respiratory alkalosis and metabolic acidosis. Salicylate affects both central and peripheral glucose homeostasis. Animal studies have shown that toxic doses of salicylate produce a profound decrease in brain glucose concentration despite normal serum glucose levels.29

Methyl salicylate ingestion can result in serious toxicity in the child. It can be found in numerous products, but the most potent form is oil of wintergreen, which is 98% methyl salicylate. Methyl salicylate can be found in some Asian herbal remedies. Deaths have been reported with as little as a teaspoon ingestion.30

Beta blockers cause hypoglycemia by blunting the typical autonomic response to hypoglycemia, including glycogenolysis, gluconeogenesis, inhibition of glucose uptake by tissues, and inhibition of insulin receptor secretion. Although there has been an increase in the number of beta blocker ingestions over the last few years, there have been no fatalities in toddlers.17 Still, there is reason to be cautious with the ingestion of a large amount of lipophilic beta blocker (propanolol) and consider monitoring of blood glucose levels. Earlier concerns that one or two tablets may be fatal have not been substantiated.

Sulfonylureas are a class of hypoglycemic drugs used in the management of adult-onset diabetes. Hypoglycemia is seen quickly after ingestion and the duration is usually less than 24 hours. For sulfonylureas, the onset can be delayed and the drug effects can be greatly prolonged. Cases have been reported in which symptoms have persisted for 3-4 days.31 Even a single dose of a sulfonylurea in a child can result in life-threatening hypoglycemia.

Other. Pentamidine is an antimicrobial agent that is used in the treatment and prevention of Pneumocystis pneumonia, usually in patients with HIV. It is also used as a prophylactic antibiotic for children undergoing chemotherapy for leukemia. The drug is cytotoxic to the pancreatic islet cells, resulting in inappropriately high levels of insulin. Accidental ingestion can cause hypoglycemia.

A frequent cause of hypoglycemia is a relative or absolute excess of insulin in the type 1 diabetic child.

Children with diabetes mellitus type 1 may develop hypoglycemia due to error in administration or preparation of insulin, failure to ingest proper quantities of carbohydrates, and late-evening exercise — which may be impossible to predict in the young child. Type I diabetic children are at high risk of hypoglycemia due to the possibility of undetected nocturnal hypoglycemia and the blunted gluconeogenesis response to glucagon and epinephrine in recurrent hypoglycemics. Typically, these disorders are nonketotic. As diabetes is a complete subject unto itself, it will not be discussed further. However, one must always be aware that diabetics can suffer from some of the other disease conditions that cause hypoglycemia, and these causes should also be considered.

Hypoglycemia in the Newborn

Hypoglycemia is one of the most commonly encountered metabolic problems in the newborn period. At no other time in life is management of hypoglycemia more important than in the newborn period. Hypoglycemia can cause neonatal encephalopathy, resulting in permanent brain damage. Several of the disorders may be present at birth or in the perinatal period. Typically these are diagnosed in the newborn nursery, but with early discharges and home deliveries, these patients may also be seen in the ED. Hyperinsulinemic hypoglycemia (HH) is a major cause of recurrent and persistent hypoglycemia.4 Delay in initial diagnosis and subsequent treatment may lead to severe brain injury and mental retardation. Congenital forms may be unresponsive to medical therapy. HH may be secondary to other risk factors, including intrauterine growth retardation, infants with perinatal asphyxia, infants of diabetic mothers (both gestational and insulin-dependent), and in some infants with Beckwith-Weidemann syndrome. In most of these conditions, HH is transitory and resolves spontaneously.4 Thus with appropriate management of their hypoglycemia these patients can have normal growth and development. Hypoglycemia should be suspected when any newborn with any potential problem comes to the ED.

Diagnosis of Hypoglycemia

As previously mentioned, there is no absolute acceptance of what blood glucose level defines hypoglycemia. Regardless, the rapid identification and treatment of hypoglycemia is required for management of the seriously ill child. Even the time taken to receive a laboratory value is time wasted. Thus, it is common practice to obtain bedside or point of care glucose determination. This is often done with AccuChek Inform (Roche Diagnostics, Mannheim, Germany). AccuChek measurements are done on whole blood, and laboratory values are done on serum. This in itself leads to the need for a correction factor. Whole blood glucose is measured lower than serum and should be multiplied by 1.11 to estimate serum values. The accuracy of AccuChek has been shown in various studies.9 Use in the ICU has been questioned because of the need for very tight glucose control in septic patients, but for the ED, it is accurate.32

At the time of ED presentation during the acute hypoglycemic episode, it is beneficial to obtain critical blood samples to determine a definitive etiology of the episode. Since the blood is drawn during the period of acute hypoglycemia, the critical sample reflects the physiologic response—or lack of response—of the child. (See Figure 1.) Critical blood sampling tubes include: red top tube for insulin, C-peptide, cortisol, and carnitine; grey top tube for beta hydroxybutyrate, free fatty acids, lactate; green top tube for growth hormone, ammonia, aminoacids; lavender top tube for glucagon; separate containers for quantitative urine sampling of organic acids, aminoacids, and reducing substances.

Figure 1. Approach to Hypoglycemia

High Lactate

  • Gluconeogenesis enzyme defect
  • Glucose 6-phosphatase deficiency
  • Fructose 1,6 diphosphatase deficiency
  • Phosphoenolpyruvate carboxykinase deficiency
  • Pyruvate carboxylase deficiency

Metabolic Acidosis

Hypoglycemia

High Ketones

  • Hypopituitarism
  • Glycogen storage disease 0, 1, 3, 6, 9
  • Ketotic hypoglycemia

Low Ketones + High Free-fatty Acids

  • Fatty acid oxidation defects
  • Carnitine deficiency

No Metabolic Acidosis

Low Ketones + Low Free-fatty Acids

  • Hyperinsulinism

Treatment

Regardless of the underlying cause of hypoglycemia, the serum glucose must be restored to normal range. This is especially true in the symptomatic child and the very young child. Ideally, an IV has been established and 0.5–1.0 grams per kilogram (2–4 mL D25W or 5–10 mL per kilogram D10W). This can be given by an intraosseous line, as well. The more concentrated dextrose solutions must be used with caution, because infiltration can cause significant tissue destruction. In the child with a small-gauge needle, D10W may be used. Monitoring of the response to the dextrose infusion should be done with bedside testing. As hypoglycemia is rarely an isolated problem, the underlying cause must be determined and additional therapies instituted as indicated. Some disorders may require additional dextrose or even continuous dextrose infusion.

Summary

The skills of the ED physician are tested when presented with a severely ill child. Treatment and stabilization are the first priority, but thought must also be given to the reason for the critical presentation. Sometimes the cause is easy to determine, as with trauma. Many times the presentation is very confusing. It is then that the ED physician must use a systematic approach to the patient's management. We are all familiar with the ABCs of resuscitation. This remains the best initial approach to these patients. The patient's vital signs are also extremely important and must be addressed as soon as any abnormality is identified. Hypoglycemia by itself can present as a child in dire distress. It can also be a symptom in association with many other abnormalities, all of which must be addressed. The ABCs are designed to deal with the most serious problems the patient has in order of severity, and the likelihood that if untreated, the patient may die or have a poor outcome. Because hypoglycemia is very prevalent in seriously ill children and because if untreated can lead to death or neurological impairment, in critical patients, blood glucose levels should be considered as important as the vital signs.

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