Hypoglycemia in the Newborn and Infant

Introduction

One of the most important metabolic events to mark the transition from fetal to neonatal life is the adaptation from an environment that has a readily available and continuous source of glucose—transplacental passage of maternal blood—to an environment in which glucose is provided in a limited and intermittent supply via feeding. At birth, after separation from the placenta, the complex mechanisms involved in the maintenance of plasma glucose concentration must be activated and coordinated to avoid hypoglycemia and resultant damage to the central nervous system. A newborn or infant with hypoglycemia presents an urgent diagnostic and therapeutic challenge. The clinical features must be rapidly assessed and a plan of action developed based on the infant’s age, maternal and parturition history, severity and persistence of hypoglycemia, and all other relevant clinical clues for definitive diagnosis and treatment. In this chapter, we review the normal physiology of glucose metabolism and the pathophysiology of the most common disorders resulting in hypoglycemia in the neonate (first 4 weeks of life) and infant (1 month to 1 year of life) with an emphasis on the approach to the diagnosis and management of these pathologies.

Principles of glucose metabolism

A systematic approach to hypoglycemia in the newborn, infant, or child requires an appreciation of the central role of glucose in the body’s fuel economy. Glucose metabolism accounts for approximately half of basal daily energy needs and is the principal metabolic fuel of the human brain. Glucose can be stored for energy in the form of glycogen and fat, although only glucose stored in liver glycogen is available for release into the circulation, and fatty acids cannot be converted back into glucose; glucose carbon can be used for synthesis of protein and for structural components (such as cell membranes). The aerobic oxidation of glucose yields high energy by producing 36 mols of adenosine triphosphate (ATP) for each mol of glucose. Although glucose is the predominant metabolic fuel for both the brain and the body in the period immediately after a meal, during longer term fasting, glucose utilization must be restricted to glycolytic tissues, such as red blood cells and the brain and the rest of the body must rely on oxidation of fatty acids released from adipose tissue triglyceride stores.

All glucose extracted by the brain is oxidized, and thus cerebral glucose utilization parallels cerebral oxygen uptake. In 5-week-old infants, cerebral glucose utilization already represents 71% to 93% of the adult level in most brain regions (ranging from 13 to 25 μmol/100 g/min). Adult levels of cerebral glucose utilization (19–33 μmol/100 g/min) are reached by 2 years of age, and they continue to increase until 3 to 4 years of age—when they reach values ranging from 49 to 65 μmol/100 g/min, which are maintained to approximately 9 years of age and then gradually decline to adult levels by the end of the second decade.

Glucose uptake by the brain occurs by means of a carrier-mediated facilitated diffusion process that is glucose concentration dependent, as well as energy, Na ⁺ , and insulin independent. This process is mediated by facilitative glucose transporter (GLUT) proteins. Several members of the GLUT family have been detected in the brain. GLUT1 is located at the blood-brain barrier, and although some neurons express GLUT2 and GLUT4, the majority use GLUT3 as their primary transporter. The main isoform present in insulin-responsive tissues is GLUT4.

Of major importance is that glucose entry into brain cells and its subsequent metabolism are not dependent on insulin but rather are dependent on circulating arterial plasma glucose concentration. Therefore a decrease in arterial glucose concentration or a defect in the glucose transport mechanism of the brain will result in intracerebral glucopenia and low cerebrospinal fluid glucose concentration (hypoglycorrhachia)—with attendant symptoms and signs of cerebral glucopenia as subsequently described. For example, genetic deficiency of the GLUT1 glucose transporter causes hypoglycorrhachia, seizures, and severe developmental delay.

In normal adult humans and in the normal newborn infant after the first few days of life, plasma glucose concentrations range from 3.9 to 5.6 mmol/L (70–100 mg/dL). In experiments using rats, brain glucose consumption outstrips glucose transport, leading to a brain glucose concentration near zero at a plasma glucose concentration of 2 mmol/L (36 mg/dL). To prevent circulating arterial plasma glucose from decreasing precipitously under normal physiologic conditions, and therefore to prevent impairment of vital function that depends on cerebral glucose metabolism, an elaborate defense mechanism has evolved. This defense against hypoglycemia is integrated by the autonomic nervous system and by hormones that act to enhance glucose production through enzymatic modulation of glycogenolysis and gluconeogenesis, while simultaneously limiting peripheral glucose use. Similar defense mechanisms against hypoglycemia function in the normal full term human newborn after separation from the placenta. Thus hypoglycemia is the result of a defect in one of these systems that maintain a normal range of plasma glucose concentration, preventing its fall to less than 3.9 mmol/L (70 mg/dL) during fasting and its rise to more than 7.8 mmol/L (140 mg/dL) during feeding.

These mechanisms, most importantly, the regulation of β-cell insulin secretion, are not fully mature at birth, when there is an abrupt transition from intrauterine life to extrauterine life, and mean plasma glucose concentrations transiently fall by 25% before recovering by 2 days of life to normal adult values. Neonates who are born with various risk factors, including birth asphyxia, intrauterine growth restriction (IUGR), maternal toxemia, and prematurity may be particularly vulnerable to hypoglycemia, often with consequences to subsequent cerebral development or function that can be prevented by early detection and treatment.

Physiology of perinatal glucose homeostasis

Hormonal and metabolic systems of fasting adaptation

Hypoglycemia in neonates, infants, and children is essentially always a problem with fasting adaptation. Postprandial hypoglycemia is exceedingly rare and is limited to a few unusual situations, such as postprandial hypoglycemia after Nissen fundoplication, hereditary fructose intolerance, or the protein-induced hypoglycemia seen in some forms of congenital hyperinsulinism. Therefore a consideration of the four major hormonal and metabolic pathways that maintain fuel homeostasis during fasting provides an important framework for understanding the causes, diagnosis, and treatment of different forms of hypoglycemia.

Three metabolic systems regulate the physiologic response to fasting: (1) hepatic glycogenolysis, (2) hepatic gluconeogenesis, and (3) hepatic ketogenesis. The key enzymatic steps in these pathways are shown in Fig. 7.1 . These metabolic systems are coordinated by (4) the endocrine system, consisting of suppression of insulin (the most important endocrine response to fasting, as insulin suppresses all three metabolic systems), and the secretion of the counterregulatory hormones: glucagon, epinephrine (a marker of sympathetic nervous system activation), cortisol, and growth hormone (GH). Table 7.1 summarizes the counterbalancing effects of these counterregulatory hormones on the three key metabolic systems. There is a hierarchic redundancy in the interaction of the counterregulatory hormones that provides a margin of safety (“fail-safe mechanism”) if only one counterregulatory hormone is impaired. Epinephrine (sympathetic activation) and glucagon are quick acting, each signaling its effects by stimulation of cyclic adenosine monophosphate (AMP). Deficiencies of glucagon, as occurs in long-standing type 1 diabetes mellitus, can be largely compensated for by an intact autonomic nervous system with appropriate α- and β-adrenergic, and cholinergic effects. Conversely, autonomic failure can be largely compensated for if glucagon secretion remains intact.

Hepatic glycogenolysis is sufficient to meet energy requirements for only a few hours. Beyond that time, glucose must be produced by hepatic gluconeogenesis from precursors, such as amino acids, glycerol, and lactate recycled from glycolysis. The major source of gluconeogenic precursors is amino acids from muscle protein. Although the pool of muscle protein is large, it is required for body function and thus in contrast to stores of glycogen in liver and fat in adipose tissue, there are no “reserves” of protein to draw on during fasting. To spare the use of essential protein during extended fasting, glucose consumption must be suppressed by switching on the mobilization of fatty acids from adipose triglyceride stores for oxidation in muscle and other tissues and of glycerol as substrate for hepatic gluconeogenesis. Fatty acids are also oxidized in liver to produce the ketone bodies, β-hydroxybutyrate and acetoacetate, which can be used by the brain as an alternative substrate to further spare glucose consumption.

The essential function of fasting adaptation is to maintain fuel supply to the brain. Glucose homeostasis is very limited in neonates and infants compared with adults, in part because of their smaller reserves of liver glycogen and muscle protein, but chiefly because of their relatively larger rates of glucose consumption because of their larger brain-to-body-mass ratio. For example, the fuel stores of a 10-kg infant are only 15% of those of an adult. However, the caloric needs are 60% of those of an adult and glucose utilization rates per kilogram body weight are 2- to 3-fold greater. As shown in Fig. 7.2 , early in fasting after absorption of a meal is completed, glucose is the primary brain fuel and accounts for over 90% of total body oxygen consumption. Glucose is initially provided chiefly from hepatic glycogenolysis, supplemented by hepatic gluconeogenesis using amino acids released by muscle protein turnover and lactate from glycolytic tissues, such as red blood cells. After 8 to 12 hours in normal infants (24–36 hours in adults), glucose production declines, because the supply of liver glycogen is depleted and the rate of gluconeogenesis from amino acids remains constant. At this time, a transition to fat as the major fuel for the body begins, with accelerated adipose tissue lipolysis and increased fatty acid oxidation in muscle and ketogenesis in liver. Lipolysis also generates glycerol, which becomes an important gluconeogenic substrate once fasting adaptation is fully active. The brain cannot directly use fatty acids, because they do not pass the blood-brain barrier. However, the brain can substitute glucose consumption with the ketones acetoacetate and β-hydroxybutyrate, which are released by the liver as the end product of hepatic fatty acid oxidation. In late stages of fasting adaptation, fatty acid oxidation and ketone utilization account for 90% of total body oxygen consumption.

The operation of the metabolic and endocrine systems of fasting adaptation is evidenced by the changes in circulating levels of metabolic fuels and hormones during a fast. As shown in Fig. 7.3 , in young infants, a 24-hour fast is accompanied by a gradual fall in plasma glucose levels as hepatic glycogen stores are depleted, a progressive decline in concentrations of gluconeogenic substrate (e.g., lactate, alanine) as they are used for hepatic gluconeogenesis, a brisk rise in free fatty acids as lipolysis is activated, and a dramatic rise in β-hydroxybutyrate (the major ketone) as hepatic ketogenesis is turned on.

By the time that plasma glucose concentration has fallen to less than 2.8 mmol/L (50 mg/dL), all the metabolic systems and the hormonal responses described earlier will have fully engaged. A “critical sample” drawn at this time will therefore provide a snapshot of the integrity of the four metabolic and endocrine fasting systems ( Table 7.2 ). The use of these critical samples in diagnosing the cause of hypoglycemia is discussed later.

Definition hypoglycemia in neonates and infants

The definition of hypoglycemia is an important concept to assist in diagnosis and management of patients with suspected or proven hypoglycemic disorders. For this reason, we recommend using various different plasma glucose thresholds for different definitions. The diagnostic threshold is the level of glucose below or at which a diagnosis of the etiology of hypoglycemia may be made. The therapeutic threshold is the level of glucose that indicates adequate therapy of a disorder of glucose dysregulation. Finally, there is the very controversial issue of what level of glucose causes brain damage.

A number of potential artifacts can interfere with measuring glucose levels in neonates and infants ( Box 7.2 ). Whole-blood glucose concentrations are 10% to 15% lower than plasma glucose concentrations because erythrocytes have a higher concentration of protein (hemoglobin) versus plasma with its higher water content, and hence higher dissolved glucose concentrations. The difference may be greater in neonates with higher hematocrits. Blood samples that are not processed promptly can have erroneously low glucose levels, owing to glycolysis by red and white blood cells. At room temperature, the decline of whole-blood glucose can be 5 to 7 mg/dL/h. The use of inhibitors, such as fluoride, in collection tubes avoids this problem.

Hospital bedside glucose meters and similar home glucose meters are less precise than clinical laboratory methods and can be expected to have an error range of 10% to 15%. These methods are also prone to errors, such as outdated strips or inadequate sampling—most of which result in falsely low glucose values. For this reason, bedside monitors can be used for screening purposes—but any glucose value below 3.3 mmol/L (60 mg/dL) should be verified in the clinical laboratory. Falsely low (or high) glucose values may occur with samples drawn from indwelling lines without adequate flushing of the saline (or glucose) infusate. Falsely low levels may also occur in critically ill infants with poor perfusion and use of bedside meters in the critical care setting is recommended only for venous or arterial samples. Modern bedside monitors use whole-blood samples but generally are calibrated to give a result expressed as a plasma glucose.

Clinical symptoms and signs associated with hypoglycemia

The clinical features of hypoglycemia in infants may be associated with both neurogenic and neuroglycopenic components ( Box 7.3 ). Symptoms are often subtle and nonspecific, therefore a high index of clinical suspicion must be maintained. Any alteration in clinical status in a newborn that suggests a change in neurologic behavior, fall in temperature, change in feeding pattern, or presence of tremors must be considered a possible initial presentation of a hypoglycemic episode. A seizure or apnea must always be considered a possible manifestation of hypoglycemia and plasma glucose should be measured immediately.