Epidemiology

For the purposes of this chapter, the term hypoglycemia refers to the condition of blood glucose concentration for which medical intervention is usually necessary. It is occasionally referred to in the literature as severe hypoglycemia.¹

The exact incidence of hypoglycemia in nondiabetic persons is unknown. However, in patients with diabetes mellitus (DM), the occurrence of hypoglycemia depends on factors such as whether the patient has type 1 or type 2 DM and what type of pharmacologic therapy the patient is receiving (i.e., insulin, an oral antihyperglycemic agent). In patients with type 1 DM, hypoglycemia reportedly occurs at an approximate rate of 1.1 to 3.2 episodes per patient per year.²

The diagnosis is often made empirically by prehospital care providers before the patient’s arrival in the emergency department (ED); however, death resulting from hypoglycemic coma may still occur if the condition is unrecognized.³ A few patients intentionally overdose, and treating them can be extremely difficult. This chapter discusses important factors in the evaluation and treatment of patients with toxicity secondary to hypoglycemic agent overdose.

Pathophysiology

The primary metabolic substrate for the central nervous system (CNS) is glucose. Usual sources of glucose are diet, endogenous production (through gluconeogenesis), and storage (through glycogenolysis). Serum glucose concentrations are relatively tightly controlled by physiologic mechanisms. After dietary sources of glucose are completely used, glycogenolysis is the major physiologic mechanism for maintaining euglycemia. Typically, an adult has enough glycogen to last approximately 6 to 8 hours. When glycogen stores are depleted, gluconeogenesis, which is fueled by amino acids from muscle, takes over. The CNS cannot make or store glucose, and it relies on the previously mentioned mechanisms to maintain normal metabolic activity during fasting periods. As glucose use exceeds glucose production and serum glucose concentrations decrease, various counterregulatory pathways are activated. Counterregulatory pathways triggered at the glycemic threshold are increases in glucagon, epinephrine, growth hormone, and cortisol. Glycemic thresholds are fairly reproducible in research studies on healthy subjects, but these thresholds can vary significantly among patients with both type 1 and type 2 DM. These thresholds also depend on other factors, such as tightness of glucose regulation, the presence of chronic hyperglycemia, and recent episodes of hypoglycemia.⁴

Hypoglycemic agents induce hypoglycemia by various mechanisms. Insulins cause rapid transport of amino acids and glucose intracellularly. Sulfonylureas stimulate insulin secretion by binding to specific membrane receptors on the pancreatic beta-islet cell. These drugs also benefit glucose homeostasis by decreasing hepatic glucose production and improving insulin sensitivity at the receptor and postreceptor levels.⁵ Other drugs may induce hypoglycemia by inhibition of gluconeogenesis, glycogenolysis, counterregulatory hormones, or other unknown mechanisms. Ethanol, a toxin commonly encountered in the ED, inhibits gluconeogenesis by depleting nicotinamide adenine dinucleotide and also inhibits the effects of cortisol, growth hormone, and epinephrine.¹

Presenting Signs and Symptoms

The symptoms of hypoglycemia can be divided into two basic groups: hyperadrenergic symptoms and neuroglycopenic symptoms (Box 156.1). Hyperadrenergic symptoms are more common with a rapid decrease in glucose and result from autonomic nervous system stimulation (both sympathetic and cholinergic). The other clinical features of hypoglycemia are mediated through altered brain activity; the resulting constellation of signs and symptoms of hypoglycemia is termed neuroglycopenia.⁶ Three neuroglycopenic syndromes are described: acute, subacute, and chronic.⁷ Subacute neuroglycopenia is characterized by episodic disorientation, somnolence, slurring of speech, personality changes, amnesia, and loss of consciousness. Precipitous loss of consciousness may occur as the sole manifestation of subacute neuroglycopenia. Both subacute and acute forms of neuroglycopenia may manifest as acute neurologic deficits (e.g., transient hemiplegia), strabismus, hypothermia, hyperthermia, seizures, and automatism. Chronic neuroglycopenia is a rare condition that usually occurs in patients with insulinoma and in patients with DM who are treated with excessive insulin and who demonstrate a gradual progressive mental illness similar to a chronic psychiatric disorder.⁷

Differential Diagnosis and Medical Decision Making

Hypoglycemia has numerous causes and may be classified into the following three categories: (1) postprandial, (2) fasting, and (3) drug- or toxin-induced (Table 156.1).¹ In healthy patients, fasting hypoglycemia is usually the result of unintentional or intentional drug ingestion and insulinoma. In patients who are severely ill or hospitalized, hypoglycemia may be a complication of the illness, drug interactions, or other iatrogenic factors.

Table 156.1 Three Categories of Hypoglycemia