Scope

Hypoglycemia is common, life-threatening, and readily treatable. It often occurs in diabetic patients as a side effect of glucose-lowering therapy and can easily be identified and treated in this setting.

Definition

Hypoglycemia is an abnormally low blood glucose concentration that causes symptoms of autonomic hyperactivity (anxiety, irritability, palpitations, trembling) or neurologic dysfunction (inattention, lethargy, altered consciousness, seizure, coma), or any combination of these symptoms. Definitive diagnosis requires fulfillment of the Whipple triad: symptoms consistent with hypoglycemia are present, the blood glucose concentration is low, and the symptoms resolve when blood glucose recovers to the normal range. An exact threshold for defining “low blood glucose” has not been firmly established because of variations in the concentration at which different people begin to experience symptoms, but a blood glucose concentration lower than 60 mg/dL is generally considered abnormally low.

Epidemiology

Patients who use insulin or oral hypoglycemic medications are at the greatest risk for hypoglycemia. These patients experience mild, self-treated hypoglycemic episodes about twice per week.¹ Severe hypoglycemia, which requires the assistance of another person to regain euglycemia, is experienced at least once per year by 27% of patients treated with intensive insulin regimens.² Hypoglycemia is the cause of death in approximately 3% of people with insulin-dependent diabetes.³ Patients taking oral hypoglycemic agents also commonly experience hypoglycemia. Although these episodes are generally associated with milder symptoms, they occur in more than 30% of patients each year.⁴ Sulfonylureas are the most widely used oral hypoglycemic agents. In 2004, 4148 sulfonylurea overdoses were reported to American poison control centers; of these, 36% occurred in children younger than 6 years, 21% required treatment of hypoglycemia, 2.5% were life-threatening, and 0.22% were fatal.⁵ The incidence of hypoglycemia is expected to rise as tight glycemic control continues to be emphasized for the 17 million Americans with diabetes.

Hypoglycemia in nondiabetic patients is quite rare and should raise concern about the possibility of a severe underlying illness, alcohol ingestion, or inappropriate exposure to insulin or an oral hypoglycemic agent.

Normal Glycemic Control

Insulin

Unlike other organs, the brain cannot synthesize glucose or store a significant glycogen supply and therefore requires an uninterrupted flow of glucose from the bloodstream for normal function and survival. Under normal physiologic conditions, the blood glucose concentration is maintained within a narrow range (70 to 110 mg/dL) through a balance of catabolic processes that increase blood glucose and anabolic processes that decrease blood glucose. Insulin, a protein released from pancreatic beta cells in response to rising blood glucose levels, is the hormone responsible for initiating anabolic glucose metabolism. It promotes glycolysis, inhibits glycogenolysis and gluconeogenesis in the liver, inhibits proteolysis in skeletal muscle, and inhibits lipolysis and promotes lipogenesis in adipose tissue. Insulin secretion is inhibited during fasting to maintain euglycemia and essentially ceases when the blood glucose concentration falls below 80 mg/dL.

Counterregulatory Hormones

The hormones glucagon, epinephrine, cortisol, and growth hormone promote catabolic glucose metabolism as part of the counterregulatory response and oppose the actions of insulin. When the blood glucose concentration drops below 65 to 70 mg/dL, glucagon is secreted from pancreatic alpha cells, and epinephrine is released from the adrenal medulla and sympathetic neurons. These hormones inhibit the entry of glucose into cells, stimulate glycogenolysis and gluconeogenesis, mobilize amino acids to act as gluconeogenic precursors, activate lipolysis, and inhibit insulin secretion.

Glycogenolysis increases blood glucose within minutes and can maintain euglycemia in a well-nourished person for 24 hours. Gluconeogenesis requires several hours to raise blood glucose levels and is the principal mechanism responsible for maintaining euglycemia if fasting is extended beyond 24 hours. Secretion of cortisol from the adrenal cortex and growth hormone from the anterior pituitary gland is a delayed response to blood glucose falling below 60 to 65 mg/dL; these hormones are not involved in the correction of acute hypoglycemia but act to maintain euglycemia over a period of days to weeks.^6,⁷

A clinically important consequence of the counterregulatory response is the Somogyi phenomenon. A nighttime insulin dose that is too large causes hypoglycemia during sleep, and the counterregulatory response causes rebound hyperglycemia at the morning glucose check. Increasing the nighttime insulin dose in response to morning hyperglycemia will cause dangerous overnight hypoglycemia and exacerbate the morning hyperglycemia. Paradoxically, decreasing the nighttime insulin dose in this case would lower the morning blood glucose concentration and is the appropriate treatment.

Many of the symptoms of hypoglycemia are caused by an acute increase in glucagon (which causes nausea, vomiting, and abdominal pain) and epinephrine (which causes anxiety, trembling, palpitations, tachycardia, and sweating). The hypoglycemic symptoms caused by epinephrine, called autonomic or hyperepinephrinemic symptoms, function as a warning that mild hypoglycemia has developed; the patient can then correct the hypoglycemia by eating before neurologic impairment ensues. Hypoglycemia unawareness, or the development of hypoglycemia without the normal autonomic symptoms to warn the patient, increases the risk for severe hypoglycemia.

Patients with type 1 and advanced (insulin-dependent) type 2 diabetes may have an impaired counterregulatory reaction. In these patients, the glucagon response is often nonexistent and the epinephrine response is greatly attenuated.⁸ This impaired counterregulatory response predisposes patients to severe hypoglycemia by blunting the glycemic response to falling blood glucose levels and thereby leaving the patient with no early warning symptoms of hypoglycemia. Furthermore, even one episode of hypoglycemia blunts the epinephrine response to future hypoglycemia and can result in hypoglycemia-associated autonomic failure.⁹ In this manner a vicious cycle of recurrent hypoglycemia can develop. Avoidance of hypoglycemia for several weeks improves hypoglycemia awareness and restores the epinephrine component of the counterregulatory response.⁸

Causes of Hypoglycemia

Hypoglycemia occurs in patients with a relative excess of insulin in comparison with the hormones of the counterregulatory response. Such excess can occur through the administration of exogenous insulin, an increase in endogenous insulin, or inhibition of the counterregulatory response. This section highlights the most important causes of hypoglycemia, the mechanisms by which they act, and the context in which they are likely to be observed in the emergency department (ED) (Table 163.1).

Table 163.1 Causes of Hypoglycemia

CAUSE (EXAMPLES)	COMMENT
Exogenous insulin (treatment of diabetes or hyperkalemia, factitious disorder, Munchausen by proxy)	Hypoglycemia caused by excessive insulin administration. Most common cause of hypoglycemia
Oral hypoglycemic agents (sulfonylureas, meglitinides)	Induce secretion of insulin from pancreatic beta cells
Alcohol (ethanol)	Inhibition of hepatic gluconeogenesis. Hypoglycemia usually requires concomitant fasting
Sepsis	Inhibition of hepatic gluconeogenesis and increased peripheral glucose utilization
Liver disease (hepatitis from infections or toxins, cirrhosis, Reye syndrome, HELLP syndrome, hepatoma, metastatic tumors)	Inhibition of hepatic gluconeogenesis and glycogenolysis
Renal disease	Decreased clearance of insulin and reduced mobilization of gluconeogenic precursors
Congestive heart failure	Hepatic congestion causes inhibition of gluconeogenesis and glycogenolysis
Starvation (prolonged fasting, anorexia nervosa, pyloric stenosis, pediatric gastroenteritis)	Depletion of glycogen stores and gluconeogenic precursors
Hormone deficiency (cortisol, growth hormone, epinephrine, glucagon, hypopituitarism)	Failure of the counterregulatory mechanism of glucose metabolism. The hormone deficiency may be either congenital or acquired
Medications not used for the treatment of diabetes mellitus (ACE inhibitors, acetaminophen, acetazolamide, aluminum hydroxide, beta-blockers, benzodiazepines, Bordetella-pertussis vaccine, chloroquine, chlorpromazine, cimetidine, ciprofloxacin, colchicine, diphenhydramine, disopyramide, doxepin, ecstasy, EDTA, etomidate, ethionamide, fluoxetine, furosemide, haloperidol, imipramine, indomethacin, isoniazid, lidocaine, lithium, maprotiline, mefloquine, monoamine oxidase inhibitors, nefazodone, orphenadrine, pentamidine, phenytoin, propoxyphene, quinine, quinidine, ranitidine, ritodrine, selegiline, terbutaline, tetracyclines, trimethoprim-sulfamethoxazole, warfarin)	Induce hypoglycemia rarely and unpredictably, usually in otherwise healthy individuals
Insulinoma	Excessive, unregulated endogenous insulin secretion from a tumor of pancreatic beta-cell origin
Nesidioblastosis	Excessive insulin secretion by hypertrophic pancreatic beta cells
Non–islet cell tumors (sarcoma, carcinoid, melanoma, leukemia, hepatoma, teratoma, colon, breast, prostate, stomach, mesothelioma)	Various mechanisms, including secretion of insulin-like growth factors, increased metabolic demand, production of insulin autoantibodies
Post–gastric surgery status (gastric bypass, gastrectomy, pyloroplasty)	Rapid dumping of glucose into the small intestine causes an exaggerated insulin response; nesidioblastosis may have a role
Inborn errors of metabolism (errors in glycogen synthesis, glycogenolysis, gluconeogenesis, mitochondrial beta oxidation, amino acid metabolism)	Congenital defect prevents normal metabolism from maintaining euglycemia
Idiopathic ketotic hypoglycemia	Fasting intolerance, possibly caused by deficiency in alanine as a gluconeogenic precursor
Autoimmune	Antibodies against insulin or the insulin receptor augment the effects of insulin
Akee fruit	Unripe akee, a fruit found in Jamaica, contains toxins that inhibit hepatic gluconeogenesis
Vacor rat poison	Damages pancreatic beta cells, which initially causes release of insulin and hypoglycemia but eventually results in impaired insulin secretion and diabetes mellitus. Banned in the United States
Transient neonatal hypoglycemia (prematurity, intrauterine growth retardation, severe infant distress syndrome, perinatal asphyxia, maternal hyperglycemia, erythroblastosis fetalis, beta-agonist tocolytic agents)	Occurs in the immediate newborn period. Rarely seen in the ED
Persistent neonatal hypoglycemia (mutation in the sulfonylurea receptor gene, glutamate dehydrogenase gene, glucokinase gene)	Occurs in the immediate newborn period. Rarely seen in the ED

ACE, Angiotensin-converting enzyme; ED, emergency department; EDTA, ethylenediaminetetraacetic acid; HELLP, hemolysis elevated liver enzymes, and low platelet count.

Exogenous Insulin and Oral Hypoglycemic Agents

Administration of insulin or an oral hypoglycemic medication is the most common cause of hypoglycemia. In a patient with diabetes who is being treated with an established regimen of insulin or an oral hypoglycemic medication, hypoglycemia can develop for a number of reasons (Table 163.2).

Table 163.2 Potential Causes of Hypoglycemia in a Diabetic Patient with an Established Regimen of Insulin or an Oral Hypoglycemic Agent

MECHANISM	EXAMPLES
Decreased glucose availability	Missed or unusually light meal Impaired gluconeogenesis: Alcohol ingestion
Increased glucose use	Unusually heavy exercise Illness, especially infection, with increased metabolic demands
Increased dose of drug	Patient or provider mistake in delivering too much drug: Patient with memory problem causing repeated doses Patient with visual impairment causing inaccurate dosing Inaccurate glucometer leading to excessive insulin dose Provider change in shift and poor documentation Insulin pump malfunction or programming error Intentional overdose: Suicide attempt Factitious disorder Munchausen by proxy Pharmacy medication filling error Physician prescribing error
Increased availability of drug	Renal insufficiency (insulin and sulfonylureas are excreted renally) Liver failure (many sulfonylureas are metabolized hepatically) Drug interactions: Warfarin inhibits metabolism of chlorpropamide and tolbutamide H₂ blockers inhibit metabolism of glipizide and glyburide Ciprofloxacin inhibits metabolism of glyburide ¹⁰ Clarithromycin displaces glyburide from serum proteins ¹¹

Oral hypoglycemic medications include the sulfonylurea and meglitinide drug classes, both of which increase endogenous pancreatic secretion of insulin. Other classes of antihyperglycemic oral medications, including biguanides, α-glucosidase inhibitors, and thiazolidinediones, do not increase insulin levels and do not induce hypoglycemia when used in isolation. However, when used in addition to insulin or an oral hypoglycemic medication, these medicines can precipitate hypoglycemia that is more refractory to treatment.

The time to peak effect and duration of action of insulin preparations and oral hypoglycemic medications dictate management and disposition (Table 163.3). Patients often cannot reliably recall which type of insulin they use; a helpful characteristic is that glargine and all rapid- and short-acting insulins are clear liquids whereas neutral protamine Hagedorn (NPH) and Ultralente appear cloudy.

Table 163.3 Features of Insulin Preparations and Oral Antidiabetic Agents Relevant to the Emergency Department Management of Hypoglycemia