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 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

Diabetes caused by chronic pancreatitis is associated with a concomitant deficiency of glucagon because of the loss of pancreatic alpha cells, thus making these patients very susceptible to the hypoglycemic effects of insulin and oral hypoglycemic medications. These medications can also cause hypoglycemia in a nondiabetic patient when taken accidentally, in a suicide attempt, or as part of a factitious disorder or Munchausen by proxy syndrome. Factitious disorder and Munchausen by proxy syndrome should be considered in cases of unexplained hypoglycemia in healthy patients, especially in female health care workers and family members of a person with diabetes.

Additional Causes of Hypoglycemia

Alcohol ingestion (ethanol), the second most common cause of hypoglycemia in the ED, inhibits the counterregulatory response by suppressing hepatic gluconeogenesis. It has minimal effects on glycogenolysis. Therefore, alcohol typically requires concomitant fasting to deplete glycogen stores before hypoglycemia ensues. The classic example of alcohol-induced hypoglycemia is a malnourished alcoholic who undertakes a prolonged binge. However, fasting for only 6 hours before significant alcohol consumption in an otherwise healthy person can cause hypoglycemia. Although hypoglycemia is rare (less than 1%) in intoxicated patients in the ED,^12,¹³ the hypoglycemic episodes seen in EDs in lower socioeconomic urban areas involve alcohol 50% of the time.¹⁴

Critical illness can cause hypoglycemia in patients with and without diabetes. Sepsis is the third most common cause of hypoglycemia. The mechanism involves increased peripheral utilization of glucose and hepatic hypoperfusion impairing gluconeogenesis. Meanwhile, severe liver disease induces hypoglycemia via failure of hepatic gluconeogenesis and glycogenolysis. Renal failure can also cause hypoglycemia; the mechanism is not completely understood but probably involves delayed clearance of insulin and reduced mobilization of gluconeogenic precursors. The kidney is just a minor contributor to gluconeogenesis, and this loss is not thought to play a significant role in hypoglycemia caused by renal failure. Congestive heart failure can also lead to hypoglycemia, probably via hepatic vascular congestion impairing gluconeogenesis and glycogenolysis.

Starvation, as in the case of anorexia nervosa, depletes glycogen stores and gluconeogenic precursors and can eventually lead to hypoglycemia. Hypoglycemia as a complication of anorexia nervosa is a late finding and implies a very grave prognosis.¹⁵

Insulinomas are tumors of pancreatic beta-cell origin that secrete insulin without the normal feedback mechanisms, thus producing unexplained hyperinsulinemia and hypoglycemia in otherwise healthy people. Insulinomas are rare, with an incidence of 4 per 1 million per year.¹⁶ Early diagnosis is important because these tumors are curable with surgery before they lead to potentially fatal hypoglycemia. Nesidioblastosis is characterized by hypertrophied (nonneoplastic) beta-cell tissue that oversecretes insulin and can also be manifested as unexplained hypoglycemia.

Non–islet cell tumors, including hepatomas, carcinoids, sarcomas, and melanomas, can cause hypoglycemia by several mechanisms: a paraneoplastic syndrome caused by secretion of insulin-like growth factors, multiple metastases to the liver with impaired hepatic function, massive tumor burden with increase metabolic demand for glucose, and production of autoantibodies to insulin or the insulin receptor. Autoantibodies that augment the effects of insulin can also occur in conjunction with autoimmune diseases such as systemic lupus erythematosus and Graves disease.

Vague autonomic symptoms after eating were once labeled postprandial hypoglycemia, alimentary hypoglycemia, or functional hypoglycemia. This poorly understood mimic of hypoglycemic symptoms has never been linked to depressed blood glucose concentrations.¹⁷ However, after gastric surgery, including gastric bypass, gastrectomy, and pyloroplasty, patients can experience a true postprandial or alimentary hypoglycemia. Traditionally, the mechanism was thought to be rapid emptying of carbohydrates into the small intestine causing an exaggerated insulin response, or dumping syndrome. Recent evidence suggests that nesidioblastosis (beta-cell hyperplasia causing hyperinsulinism) plays a role in postprandial hypoglycemia following gastric surgery.¹⁸

Medications other than those used for the treatment of diabetes have been associated with hypoglycemia (see Table 163.1).¹⁹ Quinine, quinidine, pentamidine, and disopyramide stimulate release of insulin from pancreatic beta cells and have the potential to cause severe hypoglycemia. Commonly used drugs that may cause hypoglycemia include salicylates (mechanism unknown), acetaminophen (hypoglycemia occurs only in overdose with liver damage), angiotensin-converting enzyme (ACE) inhibitors (the mechanism may involve increased insulin sensitivity), and beta-blockers (inhibit the counterregulatory response of epinephrine). ACE inhibitors and beta-blockers typically cause hypoglycemia only when used concomitantly with insulin or oral hypoglycemic agents. Nonselective beta-blockers (e.g., propranolol) have more hypoglycemic potential than do selective beta₁-blockers (e.g., metoprolol) and can occasionally cause hypoglycemia in the absence of antidiabetic medications, especially in children.

Causes of Hypoglycemia in Pediatric Populations

Children are predisposed to hypoglycemia because they have small glycogen stores and a large brain-to-body mass ratio. Neonates are at significant risk for hypoglycemia as a result of developmental immaturity of gluconeogenesis and ketogenesis combined with temporary impairment of glycogenolysis because of the stress of delivery. Neonates of mothers with poorly controlled diabetes are further predisposed to hypoglycemia as a result of the hyperinsulinemia induced by maternal hyperglycemia. Additionally, inborn errors of metabolism, such as glucose-6-phosphatase deficiency, galactosemia, and carnitine deficiency, can be manifested as hypoglycemia in neonates.

Gastroenteritis increases the risk for hypoglycemia by decreasing intestinal absorption of carbohydrates and by increasing metabolic demands of the illness. Reid and Losek ²⁰ found that 9% (18 of 196) of children aged 1 month to 5 years seen in an ED with gastroenteritis and dehydration had hypoglycemia, although none of the children exhibited altered mental status.

Idiopathic ketotic hypoglycemia is the most common cause of clinically significant hypoglycemia in nondiabetic children aged 7 months to 5 years. This syndrome is characterized by fasting intolerance and may be caused by a deficiency of alanine, an amino acid substrate for gluconeogenesis.²¹ During a 10- to 16-hour fast, the counterregulatory response converts triglycerides to ketone bodies and causes a mild metabolic acidosis and ketonuria, but it fails to maintain euglycemia. Affected children tend to be slender but not malnourished, with weight percentile below height percentile. These children often have a concurrent illness and are seen in the ED in the morning with a blood glucose concentration of 35 to 60 mg/dL, bicarbonate value of 14 to 19 mmol/L, and ketonuria. The syndrome typically remits by 6 years of age as lean body mass and alanine levels increase.

Clinical Presentation

The signs and symptoms in patients with hypoglycemia are divided into two categories: those caused by elevated levels of glucagon and epinephrine as part of the counterregulatory response (autonomic or hyperepinephrinemic symptoms) and those cause by insufficient supply of glucose to the brain (neuroglycopenic symptoms). Autonomic symptoms typically appear when the blood glucose concentration drops below 60 mg/dL and include anxiety, irritability, nausea, vomiting, palpitations, trembling, flushing, hunger, and sweating. Neuroglycopenic symptoms emerge below a blood glucose concentration of 50 mg/dL and include inability to concentrate, inattention, headache, lethargy, dizziness, blurry vision, agitation, confusion, and focal neurologic deficits.⁵ When the blood glucose concentration drops below 30 mg/dL, seizures and coma may ensue.¹ Permanent brain damage and death are rare but occur when the hypoglycemia is severe and left untreated. Predicting who will have permanent neurologic impairment is difficult in the ED, but elderly patients, those with concurrent hypoglycemia, and in particular those with previous strokes are vulnerable to incomplete recovery.

The signs and symptoms of hypoglycemia are not uniformly present with each episode. Recurrent episodes in the same person tend to be symptomatically similar, but hypoglycemia can be manifested differently among individuals. Variations include the blood glucose threshold at which symptoms develop, the severity of symptoms at a given glucose concentration, the predominance of certain symptoms, and their order of appearance. The severity of neuroglycopenic symptoms depends on many factors other than the nadir of blood glucose, including the patient’s general state of health and age; integrity of the counterregulatory response; and the severity, duration, timing, and number of previous hypoglycemic episodes. For example, Osoria et al. showed that nondiabetic, neurologically normal people who were administered exogenous insulin to decrease their blood glucose concentration to 30 mg/dL experienced only subtle neuroglycopenic symptoms and no alteration in consciousness.²² Hypoglycemic episodes blunt the symptoms of future hypoglycemia. Therefore, lower blood glucose concentrations with recurrent episodes will be symptomatically silent and predispose the patient to repeated severe hypoglycemia, which can cause cumulative cognitive decline.²³

Other than previous hypoglycemic episodes, additional features that increase the risk for hypoglycemia in diabetic patients include the use of insulin, longer duration of insulin use, higher doses of insulin, glycosylated hemoglobin values that are initially high and fall rapidly with therapy, adolescent age, and male gender.² Use of an insulin pump does not alter the risk for hypoglycemia when compared with multiple daily insulin injections.

Differential Diagnosis

The signs and symptoms of hypoglycemia are associated with a long list of diagnoses. The causes of hypoglycemia create an equally long list (see Tables 163.1 and 163.2).

Hypoglycemia should be considered in any patient with an acute neurologic abnormality, however obvious or subtle, especially if it involves an alteration in mental status. Classic examples include a diabetic patient who collapses during exercise, an alcoholic patient with seizures, and patients in coma after an overdose of oral medications. More challenging findings include strokelike focal neurologic deficits, psychotic-like bizarre and combative behavior, and septiclike hypotonia and lethargy in an infant. Hypoglycemia should be included in the differential diagnosis of each of the following diseases: stroke, transient ischemic attack, seizure, traumatic brain injury, narcolepsy, multiple sclerosis, psychosis, and drug intoxication.

Furthermore, the blood glucose concentration should be checked in all patients requiring ED resuscitation because critical illness can cause hypoglycemia. Losek ²⁴ found that 18% (9 of 49) of pediatric patients undergoing nontraumatic ED resuscitation were hypoglycemic. Additionally, hypoglycemia should be considered in all accidental and intentional drug ingestions, in children with prolonged vomiting and diarrhea, and in all diabetics encountered in the ED.

Diagnostic Testing

Glucometry

The optimal method for diagnosing hypoglycemia is rapid determination of the blood glucose concentration through point-of-care testing with a bedside glucometer. Bedside glucometers measure the concentration of glucose in whole blood, whereas laboratory tests measure the glucose concentration in plasma or serum. Because of the relative paucity of glucose in blood cells, whole blood concentrations of glucose are approximately 15% lower than plasma concentrations. Newer models of bedside glucometers calculate an estimated plasma glucose concentration based on the measured whole blood concentration. Although bedside glucometers that undergo routine quality control have adequate accuracy to direct immediate therapy, laboratory tests of glucose concentration are more accurate than bedside glucometers, especially in the extreme high and low ranges of blood glucose concentration.

The accuracy of bedside glucometry and laboratory tests of serum glucose concentration can be compromised by several mechanisms.²⁵ Bedside glucometers are less accurate with hematocrit levels above 55 or below 30 because of variations in the relative amount of blood cells and plasma. Artificially low serum glucose measurements are seen with hemolytic anemia (nucleated red blood cells consume glucose in the collection tube²⁶), with leukemia (leukocytes consume glucose²⁷), and when blood is collected in a tube lacking a glycolysis-suppressing agent such as fluoride. An artificially high glucose concentration may be reported by bedside glucometry during an acetaminophen overdose because of interference with the measuring technique.²⁸

Urinalysis

Urine ketones are expected in hypoglycemia when the counterregulatory hormones are in relative abundance in comparison with insulin because the counterregulatory response induces the production of ketone bodies from lipolysis. Therefore, urine ketones are typically present in hypoglycemia not caused by hyperinsulinemia and absent in hypoglycemia caused by hyperinsulinemia. An exception to this rule is hypoglycemia caused by an enzymatic defect in fatty acid oxidation, which prevents the synthesis of ketone bodies.

Extended Laboratory Testing

Other diagnostic tests that are useful in selected cases, especially for critically ill hypoglycemic patients, include liver function tests, blood alcohol concentration, salicylate level, acetaminophen level, random cortisol level, chest radiograph, urine cultures, blood cultures, electrocardiogram, and cardiac markers. Recent evidence suggests that hypoglycemia may be associated with cardiac ischemia. Desouza et al. found that ischemic electrocardiographic changes were more common during hypoglycemia than during euglycemia or hyperglycemia in diabetic patients with coronary artery disease.²⁹ Thus an evaluation for ischemic heart disease is indicated for patients with hypoglycemia and risk for coronary artery disease.

Critical Blood Sample

In nondiabetic patients without an immediately identifiable cause of hypoglycemia who have symptoms consistent with hypoglycemia, a normal glucose reading on a bedside glucometer excludes hypoglycemia irrespective of symptoms (Fig. 163.1). No further testing for hypoglycemia is indicated—other possible causes of the symptoms should be suspected.

Fig. 163.1 Approach to determine whether a patient’s symptoms are the result of hypoglycemia when no cause of the hypoglycemia is readily apparent.

If a symptomatic patient does have a low glucose concentration by bedside glucometer, a blood sample should be drawn as early as possible for the following laboratory tests: glucose, insulin, C peptide, proinsulin, glucagon, growth hormone, cortisol, β-hydroxybutyrate, insulin antibodies, and sulfonylurea drug levels. This so-called critical blood sample will be essential later, after the patient’s ED course, for determining the cause of the hypoglycemia. The critical blood sample is most important for the evaluation of first-time occurrences of hypoglycemia; recurrent cases of medication-induced hypoglycemia do not require such extensive testing. Treating the hypoglycemia before obtaining the critical blood sample will limit its usefulness, but in a life-threatening situation, the first duty of the emergency physician (EP) is to reverse the hypoglycemia and only secondarily to facilitate a diagnostic evaluation.

Treatment

Stabilization of a patient with hypoglycemia begins with the primary assessment. A bedside glucose measurement should be obtained, intravenous (IV) access secured, supplemental oxygen initiated, and a cardiac monitor applied. Intubation should not proceed until hypoglycemia has been treated because treatment of hypoglycemia may completely restore baseline mentation.

Treatment of hypoglycemia involves repletion of blood glucose via oral or IV administration of exogenous glucose or glucagon administration to stimulate endogenous glucose production. The specific treatment modality depends on the patient’s age, whether the patient’s mental status allows safe oral ingestion, and whether IV access can be established (Fig. 163.2).

Fig. 163.2 Initial treatment of hypoglycemia.

D₅₀W, 50% dextrose in water; ED, emergency department; IM, intramuscularly; IV, intravenous; PO, orally; SC, subcutaneously.

Methods of Administration

Monitoring and Repeated Glucose Administration

The glycemic response to oral carbohydrates, IV dextrose, and glucagon is transient. It is essential to monitor for signs of recurrent hypoglycemia and recheck glucose levels every 30 minutes for 4 hours after euglycemia is achieved. The patient should also eat a substantial meal with protein, fat, and complex carbohydrates to rebuild glycogen stores and maintain euglycemia. If the glucose concentration falls toward hypoglycemic levels again, a continuous dextrose infusion (D₅W or D₁₀W) should be started. Patients with intact pancreatic insulin secretion, including nondiabetic and some patients with type 2 diabetes, are at risk for rebound hypoglycemia 1 to 2 hours after receiving dextrose boluses or glucagon because of an endogenous insulin response induced by these therapies.

Hypoglycemia caused by short-acting insulin, alcohol, and idiopathic ketotic hypoglycemia usually responds rapidly to initial replacement and does not recur. Recurrent hypoglycemia is expected when the cause of the hypoglycemia is ongoing, as with sulfonylureas, long-acting insulin, and critical illness. In these cases, continuous IV infusion of dextrose is often necessary.

Adjunctive Treatments

Octreotide

Octreotide is used as a supplemental treatment of sulfonylurea- and insulinoma-induced hypoglycemia. It is a synthetic analogue of the hormone somatostatin and a potent inhibitor of pancreatic insulin secretion. Although octreotide does not treat existing hypoglycemia, it can prevent recurrent hypoglycemia and reduce the amount of dextrose supplementation needed.^32,³³ In sulfonylurea-induced hypoglycemia, octreotide should be used instead of continuous dextrose infusions and glucagon whenever possible because dextrose and glucagon stimulate further insulin secretion from the sulfonylurea-primed pancreatic beta cells.

The most effective octreotide dose has not been established. One recommended adult dose is 50 to 100 mcg of SC octreotide every 6 hours; continuous IV infusions of octreotide (100 to 125 mcg/hr) have also been used successfully. A recommended pediatric dose is SC octreotide, 4 to 5 mcg/kg/day divided every 6 hours. No significant side effects of octreotide have been demonstrated when used for hypoglycemia.

Diazoxide

Diazoxide, a rarely used antihypertensive medication, also inhibits pancreatic insulin secretion and can be used for sulfonylurea-induced hypoglycemia. It is considered a second-line therapy in comparison with octreotide because of lower efficacy and greater risk for toxicity.³⁴ Side effects include hypotension and sodium retention. The IV adult dose is 300 mg of diazoxide given over a 1-hour period; the IV pediatric dose is 1 to 3 mg/kg given over a 1-hour period. Doses can be repeated every 4 hours as needed.

Other Adjunctive Treatments

When hypoglycemia is caused by a massive overdose of SC insulin, one case report suggests that needle aspiration or surgical excision of the SC reservoir may reduce the systemic absorption of insulin.³⁵

Early administration of activated charcoal is indicated for sulfonylurea overdose and accidental pediatric sulfonylurea ingestion. Maximum efficacy is achieved if the charcoal is given within 1 hour of the ingestion. Glipizide undergoes enterohepatic circulation; peak plasma concentrations may be decreased by multiple doses of activated charcoal. Because of the delayed peak effects of extended-release glipizide, whole-bowel irrigation can be considered for overdoses of this preparation.

Urine alkalization can reduce the half-life of chlorpropamide from 49 hours to 13 hours through increased renal excretion. However, urine alkalization does not appear to be useful in reducing the duration of effect of other hypoglycemic agents.³⁶

Risks Associated with Presumptive Treatment

It has been suggested previously that dextrose be given to all patients with undifferentiated altered mental status as part of the “coma cocktail,” which consists of oxygen plus IV administration of 1 ampule of D₅₀W, 100 mg of thiamine, and 0.4 mg of naloxone. This practice was challenged in the 1980s when animal and retrospective human studies suggested that hyperglycemia may be detrimental to the injured brain, particularly in the setting of acute stroke, cardiac arrest, hypotension, and head trauma.³⁷ The true risk of administering a small glucose load to a euglycemic or hyperglycemic patient with a brain injury has not been established but is thought to be small. Hypoglycemia, in contrast, is known to be detrimental, especially to the injured brain. Therefore, the current recommendation is to obtain a bedside glucose measurement in patients with altered mental status and administer dextrose only when the blood glucose level is lower than 60 mg/dL. Treatment should be initiated empirically only when a glucometer is not immediately available.

Traditional teachings also warn that dextrose should never be given to patients with altered mentation without a preceding dose of thiamine because of the risk of precipitating Wernicke encephalopathy. Thiamine is a cofactor for two essential reactions in the glycolysis–tricarboxylic acid cycle (conversion of pyruvate to acetyl coenzyme A and α-ketoglutarate to succinate). Theoretically, without adequate supplies of thiamine, the energy contained in glucose cannot be converted to adenosine triphosphate, so substrates for the thiamine-dependent reactions accumulate in the brain and cause Wernicke encephalopathy. Administering dextrose to a thiamine-deficient patient increases the production of these substrates, but no clinical evidence has shown that a dextrose load dosed to reverse hypoglycemia precipitates Wernicke encephalopathy if thiamine is not given first.³⁸ When treating a patient with altered mental status and confirmed hypoglycemia or with possible hypoglycemia without access to a bedside glucometer, EPs should administer thiamine and dextrose simultaneously if possible. Dextrose administration should not be delayed if thiamine is not immediately available, even in alcoholic patients. Hypoglycemia should be corrected immediately, and thiamine should be administered as soon as possible.

Persistent Altered Mental Status

If hypoglycemia is the sole cause of the altered mental status, restoration of euglycemia should lead to reversal of the neurologic symptoms within minutes. In the case of a seizure caused by hypoglycemia, the altered mentation may persist for a short period while the patient recovers from the postictal state. If a patient’s mental status remains altered for more than 15 minutes after return to euglycemia and there is no history of seizure, a secondary cause must be considered. The EP should return to the primary assessment and consider a broad differential diagnosis, including traumatic brain injury, anoxic brain injury, stroke, alcohol intoxication, opioid intoxication, central nervous system infection, liver failure, and renal failure. The coma cocktail should be given in full, if not administered earlier. Rapid-sequence intubation, computed tomography of the brain, and lumbar puncture may be indicated. If a lumbar puncture is performed, a low cerebrospinal fluid glucose value is not necessarily a sign of central nervous system infection because this value remains depressed for several hours after a low blood glucose concentration has been corrected.³⁹

Disposition

Discharge

Patients with hypoglycemia caused by a short-acting, easily reversed mechanism that is unlikely to recur may be considered for discharge (Box 163.1). A history of recurrent episodes of hypoglycemia may be an indication for hospital admission to adjust medications. When taken in massive doses, even short-acting insulin preparations can cause delayed, recurrent hypoglycemia because of altered pharmacokinetics. Renal failure also increases the half-lives of insulin preparations and can cause unexpected recurrent hypoglycemia.

For patients who are discharged from the ED, insulin doses should be reduced by 25% for the next 24 hours to reduce the risk for recurrent hypoglycemia. Patients should be educated about how to prevent hypoglycemia (see the “Patient Teaching Tips” box), and short-term follow-up with a primary care physician should be arranged.

Children with known idiopathic ketotic hypoglycemia can also be discharged home after the hypoglycemia has been reversed and an uneventful ED observation completed. Parents should be educated to avoid prolonged fasts in these children and to provide a bedtime snack. An initial diagnosis of idiopathic ketotic hypoglycemia should not be made in the ED; patients with symptoms consistent with this diagnosis require admission to exclude other potential causes of hypoglycemia.

Patient Teaching Tips

Know the symptoms of hypoglycemia. Train yourself to estimate your blood glucose concentration through your symptoms.

Carry fast-acting carbohydrates with you at all times. Immediately take 15 to 30 g when you experience symptoms of hypoglycemia. Do not delay to check your blood glucose level. After the symptoms resolve, eat a small snack of complex carbohydrates and protein (cheese or peanut butter and crackers).

Stop driving immediately if you experience symptoms of hypoglycemia.

Even moderate alcohol consumption increases the risk for hypoglycemia.

Train friends and family when and how to administer glucagon. These people should know where the glucagon kit is and should practice mixing the glucagon mixture. Know the expiration date on your glucagon kit.

The risk for hypoglycemia is increased in the hours to days after an initial hypoglycemic episode. You should increase your vigilance and check your blood glucose more frequently in the 24 hours following a hypoglycemic episode.

Call your doctor for a hypoglycemic episode requiring fast-acting carbohydrates that you cannot readily explain and the use of glucagon.

Call 911 for an incomplete response to glucagon or oral fast-acting carbohydrates or a seizure.

More information is available through the American Diabetes Society (www.diabetes.org).

Observation and Admission

Patients who do not meet the criteria outlined in Box 163.1 require admission or monitoring in an observation unit for at least 24 hours (Fig. 163.3). Because of the risk for recurrence, hospitalization is recommended for those with hypoglycemia caused by an oral hypoglycemic medication or an intermediate- or long-acting insulin. Hypoglycemia caused by sulfonylureas tends to be prolonged and severe, and intensive care unit admission may be necessary, especially if a continuous dextrose infusion is needed in addition to octreotide to maintain euglycemia. Experience with hypoglycemia caused by the meglitinides is limited, so these patients should be managed similar to those with sulfonylurea-induced hypoglycemia.

Fig. 163.3 Approach to a hypoglycemic adult in the emergency department.

CHF, Congestive heart failure; H + P, history and physical examination; ICU, intensive care unit; OHA, oral hypoglycemic agent.

Patients with hypoglycemia that cannot be completely reversed in the ED, as well as patients with hypoglycemia caused by massive insulin overdoses, starvation, sepsis, liver failure, and adrenal insufficiency, should be admitted to the intensive care unit.

Psychiatry consultation is appropriate for cases of hypoglycemia involving suicide attempts, factitious disorder, and Munchausen by proxy.

Patients Treated in Prehospital Setting

Emergency medical service (EMS) personnel frequently treat hypoglycemia in the prehospital setting. After treatment and resolution of the symptoms, patients often refuse transport to the ED. Recent studies suggest that the risk for recurrent hypoglycemia is not different in patients transported to the ED and those released on the scene.^40,⁴¹ Mechem et al.⁴² reported that 9% (9 of 103) of patients who initially refused transport to the ED contacted EMS again within 3 days because of recurrent hypoglycemia. Similarly, Lerner et al.⁴³ found that 8% (3 of 38) of patients released by EMS experienced recurrent hypoglycemia in 24 to 48 hours. However, caution is advised because fatal cases of hypoglycemia have occurred following release by EMS.⁴² EMS personnel should encourage all patients with symptomatic hypoglycemia, especially those who do not meet the criteria listed in Box 163.1, to be transported to the ED.

Special Consideration: Accidental Pediatric Sulfonylurea Ingestion

Children are particularly susceptible to the effects of sulfonylureas, and significant hypoglycemia can develop after the ingestion of a single tablet.^44,⁴⁵ Therefore, all pediatric patients with possible sulfonylurea ingestion should be evaluated in the ED. If hypoglycemia is present on arrival at the ED, treatment as outlined previously with dextrose, octreotide, oral feedings, and hospital admission is indicated. The optimal management of a child who ingested a sulfonylurea or is thought to have done so and who has a normal blood glucose concentration is debated in the literature, with recommendations varying from mandatory admission to 8-hour ED observation.⁴⁵^–⁴⁸

Two studies provide the best available data for directing the management of asymptomatic pediatric sulfonylurea ingestions. In a retrospective study of pediatric patients after sulfonylurea ingestion, Quadrani et al.⁴⁹ found that 27% (25 of 93) had a blood glucose concentration lower than 60 mg/dL 30 minutes to 16 hours after ingestion, with the mean time to development of hypoglycemia being 4.3 hours. All four patients in whom hypoglycemia developed after 8 hours had received a continuous dextrose infusion while euglycemic during the observation period. It is thought that the dextrose infusions delayed the onset of hypoglycemia in these patients.

In a prospective study of pediatric sulfonylurea ingestions, Spiller et al.⁵⁰ found that hypoglycemia developed in 29% (54 of 185). In all but one of the hypoglycemic patients, low blood glucose developed within 8 hours of ingestion. The lone patient in whom hypoglycemia developed after 8 hours had been given a continuous dextrose infusion after a blood glucose measurement of 62 mg/dL at 3 hours.

In both studies, hypoglycemia developed more than 8 hours after ingestion only in patients who received prophylactic dextrose infusions. These infusions probably masked early hypoglycemia and potentially stimulated further pancreatic insulin secretion.

An 8-hour ED observation period for pediatric patients with asymptomatic sulfonylurea ingestion appears to be safe when the following protocol is used. An blood glucose measurement should be obtained immediately. Activated charcoal should be administered if the child is initially seen within 1 hour of ingestion and there is little risk for vomiting and aspiration. For an asymptomatic patient with a blood glucose concentration higher than 60 mg/dL, oral carbohydrates should be encouraged but no IV dextrose given. The blood glucose concentration should be checked every 30 to 60 minutes; a decrease in concentration to below 60 mg/dL is an indication for an IV dextrose bolus and hospital admission.

If the patient remains asymptomatic and blood glucose remains higher than 60 mg/dL for 8 hours after ingestion, the patient may be discharged with appropriate return precautions. However, hospitalization is advised if IV dextrose is administered at any time, if the ingestion involved extended-release glipizide (Glucotrol XL—a sulfonylurea with peak effects possibly delayed longer than 8 hours), or if the ingestion may have been intentional.

References

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2 Diabetes Control and Complications Trial Research Group. Hypoglycemia in the diabetes control and complications trial. Diabetes. 1997;46:271.

3 Laing SP, Swerdlow AH, Slater SD, et al. The British Diabetic Association Cohort Study, II: cause-specific mortality in patients with insulin-treated diabetes mellitus. Diabet Med. 1999;16:466.

4 Miller CD, Phillips LS, Ziemer DC, et al. Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med. 2001;161:1653.

5 Watson WA, Litovitz TL, Rodgers GC, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2005;23:589.

6 Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol. 1991;260:E67.

7 Schwartz NS, Clutter WE, Shah SD, et al. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 1987;79:777.

8 Cryer PE. Current concepts: diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2004;350:2272.