Hypoglycemia in Adults

Authors:

Cara O'Shaughnessey, DO, Diabetes Fellow, Ohio University Heritage College of Osteopathic Medicine, O'Bleness Health System, Athens, OH

Jay H. Shubrook, Jr., DO, FACOFP, FAAFP, Associate Professor of Family Medicine and Director of Diabetes Fellowship, Ohio University Heritage College of Osteopathic Medicine, Athens, OH

Peer Reviewer:

Ademola Adewale, MD, FAAEM, Director of Research and Medical Simulation, Assistant Program Director, Florida Hospital Emergency Medicine Residency, Orlando, FL

This article is adapted from an article that originally appeared in the May 2012 issue of Primary Care Reports.

Almost every emergency physician I know has missed a case of hypoglycemia in their career. I have. I have also been practicing long enough to have used "Dextrostix." Remember using them? Remember some of the values you obtained? Sometimes the results made no sense. But while they were imperfect, at least they enabled us to sometimes detect severe hypoglycemia at the patient's bedside in the emergency department (ED) without waiting for the central laboratory. Now, we have point-of-care (POC) glucose testing, so we have increased ability to detect hypoglycemia and almost no barriers to rapid detection. This is timely, because along with the increase in the diabetic population provoked by the obesity epidemic, there is increased emphasis on glycemic control. And one complication of tighter glucose control is the increased risk for hypoglycemia. And as we all experience, patients with acute symptoms, such as those produced by hypoglycemia, are likely to come to the ED. This issue of EM Reports is about hypoglycemia in diabetic adults, from pathophysiology to recognition and acute management, and with recommendations for follow-up.

— J. Stephan Stapczynski, MD, Editor

Introduction

Emergency physicians are exposed to the many faces of hypoglycemia. We see it as treatment-induced hypoglycemia in patients with type 1 diabetes and in many patients with advanced type 2 diabetes.1-4 We see hypoglycemia caused by non-hypoglycemic drugs and toxins. We see it in patients with chronic liver or renal disease. We see hypoglycemia in sepsis and septic shock. We may even see patients with postprandial hypoglycemia due to an imbalance between eating and insulin release. (See Table 1.) The presenting symptoms of hypoglycemia usually include some alteration in mental status along with an autonomic response, but may be masked or obscured with co-morbid conditions, drugs, or toxins. It is an axiom that severe, untreated hypoglycemia can be fatal, but it is also important to recognize that lesser degrees of hypoglycemia, especially if prolonged or recurrent, can produce significant morbidity.1

Table 1: Pathophysiologic Classification of Hypoglycemia in Adults

Mechanism

Drug or Toxin

During Fasting

Postprandial

Increased insulin activity

Excess insulin

Sulfonylureas

Cibenzoline*

Gatifloxacin*

Pentamidine*

Quinine*

Indomethacin*

Insulinoma

Functional beta-cell disorders

Antibodies to insulin receptor or insulin

Post GI surgery

Alimentary

Liver dysfunction

Ethanol

Non-selective beta-blockers

Septic shock

Heart failure

Multi-endocrine deficiency

Ackee fruit

Decreased substrate

Chronic renal insufficiency

Uremia

Large tumors

Severe wasting

Increased glucose consumption

Prolonged exercise

* Drugs with moderate quality of evidence for causing hypoglycemia

Definition

In 1938, American surgeon Allen Whipple defined hypoglycemia by the following triad: typical signs and symptoms of hypoglycemia; documented low glucose level; and correction of signs and symptoms with normalization of glucose levels.5

Different glucose levels have been used to characterize hypoglycemia. One difficulty with a precise defined level is the variation in symptoms and glucose levels between individuals. During fasting, some healthy adults will have serum glucose levels below 60 mg/dL and have no symptoms. Thus, there is an overlap between those who satisfy, Whipple's triad as defined above and those who only have a low glucose level but without symptoms. For clinical use, a value is usually chosen to identify nearly all the symptomatic patients with hypoglycemia and to avoid over-classification of hypoglycemia in asymptomatic patients.6,7

In 2005, the American Diabetes Association (ADA) Workgroup on Hypoglycemia defined hypoglycemia in patients with diabetes as "all episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm."8 The workgroup recommended that patients with drug-treated diabetes should become concerned about developing hypoglycemia when their self-monitored blood glucose level is < 70 mg/dL8 or is falling rapidly.1 The plasma glucose concentration of 70 mg/dL was used as it approximates the lower limit of the fasting non-diabetic glucose concentration range and the normal glycemic threshold for glucose counter-regulatory hormone activation.2 This value also is low enough to reduce glycemic defenses against further hypoglycemia in non-diabetic individuals1,9,10 and is higher than the glycemic level required to produce symptoms of hypoglycemia (~ 55 mg/dL [3.0 mmol/L]) or impair brain function in those without diabetes.11,12

Despite significant advances, POC glucose meters are not always precise, especially at low plasma glucose levels,1,13 and can have an acceptable error rate of up to 16%. Therefore, a cutoff value of 70 mg/dL provides the patient with time to prevent a symptomatic hypoglycemic episode, as well as some margin for potential inaccuracy of glucose meter readings.1

The ADA Workgroup proposed a classification of hypoglycemia in diabetes that includes the following: severe, documented symptomatic, asymptomatic, probable symptomatic, and relative hypoglycemia (see Table 2).8 Severe hypoglycemia requires the assistance of another individual to provide hypoglycemic treatment, but does not require the measurement of a plasma glucose level during the event.14 Recovery of neurologic symptoms with a normal plasma glucose level provides sufficient evidence that a severe hypoglycemic event took place.

Table 2: Types of Hypoglycemia

Type of Hypoglycemia

Glucose Level

Etiology

Related to Diabetes or Other Disease

Mild asymptomatic

< 70 mg/dL but > 50 mg/dL

Many

Sometimes related

Mild symptomatic

< 70 mg/dL but > 50 mg/dL

Many

Sometimes related

Severe hypoglycemia

< 50 mg/dL or any low glucose that requires assistance from others

Hypoglycemic agents or excessive insulin secretion

Yes

Probable hypoglycemia

Not measured

Many

Likely related

Relative hypoglycemia

> 70 mg/dL

Likely in patient with diabetes on treatment

Yes, both type 1 and type 2

Reactive hypoglycemia

Initial rise above normal after meal, followed by a 75 mg/dL drop

Altered insulin secretion — usually first phase insulin secretory defect

Can occur in prediabetics

Post-absorptive hypoglycemia

Typically drops after meals without prior rise

Altered GI transit

No — diabetes

Yes — bowel disorders

Symptomatic hypoglycemia makes up the majority of hypoglycemic episodes and can occur in people with diabetes regardless of treatment and even in people who do not have diabetes. Asymptomatic hypoglycemia is especially concerning if glucose levels are lower than 50 mg/dL or if it occurs frequently. Relative hypoglycemia is most often seen in people who are chronically hyperglycemic, have become accustomed to being hyperglycemic, and then develop symptoms related to the drop in glucose, not the absolute value. (See Table 2.)

Frequency

Hypoglycemia occurs frequently in patients with type 1 diabetes.2-6,15,16 The average patient with type 1 diabetes experiences two episodes of symptomatic hypoglycemia per week,1,17 and typically one episode of severe, and at least temporarily disabling, hypoglycemia (with seizure or coma) per year.1,17 This does not include the numerous episodes of asymptomatic hypoglycemia with plasma glucose concentrations as low as 50-60 mg/dL (2.8-3.3 mmol/L). People can be low as much as 10% of the time.2,17 Severe hypoglycemic events have been reported to range from 62 to 170 episodes per 100 patient years in type 1 diabetes.1,2,17-19

Hypoglycemia also may affect patients with type 2 diabetes.20,21 This is most likely to occur in those treated with either insulin or insulin secretagogues.1-3,15,17 Hypoglycemia rates approach those of type 1 diabetes as the disease becomes more advanced and insulin deficiency ensues.1-3 The UK Hypoglycemia Study Group reported that the prevalence of severe hypoglycemia in patients with type 2 diabetes treated with insulin for less than 2 years was only 7%, while the prevalence of severe hypoglycemia with type 2 diabetes more than 5 years increased to 25%.22 The overall event rate for hypoglycemia in insulin-treated type 2 diabetes is approximately 30% of that in type 1 diabetes, according to a population-based, prospective study by Donnelly et al (1600 vs. 2400 per 100 patient-years, respectively).17 Tight glycemic control also is associated with an increased incidence of symptomatic hypoglycemia in patients with type 2 diabetes.23-27 Elderly (age 65 years or older) patients with type 2 diabetes have nearly twice as many hypoglycemic episodes as those younger than 65 years.28 Thus, since there are 20 times more people with type 2 diabetes, most episodes of iatrogenic hypoglycemia will occur in patients with type 2 diabetes.

Table 3: Physiologic Response to Hypoglycemia

Glucose Level

Response

Result

80-85 mg/dL

Suppression of insulin secretion

Primary defense against hypoglycemia

65-70 mg/dL

Increased glucagon secretion

Increased cortisol and growth hormone secretion

Primary counter-regulatory response

Slower counter-regulatory response, minor role

50-55 mg/dL

Hunger

Increase in exogenous glucose

< 50 mg/dL

Neuroglycopenic symptoms

Compromised response

Pathophysiology

Normally, hypoglycemia is prevented or promptly ameliorated by redundant glucose counter-regulatory mechanisms.1,12 The critical physiological mechanisms involved include a marked reduction in insulin secretion as glucose levels drop within the physiological range; an increase in glucagon secretion or epinephrine secretion (if the former is absent) as glucose levels drop just below the physiological range; and an increase in cortisol and growth hormone secretion, both occurring with prolonged hypoglycemia.1 Plasma glucose levels will continue to drop if these defenses fail to halt the episode. When the plasma glucose concentration reaches 55 mg/dL (3.0 mmol/L) or less, hypoglycemic symptoms trigger the behavioral defense of food consumption.1,11,12

With the above physiologic defenses in mind, hypoglycemia in patients with type 1 or advanced type 2 diabetes is the consequence of insulin excess,1,29 defective glucose counter-regulation (decreased ability to suppress endogenous insulin production and increase glucagon secretion),5,6,29 or compromised behavioral defenses against falling plasma glucose concentrations.1,16

Early in the course of type 2 diabetes, the incidence of hypoglycemia is relatively low, even with insulin treatment, because the above glycemic defenses are intact. However, with long-standing type 2 diabetes, beta-cell failure leads to absolute endogenous insulin deficiency.22 Patients with type 1 and advanced type 2 diabetes become critically dependent on the third defense, epinephrine secretion, because they have lost the insulin and glucagon defenses.5,30,31 The epinephrine response to hypoglycemia often becomes attenuated in these patients,5,30-32 leading to the clinical syndrome of compromised glucose counter-regulation and increasing the risk of severe hypoglycemia by 25-fold.32 The glycemic thresholds for epinephrine activation can be shifted to lower plasma glucose levels due to recent and recurrent hypoglycemia,30,31 as well as other potentially reversible factors including exercise and sleep.2,17,33,34 (See Tables 3 and 4.)

Table 4: Response to Hypoglycemia: Normal Vs. Diabetics

Condition

Insulin

Glucagon

Epinephrine

Normal

Sharply decreases

Increases

Increases

Early type 2 diabetes

Decreases

Increases

Increases

Late type 2 diabetes

No decrease

No increase

Attenuated increase

Type 1 diabetes

No decrease

No increase

Attenuated increase

The most serious form of an attenuated response to the normal defenses to hypoglycemia is the syndrome of hypoglycemia-associated autonomic failure (HAAF). It is the result of the reduced sympathoadrenal, predominantly sympathetic neural response to hypoglycemia failure.5,33,34 The key concept of HAAF in patients with type 1 and advanced type 2 diabetes is that antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia by causing further impairment of glucose counter-regulation to subsequent hypoglycemia, thus leading to hypoglycemia unawareness.1,5 HAAF is a functional disorder that can be induced by prior hypoglycemia and reversed by avoidance of hypoglycemia for at least 2-3 weeks.5 Hypoglycemia unawareness is defined as the onset of neuroglycopenia before the appearance of autonomic warning symptoms.35 Patients with hypoglycemia unawareness lose the adrenergic symptoms that previously triggered the behavioral defense to consume carbohydrates and correct developing hypoglycemia.1,2

Hypoglycemia unawareness occurs more frequently in patients who are older, in those who achieve tight glycemic control, and during times of increased insulin sensitivity such as exercise and sleep.36

Nocturnal hypoglycemia is common in patients with type 1 diabetes and is usually asymptomatic.37-38 Almost 50% of all episodes of severe hypoglycemia in patients with type 1 diabetes occur at night during sleep.38 Nocturnal hypoglycemia can lead to disruption of sleep and delays in correction of the hypoglycemia.1,38

Symptoms and Signs

Hypoglycemia may cause adrenergic, cholinergic, and/or neuroglycopenic symptoms, although these can sometimes be nonspecific and relatively insensitive.29,39,40 (See Table 5.)

Table 5: Signs and Symptoms of Hypoglycemia

Adrenergic

Cholinergic

Neuroglycopenic

Palpitations

Anxiousness

Tremors

Irritability

Pallor

Sweating

Hunger

Paresthesias

Confusion

Decreased sharpness of senses

Behavior changes

Lethargy

Seizures

Coma

Common signs of hypoglycemia include diaphoresis and pallor,1 as well as slight elevations in heart rate and systolic blood pressure. Neuroglycopenic symptoms may include cognitive impairment, behavioral/personality changes, difficulties speaking, dizziness, blurred vision, weakness, incoordination, hemiplegia, seizures, and coma.40,41 Neuroglycopenic manifestations are usually recognized by others.

These symptoms and signs can be mild, moderate, or severe, depending on how low the glucose falls and a variety of other factors. Manifestations of hypoglycemia may vary from person to person and can even vary within the same patient on different occasions.42 Because the manifestations of hypoglycemia are nonspecific, many episodes go unrecognized. The patient may not notice any symptoms/signs of hypoglycemia, even though these are apparent to others. Older adults tend to have more neuroglycopenic manifestations compared with autonomic manifestations, and, thus, tend to have delayed recognition.36

Complications

Hypoglycemia often causes recurrent physical morbidity, recurrent or persistent psychosocial morbidity, or both in most patients with type 1 diabetes and many with type 2 diabetes.43 In elderly patients with diabetes, even mild episodes of hypoglycemia may lead to adverse outcomes. The neuroglycopenic symptoms of hypoglycemia can increase the risk of falls and fractures.44

Because glucose is an obligate metabolic fuel for the brain, hypoglycemia can have potentially devastating effects on the brain.11,29 Recurrent hypoglycemia has been associated with cognitive impairment in young children and elderly patients with diabetes, but the extent of these effects is unknown in other age groups. Prolonged and profound hypoglycemia may result in permanent neurological damage and even brain death,11 although these effects are rare.45

While rare, it is believed that diabetic hypoglycemia will cause sudden death.45 In both type 1 and type 2 diabetes, the frequency of hypoglycemic episodes correlates with mortality.2,3,23-25,43,45,46 Although the exact cause of mortality in these trials is not known, it is plausible that iatrogenic hypoglycemia may have resulted in cardiac arrhythmias, thus possibly contributing to an untimely death.1 The "dead in bed syndrome," the unexpected death of a person that occurs while sleeping at night, is thought to be caused by a fatal ventricular arrhythmia.1,47,48 It is believed that the sympathoadrenal response to hypoglycemia may cause a transiently prolonged QT interval and increased QT dispersion, resulting in a fatal arrhythmia.1,47,48

Risk Factors

Risk factors for hypoglycemia include insulin excess, decreased glucose availability, and defective counterregulatory responses.1,2

Insulin Excess: Absolute or relative insulin excess may occur in patients with diabetes.1,2

• Exogenous insulin and insulin secretagogues are the most common medications associated with hypoglycemia.2,49 The prevalence of mild hypoglycemic symptoms has been reported in 30-50% of patients treated with insulin and 16-20% of patients treated with sulfonylureas.49-52 Insulin secretagogues stimulate endogenous insulin secretion, suppress hepatic and renal glucose production, stimulate glucose utilization, and can cause hypoglycemia even in the setting of intact glycemic defenses if given in sufficient doses. Among the commonly used insulin secretagogues, those with a longer duration of action, such as glyburide, are associated with hypoglycemia more often.49,53-55

• Hypoglycemia occurs more frequently in patients treated with intensive hypoglycemic therapy,56 and hypoglycemia is the most common adverse effect of intensive insulin therapy in both the hospital and outpatient settings.1

Decreased Glucose Availability: This can occur from reduced intake or endogenous production.

• Decreased exogenous glucose intake, which may occur during an overnight fast, or with small, delayed, or missed meals, increases the potential for hypoglycemia.2

• Decreased endogenous glucose production may occur as a result of alcohol consumption or in patients with sepsis. Alcohol consumption is often the cause of, or a contributing factor to, hypoglycemia seen in patients who present to the ED.57 Alcohol inhibits gluconeogenesis and can result in hepatic glycogen depletion and hypoglycemia, especially if there is limited food consumption.1 Sepsis is a relatively common cause of hypoglycemia1,58-61 and is likely due to cytokine-induced inhibition of gluconeogenesis in the setting of glycogen depletion, in addition to cytokine-accelerated glucose utilization.59

• Increased insulin-independent glucose utilization, such as from exercise-induced glucose utilization by muscle, can cause hypoglycemia in patients treated with insulin.1,62 Even when plasma glucose levels are near normal or moderately elevated at the start of exercise, hypoglycemia can occur both during or shortly after exercise.1,62

• Increased sensitivity to insulin is often seen after weight loss, hours after exercise, following improved glycemic control, in the middle of the night, after withdrawal of glucocorticoid therapy,1 and occasionally in patients with type 1 diabetes mellitus who develop adrenal insufficiency.37,41 Among the latter patients, sensitivity to insulin is increased because of loss of the gluconeogenic effect of cortisol and the hyperglycemic effects of epinephrine.34,51

Decreased Clearance of Insulin:

• Decreased insulin clearance is commonly seen in patients with acute or chronic renal failure1 who are treated with insulin or insulin secretagogues. Hypoglycemia in patients with chronic kidney disease may also be due to impaired gluconeogenesis and reduced renal glucose production.1

Defective Counter-Regulatory Responses:

• Insulin excess alone explains only a minority of episodes of hypoglycemia.1,63 Impaired counter-regulatory response is the primary risk factor for subsequent hypoglycemia.63 People with type 1 diabetes do not have the normal insulin and glucagon responses to hypoglycemia. As they experience recurrent hypoglycemia, the glycemic threshold becomes lower for the sympathoadrenal response to subsequent hypoglycemia, which leads to defective glucose counter-regulation.5

Diagnosis

The detection of hypoglycemia has been greatly facilitated by the development of reliable POC glucose testing devices. These devices are widespread, routinely carried by EMS vehicles, and extensively used in the ED, hospital, and physician offices. There are, however, technical aspects associated with the use of these devices that may provide false or markedly elevated values. If the health care provider performing the test has even a small amount of sugar on his or her hands, as from a powdered-sugar pastry or donut, the test strip may become contaminated and report false elevated results.

Another potential problem with POC glucose testing is with the specimen source. In most settings where this test is used for rapid screening, the specimen source is capillary blood obtained by fingerstick using a lancet. A potential problem is that in critically ill patients, blood obtained by fingerstick (capillary source) tends to have higher glucose concentrations than that of arterial or venous samples.64 Thus, hypoglycemia may go undetected in these critically ill patients.

Additional laboratory testing is guided by the clinical circumstance. Patients with a clearly defined precipitating circumstance (e.g., insulin-dependent diabetic who took his or her regular amount of prescribed insulin and then did not eat) do not require additional testing, especially if they respond as expected to treatment. However, for hypoglycemic ED patients who predominately presented for altered mental status, an observational study found that more than half of these patients had abnormalities on serum electrolytes or renal function.65 Thus, it could be argued to have a low threshold for routine laboratory testing for such ED patients. Patients with hypoglycemia due to drug overdose or toxicity often have other blood chemistry abnormalities, and expanded testing is recommended.

For patients without diabetes who present with symptomatic hypoglycemia, a panel of tests obtained during the hypoglycemic episode is used to identify and classify potential causes. The panel includes measurement of plasma glucose, insulin level, c-peptide level, proinsulin level, beta-hydroxybutyrate, and a urine drug screen for oral hypoglycemic agents.1 If possible, this specimen should be drawn before treatment.

Treatment

Patients with drug-treated diabetes should be instructed to undertake defensive actions when their plasma glucose concentration is < 70 mg/dL because of the concern of developing hypoglycemia.8 Such actions include repeating the self-monitored blood glucose (SMBG) level to confirm hypoglycemia, consuming carbohydrates, and abstaining from tasks such as driving or operating heavy equipment while hypoglycemic.8 (See Table 6.)

Table 6: Treatment of Hypoglycemia

Setting

Mild

Severe

Outpatient community

Oral glucose, "rule of 15"

Glucagon injection

Outpatient health care office

Oral glucose, "rule of 15"

Glucagon injection

Extended care facility

Oral glucose, "rule of 15"

Glucagon injection

Hospital

Oral glucose, "rule of 15"

IV glucose (dextrose)

Most episodes of asymptomatic or mild-to-moderate symptomatic hypoglycemia are effectively self-treated by the consumption of carbohydrates. Plasma glucose concentration should be raised to the normal range. The "15-15 rule" can be used in the majority of cases in adults. This involves the ingestion of 15 g of fast-acting carbohydrates and a recheck of SMBG level 15 minutes later to ensure that the glucose level is > 70 mg/dL. If the glucose level is not above 70 mg/dL, the steps should be repeated until it is achieved.66 Readily available items that contain 15 g of fast-acting carbohydrates include: 4 ounces of carbohydrate-containing juice or regular, non-diet soda; 8 ounces of milk; 3-4 glucose tablets; 1 tube of glucose gel; 5-6 hard candies; 2 tablespoons of raisins; 4 or 5 saltine crackers; 4 teaspoons of sugar; and 1 tablespoon of honey or corn syrup. Food that contains fat (like candy bars) or protein (cheese) should be avoided initially, since they slow the absorption of glucose.

In adults, 15-20 g of carbohydrates are usually sufficient to raise blood glucose to a safe range without causing hyperglycemia.1,66 Clinical improvement should occur within 15-20 minutes of treatment.67 Although most episodes of hypoglycemia are reversed once the glucose level is raised to the normal range, the glycemic response to oral glucose may be transient, especially in basal or intermediate insulin-induced hypoglycemia (often < 2 hours). Therefore, a long-acting carbohydrate with protein, such as a meal or more substantial snack, if the next meal is > 1 hour away, should be consumed shortly after the plasma glucose is raised to prevent recurrent symptoms.1,66 It is also recommended that patients check their blood glucose levels serially after treatment with carbohydrates to ensure that they continue to remain within the euglycemic range, as individual responses may vary.1 Rebound hypoglycemia is common due to ingestion of more carbohydrates than needed for the situation. Training patients and their families on a prompt but appropriate response to hypoglycemia may reduce this overshoot.

Patients treated with insulin or a secretagogue in combination with an alpha-glucosidase inhibitor should only consume pure glucose (dextrose) to treat symptomatic hypoglycemia. Alpha-glucosidase inhibitors slow the digestion of other carbohydrates, such as table sugar (sucrose), and, thus, consumption of non-dextrose carbohydrates will be less effective in raising blood sugar.

In cases of severe hypoglycemia occurring outside the hospital, when the patient is unconscious or is unable/unwilling to ingest carbohydrates, glucagon treatment is recommended.1 Relatives and close friends should be trained to recognize the signs and symptoms of hypoglycemia and provide treatment should this complication occur. If hypoglycemia is suspected, a blood glucose level should be checked initially, especially if the patient is unconscious, to ensure that hyperglycemia is not the culprit. If this is not possible, then empiric treatment for hypoglycemia should be performed.1

Glucagon, injected subcutaneously or intramuscularly in a dose of 1 mg in adults, can be lifesaving in cases of severe hypoglycemia, especially if there is no intravenous access.68 Glucagon rapidly counters the metabolic effects of insulin in the liver through stimulation of glycogenolysis and gluconeogenesis. Injected glucagon can raise blood glucose levels by 30-100 mg/dL within minutes and can lead to transient, but significant hyperglycemia.1,68 Resolution of hypoglycemic symptoms with recovery of consciousness usually occurs within 10 minutes after glucagon administration.68 Rarely, nausea and vomiting may follow with this dose of glucagon. Therefore, the patient should be placed onto his or her side if unconscious to avoid the risk of aspiration. Once the patient is awake and able to tolerate oral food, he or she initially should consume a fast-acting carbohydrate and then a long-acting carbohydrate with protein, since glucagon depletes glycogen stores and potentially can lead to rebound hypoglycemia. If the patient remains unconscious 10 minutes after the glucagon injection, another injection should be given.

There are no efficacy data to guide the management of hypoglycemia outside the hospital if glucagon is not available prior to the arrival of emergency personnel. In the absence of other options, some experts suggest treatment with either glucose gel or cake frosting placed in the buccal mucosa or table sugar placed sublingually. Other experts do not recommend these options since there is no supporting evidence69 and there also is a potential risk of aspiration. Hypothetically, an epinephrine injection will also raise the glucose but should only be used when other evidence-based treatments are not available.

In the ED and hospital, the standard parenteral therapy for hypoglycemia is intravenous glucose. The standard initial glucose dose for adults is 25 g of 50% glucose (D50) IV. This dose will typically raise serum glucose about 160 mg/dL, although the response is variable,70 leading to the caution that serum glucose response cannot be reliably predicted after D50 administration. Usually, the glycemic response is only transient and, thus, a subsequent dose or glucose infusion often is required. It is recommended that patients ingest food with carbohydrates as soon as they are able to tolerate food by mouth.1

For patients under the influence of excess insulin activity, oral glucose ingestion may not be adequate to maintain blood glucose above 70 mg/dL. The reason is that one of the effects of insulin is to stimulate the incorporation of glucose delivered by the portal venous blood into hepatic glycogen, reducing the amount that can get through the liver and reach the systemic circulation. Thus, continued infusion of glucose is recommended to maintain blood glucose in cases of insulin or oral hypoglycemic overdose.14,71-76 Similar to that seen with the variable response to D50, the response to glucose infusion is also variable. Typical glucose infusion rates reported to maintain euglycemia in insulin and sulfonylurea overdose are 100 to 200 mL/h of 10% glucose (D10),77 although higher infusion rates may be necessary.72,74,76

Octreotide inhibits pancreatic insulin release and is used to treat hypoglycemia induced by sulfonylureas.77,78 Published case reports have used doses of 50 to 100 micrograms IV or SC every 6 hours. Alternatively, an IV bolus of 50 micrograms followed by an infusion of 25 to 50 micrograms/h can be used.79

Prevention

Frequent or severe hypoglycemia should lead to consideration of significantly changing the treatment regimen based on the review and application of the principles of aggressive glycemic therapy.66 These principles include: patient self-management achieved through education and empowerment, ongoing professional guidance and support, frequent SMBG testing or continuous glucose sensing, flexible and individualized drug regimens, and individualized glycemic goals.1

Patient self-management can be improved through professional guidance and support, which is best provided by a chronic care model conducted by a diabetes care team.80 Patients should be educated about the recognition and treatment of hypoglycemia.81 They also should be informed that the typical hypoglycemic manifestations may be impaired after an episode of hypoglycemia, especially if severe. Frequent SMBG data can help detect glycemic variability and reduce the risk of hypoglycemia. This also means carrying testing supplies and items to treat hypoglycemia with them all of the time. ED discharge instructions after treatment for hypoglycemia should incorporate these recommendations.81

Treatment regimens should be flexible and individualized to minimize the risk of hypoglycemia. Among the insulin secretagogues, hypoglycemia is less common with glimepiride compared with glyburide.53-55 Analog insulins have less hypoglycemia compared with NPH, regular, or premixed insulin.82-84 Rapid-acting insulin analogs (Lispro, Aspart, Glulisine) reduce nocturnal hypoglycemia in patients with type 1 diabetes.86 Long-acting insulin analogs (Glargine, Detemir) reduce nocturnal hypoglycemia and symptomatic hypoglycemia in patients with type 1 and type 2 diabetes.82-84

To date it appears insulin pump therapy does not reduce the hypoglycemia risk, as a recent systematic review of 15 randomized trials found no difference of mild, nocturnal, or severe hypoglycemia between continuous subcutaneous insulin infusion and multiple daily injection therapy with insulin analogs.85 However, when the pump uses sensor-augmented continuous subcutaneous insulin infusion, it has been shown to achieve lower A1C levels without an increase in hypoglycemia.86

Ultimately, glycemic goals should be individualized to match the health and life expectancy of the individual patient. Although intensive glycemic therapy has been shown to prevent or delay microvascular complications, including retinopathy, nephropathy, and neuropathy, the risk of hypoglycemia is also increased;63,87-89 severe or frequent hypoglycemia is an absolute indication for setting less-aggressive glycemic goals. In addition, patients who are very young or old; patients who have multiple comorbidities, advanced microvascular or macrovascular complications; or patients with a limited life expectancy should have relaxed glucose goals that reduce the risk of hypoglycemia.66

Hypoglycemia in Patients Without Diabetes

Although hypoglycemia is a common event in persons with diabetes, it is a rare event in those healthy patients without diabetes because of the effectiveness of the key physiologic defenses in response to declining plasma glucose levels.90 Hypoglycemia has become ensconced in the popular culture, and a variety of symptoms has been ascribed to it by the lay public. Only those non-diabetic individuals with documented Whipple's triad should undergo evaluation and management of hypoglycemia to avoid unnecessary workup and costs.91

Table 7: Hypoglycemia in Patients Without Diabetes

Well-appearing

  • Accidental, surreptitious, or malicious use of hypoglycemic drugs
  • Post-gastric bypass
  • Insulinoma
  • Functional beta-cell disorders (nesidioblastosis)
  • Autoimmune hypoglycemia
  • Reactive hypoglycemia
  • Alimentary hypoglycemia

Ill-appearing

  • Critical illness: sepsis, hepatic, renal or cardiac failure
  • Cortisol deficiency
  • Alcohol

Medication-induced

  • Insulin
  • Insulin secretagogues
  • Cibenzoline, Gatifloxacin, Pentamidine, Quinine, Indomethacin, Glucagon (used during endoscopy)

Hypoglycemia in patients without diabetes can be categorized clinically based on whether the patient is well- or ill-appearing and/or treated with certain medications.90 (See Table 7.) In those patients who are well-appearing, hypoglycemia usually is caused by either endogenous hyperinsulinism or accidental, surreptitious, or malicious administration of an insulin secretagogue or insulin.

Case reports have described patients who have developed hyperinsulinemic hypoglycemia after undergoing bariatric surgery. These cases can occur years after surgery and are difficult to treat. As there is an increasing number of people undergoing these procedures, this is an important potential complication of which to be aware.92

Drugs, including insulin, insulin secretagogues, alcohol, and others, are the most common cause of hypoglycemia, especially in the setting of critical illness or when enteral or parenteral nutrition is disrupted.90 In patients who are ill-appearing and not receiving treatment with culprit medications, renal failure, hepatic failure, cardiac failure, sepsis, and inanition are the most common causes of hypoglycemia.8,90 Although uncommon, hypoglycemia can occur in patients with cortisol or growth hormone deficiencies after prolonged fasting.91 Fasting hypoglycemia also can occur rarely in patients with a non-islet cell tumor, which is typically a large mesenchymal or epithelial tumor (hepatomas, adrenocortical carcinomas, carcinoids) caused by the overproduction of an incompletely processed form of insulin-like growth factor II.91

Reactive hypoglycemia was first described in 1924.93 This condition occurs in people who have a mismatch between insulin secretion and glucose absorption. Reactive hypoglycemia is defined as hypoglycemia that occurs within 4 hours of ingestion of food.16 Patients who experience reactive hypoglycemia typically initially will experience mild, early post-meal hyperglycemia, and this will be followed with a vigorous insulin response with a greater than 75 mg/dL drop in glucose that overshoots the normal range and results in mild hypoglycemia. Although the recommended diagnostic workup is controversial,94 many clinicians will utilize a 3- to 4-hour glucose tolerance test or results of the patient's mixed nutrient meal documentation. This condition often is considered a prediabetic condition. Reactive hypoglycemia is treated by small frequent meals with low carbohydrate content.

Alimentary hypoglycemia is an uncommon form of hypoglycemia.95 This tends to occur in young, thin women who experience rapid transit through the gastrointestinal tract. This condition is very worrisome to the patient but rarely results in severe hypoglycemia. Further, it is not related to diabetes mellitus and does not predict an increased risk of diabetes mellitus in the future. This is more common in people with irritable bowel syndrome. Although not validated in controlled clinical trials, antispasmodic agents, such as dicyclomine and hyoscyamine, appear to be helpful.

Summary

Hypoglycemia is a common and significant problem in diabetes; it is the rate-limiting factor for intensive glucose treatment. Hypoglycemia can be divided into mild, severe, asymptomatic, and relative hypoglycemia. The treatment of hypoglycemia varies based on its severity, cause, and location of treatment.

References

1. Cryer PE, et al. Evaluation and management of adult hypoglycemic disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009;94:709-728.

2. Cryer PE. Hypoglycemia in Diabetes. Pathophysiology, Prevalence and Prevention. American Diabetes Association, Alexandria, VA, 2009.

3. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008;57:3169-3176.

4. McCrimmon RJ, Sherwin RS. Hypoglycemia in type 1 diabetes. Diabetes 2010;59:2333-2339.

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