I. Problem Definition.

Hypoglycemia is a common metabolic emergency, defined as a blood glucose level below 60mg/dL (or 3.0mmol/L). Hypoglycemia can be asymptomatic, or can be associated with typical symptoms which can be categorized as either sympathetic effects, or those related to the impact on the brainstem. Symptoms related to sympathetic effects (or autonomic, as related to sympathoadrenergic discharge) include tremor, sweating, anxiety, fear, and palpitations. Those that relate to the brain sensing low glucose (or neuroglycopenic symptoms) include confusion, slurred speech, weakness, and blurred vision.

These symptoms can be most pronounced at blood glucose levels below 50mg/dL, but they can occur at levels below 70mg/dL (or 3.9mmol/L). As such, the exact numerical definition of hypoglycemia varies, but the symptoms are widely agreed upon. If treated adequately, most symptoms completely resolve with treatment, except the most severe neuroglycopenic symptoms. Symptoms of hypoglycemia can relapse if the blood sugar declines again below the normal threshold.

Diabetes mellitus (DM) is the disease most commonly associated with hypoglycemia. Type 1 DM patients can experience asymptomatic hypoglycemia as their disease progresses, while this is less common in patients with Type II DM. Although a given patient with Type II DM is less likely to experience hypoglycemia than a patient with Type 1 DM, the absolute number of cases of hypoglycemia is significantly higher in patients with Type II DM given the much higher prevalence of the disease.

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Less commonly, hypoglycemia can occur in those with impaired glucose tolerance or diabetes, following the ingestion of a glucose load, related to the underlying impaired glucose handling and not associated treatments.

II. Diagnostic Approach

A. What is the differential diagnosis for of hypoglycemia?

Many of the common causes of hypoglycemia relate in some way to DM, either diagnosed or undiagnosed. The differential diagnosis of hypoglycemia also includes adverse events related to non-endocrinologic medications, other endocrinopathies including insulinoma or hormone deficiencies, surreptitious use of insulin or oral hypoglycemics, or recent surgery.

The vast majority of inpatients with hypoglycemia are known diabetics with either excessive intake of medication, poor oral intake, or decreased clearance of diabetic medications.

It is less common for those patients without DM, including newly diagnosed DM, to present with hypoglycemia. If hypoglycemia is confirmed, and associated with the above symptoms, several less common conditions should be excluded: surreptitious or accidential ingestion of oral hypoglycemic or insulin-containing pharmaceuticals; evaluation for insulin antibodies; evaluation for specific ingestions related substances including ethanol; consideration of ingestion of non-DM-related medications; and screening for insulinoma.

Medications which can be associated with hypoglycemia as a side-effect or adverse drug effect include quinine, indomethacin, glucagon (administered during endoscopy), ethanol, pentamidine, and less commonly lithium, gatifloxacin, IGF-1, and propoxyphene. While commonly thought to be associated with hypoglycemia, trimethoprim/sulfamethoxazole and beta-blockers have less evidence of association with this condition.

Consideration of insulinoma, and the appropriate work-up and treatment approach will be discussed elsewhere. Related hormone deficiencies that can result in hypoglycemia will also be covered separately.

B. Describe a diagnostic approach to the patient with hyoglycemia.

Confirming the existence of hypoglycemia is agreed upon as important. Also determining if the patient is experiencing symptoms of either sympathoadrenergic or neuroglycopenic type associated with the documented hypoglycemia.

The most common causes of hypoglycemia relate to DM, and this association should be considered first. The diagnosis can include basic blood glucose measurements, and more specific tests evaluating for the less common causes of endocrinologic etiologies once the initial work-up is completed. A thorough medication and substance history will be important to exclude ingestions.

For those patients in whom no clear pathophysiologic etiology is identified, it is important to consider either intentional or accidental ingestion of oral or injected medications used to treat DM. These are referred to as accidental, surreptitious or malicious cases of hypoglycemia.

1. Historical information important in the diagnosis of hyoglycemia.

DM remains the most common diagnosis associated with hypoglycemia. Risk factors for hypoglycemia in diabetes can be categorized as relating to excess action of medications, or those associated with autonomic failure. Those relating to the excess of medication include excessive, ill-timed or the wrong preparation, lack of food associated with administration of insulin, increased sensitivity to a previously-effective dose after exercise or weight loss, or when insulin clearance is decreased, as in acute or chronic renal failure.

As the patient may not realize the impact of the above constitutional changes, a thorough history relating to these risk factors is essential. In particular, recent changes in weight or exercise patterns are important to elicit, as they are commonly associated with changes in insulin metabolism and effect.

During the history, report of associated sympathoadrenergic and neuroglycopenic symptoms, timing of symptoms including timing and duration, and any aggravating factors can provide imporant insight. It is uncommon to see symptomatic hypoglycemia without documented low blood glucose levels, but this can occur, particularly with neuroglycopenic symptoms.

For those who do not carry a diagnosis of DM, family history or prior diagnosis of impaired glucose tolerance or gestational diabetes is integral to evaluating for new-onset DM. Alcohol history should be obtained, as hypoglycemia has been linked with alcohol intake, and in particular those patients at high risk for alcoholic or starvation ketoacidosis.

If all conditions related to DM have been excluded, other endocrinopathies and drug effects should be considered, prior to asking the patient about potential intentional ingestions. Common ingestions to ask all patients about include recent procedures (relating to the glucagon), new medications in the patient’s regimen including quinine, indomethacin, pentamidine, or gatifloxacin.

Specific questions to elicit relating to insulinoma and other endocrinopathies will be discussed separately.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of hypoglycemia.

The first principle is to correct the hypoglycemia, particularly in those patients with neuroglycopenic symptoms. Once this is done, a more complete physical exam should be pursued including a full neurologic examination with focus on mental status and to evaluate for evidence of tremor or visual deficits. More rarely, seizure activity and persistent neurologic deficits can be seen with more severe cases of hypoglycemia.

Findings consistent with insulin resistance may also be elicited, including central obesity, acanthosis nigricans, peripheral neuropathy, although these are more related to the underlying diagnosis with DM, and do not relate specifically to risk or existence of hypoglycemia. Evaluation of global nutritional status, including assessment for cachexia or dehydration can be useful in the patient where starvation or weight loss may be implicated in the cause of hypoglycemia.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Confirming the existence of hypoglycemia, or a serum blood glucose level below 60mg/dL (3.0 mmol/L) is a primary goal, particularly if the intial level was taken as a finger-stick blood glucose level via a glucometer.

For the patient with known DM, assessing renal function with serum creatinine can be useful, as many medications are renally cleared, which may affect dosing needs. A standing weight can also be helpful, when appropriate and when baseline data is available, to evaluate for either intentional or unintentional weight loss.

When a patient who was previously stable on their diabetes medications presents with hypoglycemia, evaluation for infection with a complete blood count, as well as a chest radiograph or urinalysis when appropriate, would be warranted to evaluate for associated infection.

If the patient is not known to be a diabetic, but is confirmed to have hypoglycemia, a C-peptide level can be helpful in determining if exogenous insulin is suspected. While IGF (insulin-like growth factor) levels can be useful in the differentiation of causes of non-insulin-mediated hypoglycemia, these tests are not readily available.

If alcohol intake is suspected or history is elicited from the patient, assessment of serum or urine ketones could be appropriate. Alcoholic or starvation ketoacidosis could be diagnosed with serum chemistries including bicarbonate and the presence of serum or urine ketones. Blood sugar may be normal, elevated, or low in the case of alcoholic ketoacidosis, mediated through lipolysis in the liver in the setting of insulin deficiency.

The appropriate serologic and imaging examinations to diagnose insulinoma and other hormone deficiencies which can also cause hypoglycemia will be discussed separately.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Hypoglycemia is a common metabolic emergency, defined as a blood glucose level below 60mg/dL (or 3.0 mmol/L). Some sources cite a blood glucose level below 70mg/dL (or 3.9 mmol/L) as hyoglycemia. Many of the medications associated with hypoglycemia would not be commonly checked on serum examinations, and so levels would not be regularly checked in the work-up of hypoglycemia.

If alcohol use is suspected, blood alcohol level can be checked to evaluate for acute intoxication, although this will only indicate recent ingestion. If alcoholic or fasting ketoacidosis is suspected, ketones can be checked for in urine or serum samples. Their presence is diagnostic of ketoacidosis, and is generally done with the nitroprusside tablets or reagent.

In a patient not known to be diabetic, but in whom significant hypoglycemia is present, a serum insulin level can be useful. An insulin level of greater than 6microunits/mL in the setting of a blood sugar less than 45mg/dL, would warrant checking a C-peptide level for further clarification of the cause of the hypoglycemia.

A C-peptide level less than 200mg/dL, in conjunction with elevated serum insulin levels, is associated with exogenous insulin ingestion in a hypoglycemic patient. If the C-peptide level is greater than 200mg/dL, in a patient with an elevated serum insulin level, either sulfonylurea ingestion or insulinoma would be considerations. In this case, history of sulfonylurea ingestion or recent prescription history will be critical in determining if further evaluation for insulinoma with serologic testing and potential imaging with MRI is warranted.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

In most cases of hypoglycemia, the patient is a known diabetic, and therefore appropriate work-up should include tests to confirm the blood glucose level and evaluate for any infection or changes in renal function that could affect clearance and metabolism of the medications used to control diabetes. In these cases, an insulin level or C-peptide level are not indicated, as the patient is known to be diabetic.

Insulinoma is a rare cause of hypoglycemia, and therefore if suspected, an appropriate work-up should be pursued. However, imaging to evaluate for insulinoma should only be pursued if no other clear causes of hypoglycemia are identified in the initial work-up.

III. Management while the Diagnostic Process is Proceeding

A. Management of hypoglycemia.

If mild symptomatic hypoglycemia is suspected, and confirmed, administration of dextrose either via oral route or intravenous route is appropriate. When the patient is able to tolerate oral intake, a 15-20g dose of carbohydrates in the form of a fast-acting solution, juice or glucose tablet should be adequate to raise the blood sugar acutely but not induce hypoglycemia.

Of note, this should be followed by a longer-acting carbohydrate if recurrent hypoglycemia is a concern. In some cases of patients taking both insulin combined with an alpha-glucosidase inhibitor (such as acarbose), glucose is not adequate to overcome the hypoglycemia.

In the patient unable to tolerate oral intake, or in the case of severe hypoglycemia, intravenous administration of dextrose is critical. Patients in the hospital can be given 25-50g of dextrose intravenously. If this is unavailable, a subcutaneous or intramuscular injection of 0.5-1.0mg of glucagon can be useful for an unconscious patient although can cause associated nausea and vomiting. Buccal absorption of glucose solutions is not felt to be adequate for the unconscious or critically ill patient with hypoglycemia.

If glucose testing is unavailable, and hypoglycemia is a concern in a known or suspected diabetic patient, glucose should be given empirically, given the greater risks of persistent hypoglycemia.

Following administration of an acute bolus of either dextrose or glucagon, efforts should be focused on maintaining the blood sugar monitoring to ensure that the level does not again fall into a critical level. Of note, when ingestion is suspected or when renal failure is associated with decreased clearance of medications, hypoglycemia is at a great risk of recurring and the patient will require close monitoring with blood glucose measurements to ensure appropriate treatment.

Potassium levels should be monitored in appropriate patients, especially those presenting with hypokalemia initially. As dextrose will cause insulin-mediated shunting of potassium intracellularly, potassium levels can fall with treatment, particularly in patients whose total body stores are depleted. This scenario can be exaggerated in patients presenting with alcoholic or starvation ketoacidosis.

A bedtime snack can be useful in addressing mild nocturnal hypoglycemia in a stable diabetic patient, although associated adjustment of medications has been found to be equally important in these cases.

Acute management

  • 25-50 grams IV dextrose (0.5-1amp)
  • Alternative if no IV access: 0.5-1.0mg glucagon IM

Please note that the administration of dextrose containing fluids can affect potassium, and should be done judiciously in the patient with known hypokalemia.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

The cause of hypoglycemia will determine the duration and intensity of monitoring commensurate to the patient. For a patient with suspected sulfonylurea toxicity, for example, this can take 24 hours or longer to resolve and the patient is at high risk of recurrence of the hypoglycemia. This is different from the case of a patient who took their short-acting insulin without oral intake, and will require different intensity of monitoring and frequency of blood glucose checks.

Once the initial dextrose dose is administered to a severely hypoglycemic patient, and the patient is stabilized, appropriate treatment may include continued administration of dextrose-containing intravenous fluids to lower the risk of recurrent hypoglycemia. The intensity of this therapy should be determined by the suspected underlying cause of the hypoglycemia.

The administration of dextrose-containing fliuds and solutions should be done with caution in the patient with existing hypokalemia, given the insulin-mediated effect of intracellular shunting of potassium after dextrose is given.

When administering glucagon, note that nausea and vomiting are potential side effects. In the neurologically-impaired patient, aspiration is therefore a risk, and the patient’s airway should be monitored closely.

What’s the evidence?

McMahon, GT, Mushlin, SB, Greene, HL. “Hypoglycemia. Decision Making in Medicine: An Algorithmic Approach”. Endocrinology,.

Cryer, PE. “Evaluation and Management of Adult Hypoglycemia. An Endocrine Society Clinical Practice Guideline”. Journal of Clin Endocinol Metab. vol. 94. 2009. pp. 709-728.

Briscoe, VJ, Davis, SN. “Hypoglycemia in Type 1 and Type 2 Diabetes: Physiology, Pathophysiology, and Management”. Clinical Diabetes. vol. 24. 2006.

Heller, SR. “Hypoglycaemia: Its pathophysiology in insulin treated diabetes and hypoglycaemia unawareness”. Br J Diabetes Vasc Dis. vol. 11. 2011. pp. S6-S9.

Cryer, PE. “The Barrier of hypoglycemia in diabetes”. Diabetes. vol. 57. 2008. pp. 3169-3176.