By Steven R. Offerman, MD
There are multiple oral agents available for the treatment of diabetes. These include several pharmacological classes: the sulfonylureas, biguanides, a-glucosidase inhibitors, thiolidinediones, and metglitinides. The biguaniudes, glycosidase inhibitors, and glitazones do not increase insulin secretion and are therefore unlikely to lead to hypoglycemia in overdose. In the U.S., the sulfonylureas and metformin (the only available biguanide) are by far the most widely prescribed oral antidiabetic agents. Consequently sulfonylureas are involved in the vast majority of oral hypoglycemic toxicity. Untreated, overdose of sulfonylurea medications may cause significant morbidity or mortality. Furthermore, these agents may be particularly dangerous for pediatric patients, as even small doses (1-2 pills) may produce deadly effects in a toddler. This article will focus on the pathophysiology, recognition, and treatment of acute sulfonylurea overdose.
A 2 year-old male is brought to the emergency department by his parents approximately 30 minutes after being found playing with his grandfather’s medication bottles. Most of the containers in question were child-resistant and unopened. Unfortunately, a bottle of glyburide tablets were opened and scattered about. Several tablets were found in the patient’s diaper, another in his mouth, and four others are unaccounted for. Upon presentation the patient’s vital signs and physical examination are normal. A finger-stick blood glucose reading is 76 mg/dL.
- What is a sufficient period of observation for the asymptomatic oral hypoglycemic overdose patient?
- When is treatment indicated after oral sulfonylurea overdose or exposure?
- What treatment options are available for treatment of sulfonylurea toxicity?
In the 2002 annual report of toxic exposures published by the American Association of Poison Control Centers (AAPCC), over 80% of oral hypoglycemic exposures involved sulfonylureas or metformin. Sulfonylureas represented the majority of these acute poisonings.
All sulfonylurea medications act on pancreatic beta-islet cells to stimulate the release of preformed insulin. By blocking ATP-dependent potassium channels on beta-islet cells, calcium influx is increased, ultimately resulting in exocytosis of insulin secretory granules.
Currently available sulfonylurea medications are divided into first and second generations. Although second generation sulfonylureas are more potent than first generation agents on an equimolar basis, both have an identical mechanism of action. All sulfonylureas are 100% bioavailable and reach peak serum levels and effectiveness by 4-6 hours after oral ingestion.
The clinical effects of sulfonylurea toxicity are the direct result of hyperinsulinemia and subsequent hypoglycemia. Although hypoglycemia is defined as serum glucose below 60 mg/dL, the clinical manifestations of low blood sugar vary widely between individuals. While most healthy patients will begin to experience symptoms when blood glucose is at or below 50 mg/dL, poorly controlled diabetics may develop symptoms with blood glucose levels as high as 80 mg/dL.
Early symptoms of hypoglycemia consist of dizziness, lightheadedness, and mild nausea. As serum glucose falls, patients may develop altered mental status, CNS depression, coma, seizures, or even focal neurological findings. In one study, 2.5% of hypoglycemic patients presented with hemiparesis. In young children, these effects may be subtle, manifesting as difficulty feeding, nausea and vomiting, CNS depression, seizures, or coma.
While serious adverse outcomes are unusual in cases where hypoglycemia is promptly recognized and treated, permanent sequelae are frequently reported in cases where recognition is delayed. Severe, prolonged hypoglycemia may cause permanent neurological injury directly or result in indirect injury related to seizures or anoxia. In two studies including 101 patients with sulfonylurea overdose, there were five deaths and five cases of permanent neurological damage. In similar studies of pediatric sulfonylurea exposures, serious adverse outcomes were much less common probably due to the smaller size of most (unintentional) pediatric ingestions.
A bedside blood glucose level should be determined early in any patient presenting with altered mental status, seizures, or focal neurological deficits. When hypoglycemia is discovered, sulfonylurea overdose should always be considered, especially in patients with access to these medications. Due to the availability of an effective antidote, physicians should maintain a high level of suspicion.
For asymptomatic patients presenting with a history of possible sulfonylurea ingestion, a 6-8 hour period of observation and serial blood glucose determinations will differentiate true toxic exposures from those without danger.
Patients presenting soon after a potentially dangerous sulfonylurea ingestion should be given oral activated charcoal. Further management after sulfonylurea exposure depends on the presence of symptoms and level of serum glucose.
Asymptomatic + normal glucose: Patients with normal serum glucose levels do not necessarily require treatment or hospital admission. Because all currently available sulfonylurea agents have a time to peak effect of approximately 4-6 hours, patients who develop toxicity after exposure will invariably become hypoglycemic within eight hours. Therefore, patients who remain euglycemic and asymptomatic for an eight-hour period of observation may be considered safe for discharge home directly from the emergency department. During this period of observation, patients should be monitored continuously for changes in mental status with blood glucose checked at least hourly. Oral intake should not effect evaluation, however any intravenous administration of dextrose may postpone the onset of hypoglycemia and therefore necessitates a longer period of observation (up to 18-24 hours).
Symptoms/hypoglycemia: Patients who develop hypoglycemia after sulfonylurea exposure require hospital admission for at least 24 hours. Hypoglycemia should initially be treated with intravenous dextrose boluses to restore normal blood glucose levels (>60 mg/dL). Serum glucose should be monitored every 15 to 60 minutes. Since patients with poorly controlled diabetes may experience hypoglycemic symptoms with blood glucose levels of 60-80 mg/dL, these patients may require treatment despite a “normal” blood glucose.
Octreotide (Somatostatin), a synthetically derived hormone that suppresses insulin release from beta islet cells, can act as a specific sulfonylurea antidote and can be administered either subcutaneously or intravenously to patients exhibiting hypoglycemia following sulfonylurea poisoning. In studies comparing treatments for sulfonylurea-induced hypoglycemia, octreotide was shown to improve hypoglycemia and decrease the need for dextrose administration. The dose of octreotide is 50–100 mcg given IV or SQ every 8 to 12 hours. Some sources have recommended more frequent dosing or a continuous infusion of octreotide. When used for short-term therapy, as in the treatment of sulfonylurea overdose, octreotide has essentially no side effects. Pediatric dosing is not well established. Because octreotide is dispensed in 50 mcg vials, use of 50 mcg per dose in children (regardless of size) is reasonable. The long-acting preparation of octreotide, Sandostatin LAR, should not be used in the management of sulfonylurea poisoning.
As stated above, intravenous dextrose boluses should be initiated promptly upon recognition of hypoglycemia. For adults, 1-2 ampules (0.5-1 g/kg, or 1-2 mL/kg) of 50% dextrose solution may be given. Pediatric patients are treated with 2-4 mL/kg of 25% dextrose solution. A 10% dextrose infusion may be instituted in patients with persistent hypoglycemia or in those refractory to octreotide. Due to an unfavorable risk/benefit profile, diazoxide is no longer indicated.
Summary and discussion of case questions
- All available sulfonylurea agents have a similar time of onset (around 4-6 hours), but some, like chlorpropamide, may last considerably longer than others. Emergency department disposition without treatment may be considered for patients who remain euglycemic and asymptomatic for at least eight hours after ingestion, provided no parenteral dextrose or octreotide was administered during or previous to the period of observation.
- Hospital admission and institution of therapy should be initiated in all patients with documented hypoglycemia, regardless of current symptoms.
- Early decontamination of large or potentially dangerous ingestions may be attempted with oral activated charcoal. Hypoglycemia should initially be treated with dextrose bolus therapy (D50 or D25). Octreotide is a synthetic somatostatin analog that inhibits insulin release from pancreatic beta islet cells, and therefore acts as a specific antidote in sulfonylurea toxicity. Parenteral octreotide should be administered to all patients manifesting hypoglycemia after sulfonylurea exposure. Continuous dextrose infusion is only necessary in those patients refractory to octreotide therapy.