Sulfonylureas stimulate pancreatic beta cells to release insulin.3 (Figure 121-1). Second-generation sulfonylureas (glimepiride, glipizide, and glyburide) are more commonly prescribed than the first generation (tolbutamide and chlorpromide). All of the second-generation agents are rapidly absorbed, have a duration of action of approximately 24 hours, and a single dose may produce mild symptomatic hypoglycemia in a young child.
Site of action for insulin secretagogues. (Reproduced with permission from Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc.;2011 All rights reserved.)
Case reports, prospective case series, and a retrospective review document mild to moderate hypoglycemia following reported single-dose sulfonylurea ingestions.4–6 There are no reports of deaths or permanent sequelae in young children after unintentional ingestion of these drugs.
Signs and symptoms of hypoglycemia include dizziness, diaphoresis, anxiety, headache, confusion, fatigue, slurred speech, coma, and seizures. Delayed onset of toxicity has been reported, but this is seen in patients receiving parenteral dextrose administered to euglycemic patients with the intent of preventing hypoglycemia.
Duration of observation of asymptomatic young children presenting with the history of sulfonylurea ingestion is problematic because of reports of delayed onset of hypoglycemia. Recommendations vary from 8–24 hours. Since delayed hypoglycemia occurred in children receiving prophylactic intravenous dextrose, this practice should be avoided. A 2005 literature review4 and a 1997 prospective multi-center observational series in 185 children7 both recommend 8 hours of observation. A 2011 retrospective medical record review of 93 children admitted to a single institution recommended 16 hours of observation.6 The median time for hypoglycemia was 4.0–5.5 hours with the longest interval 13.0 hours. However there was no mention of whether or not parenteral dextrose was administered. A 1996 retrospective poison center review of 93 children recommended 24 hours of observation.8 Fifty-three of the 93 children received parenteral dextrose, and hypoglycemia beyond 4 hours was documented in only four (at 11, 12, 12 and 16 hours). All four were being treated with parenteral dextrose.
Therefore, asymptomatic young children presenting with the history of sulfonylurea ingestion should not be treated with prophylactic intravenous dextrose. They should receive hourly point of care blood sugar measurements and may be discharged from the emergency department if 8 hours of euglycemia is documented.
If the patient presents less than 1.0 hour after the ingestion of potentially toxic sulfonylurea, consider the administration of activated charcoal. If hypoglycemia occurs, administer an intravenous bolus of 0.5 g/kgof 25% dextrose followed by a 5% or 10% dextrose infusion. This often reverses the hypoglycemia of mild sulfonylurea poisoning. Unfortunately, dextrose is a secretagogue for sulfonylurea-sensitized beta cells resulting in insulin release. Thus, hypoglycemia may be refractory to supplemental dextrose administration. Glucagon and corticosteroids, because of their hyperglycemic actions, may be considered for sulfonylurea-poisoned patients resistant to dextrose therapy. However, these interventions are ineffective because they also stimulate insulin secretion.
Octreotide, a synthetic analogue of somatostatin, is indicated in all sulfonylurea-poisoned patients unresponsive to parenteral dextrose. Octreotide inhibits pituitary release of growth hormone and inhibits glucagon and insulin release.9 Although there are limited data, animal models of SU overdose indicate that octreotide reduces the number of refractory hypoglycemic episodes.10,11 Case series indicate that octreotidedecreases the need for supplemental glucose and the number of hypoglycemic events.11,12 There are reports of octreotide being used in children with sulfonylurea poisoning.13–15 When used in acute overdose, complications of this antidote are infrequent and include nausea, vomiting, abdominal pain, and diarrhea.11 Consider administering 1–1.25 μg/kg if hypoglycemia occurs despite dextrose infusion. Octreotide may be administered intravenously or subcutaneously. If additional octreotide doses are required, consider a continuous infusion. Diazoxide also blocks insulin secretion and is effective for sulfonylurea-induced hypoglycemia,2 but the intravenous preparation is no longer available.
Children who remain asymptomatic and euglycemic for 8 hours without parenteral dextrose administration may be discharged from the emergency department. If hypoglycemia is documented, initiate treatment and admit to hospital.
Currently available meglitinides include repaglinide and nateglinide. Although structurally different from sulfonylureas, these drugs also stimulate insulin secretion (Figure 121-1) and can produce hypoglycemia.3,16 Peak plasma concentrations of each occur within 1 hour and elimination half-life is approximately 1–1.5 hours. Meglitinides are not approved for use in children. Pediatric dosing is not available, and there are no reports of pediatric overdose. Since therapeutic doses have caused hypoglycemia in non-diabetic adult patients, any dose in pediatric patients may potentially cause hypoglycemia.17
There is no overdose experience in children and negligible experience in adults. Because of their shorter duration of action, they are expected to cause less severe hypoglycemia than sulfonylureas. If hypoglycemia is documented, follow the sulfonylurea management.
Currently available DPP-IV inhibitors include linagliptin, sitagliptin, and saxagliptin. DPP-IV is an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This stimulates insulin release and inhibits glucagon secretion (Figure 121-1).3,18 The release of insulin stimulated by GLP-1 and GIP is glucose dependent and should only occur in the setting of high or normal glucose. Thus, the development of significant hypoglycemia is not expected. Peak plasma concentrations generally occur within 1–4 hours with a variable half-life depending on the agent. DPP-IV inhibitors are not approved for use in children, and there are no case reports of overdose in children. While not as potent hypoglycemic agents as the sulfonylureas, hypoglycemia may occur following ingestion. The only reported adult overdose occurred in an 86-year-old female who ingested 1700 mg of sitagliptin (17 times recommended therapeutic dose) who was treated with intravenous dextrose for 11 hours following ingestion and did not develop hypoglycemia.19
For children presenting with overdose of one of these drugs, hourly point of care blood sugar measurements for 4–6 hours should suffice. Administer parenteral dextrose only if hypoglycemia is documented. Significant hypoglycemia is not expected.