Are one or two dangerous? Sulfonylurea exposure in toddlers

The Journal of Emergency Medicine, Vol. 28, No. 3, pp. 305–310, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/05 $–see front matter

doi:10.1016/j.jemermed.2004.09.012

Selected Topics: Toxicology ARE ONE OR TWO DANGEROUS? SULFONYLUREA EXPOSURE IN TODDLERS Gary L. Little,

MD

and Keith S. Boniface,

MD

Department of Emergency Medicine, George Washington University Hospital, Washington, DC Reprint Address: Jeffrey N. Love, MD, Department of Emergency Medicine, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC 20007

e Abstract—Sulfonylurea-based oral hypoglycemics are in widespread use in the adult population, increasing the potential for unintentional exposure in children. This article examines the risk of toxicity in children under 6 years of age who ingest one to two tablets of a sulfonylurea. We review the literature on sulfonylurea toxicity, including cases reported to the American Association of Poison Control Centers (AAPCC). The ingestion of one to two sulfonylurea tablets by a small child can lead to profound hypoglycemia with severe sequelae if untreated. As a result, all potential sulfonylurea ingestions by young children should be evaluated by a physician. A capillary glucose level must be rapidly determined at presentation and should then be repeated at regular intervals for up to 8 hours. A longer observation period is recommended for the extended release preparation of glipizide. Asymptomatic children who do not develop hypoglycemia within the recommended observation period may be safely discharged home. All children who exhibit clear symptoms of hypoglycemia or glucose levels < 60 mg/dL should be admitted for supplemental glucose (oral or intravenous), with careful observation of clinical condition and monitoring of serum glucose levels. In cases refractory to intravenous glucose, therapy with octreotide or diazoxide may be beneficial. © 2005 Elsevier Inc.

INTRODUCTION Sulfonylurea agents are widely used in the management of type 2 diabetes mellitus. Glyburide and glipizide are consistently listed in the top 200 prescribed medications. In the year 2000, Glucotrol XL® (extended-release glipizide) and glyburide produced over $4 million and $1.8 million in revenue, respectively (1). Although sulfonylurea medications provide effective treatment of type 2 diabetes, they can cause potentially life-threatening hypoglycemia in overdose. Widespread use of these medications allows access by small children, making unintentional ingestions a serious concern. Ingestion of a few tablets by a small child is said to have the potential to cause serious morbidity or mortality. If true, unintentional ingestion of sulfonylureas can lead to profound hypoglycemia and adverse neurologic effects, including coma or death. The major objective of this article is to define the risk of death and major neurologic sequelae from the ingestion of 1–2 tablets of a sulfonylurea compound in toddler-age children. In addition, we review the existing evidence guiding the management of sulfonylurea poisoning in young children.

e Keywords—sulfonylureas; children; pediatrics; toxicity; overdose; poisoning

CASE PRESENTATION Series Editors: Jeffrey N. Love, MD, The Georgetown University Emergency Department, Washington, DC; Wendy Klein-Schwartz, PharmD, MPH, The Maryland Poison Control Center, Baltimore, MD; Liesl Curtis, MD, The Georgetown University Emergency Department, Washington, DC.

A 2 year-old girl was brought to the emergency department (ED) due to lethargy. The parents stated that 4 hours earlier the child was witnessed to have been playing with the father’s bottle of Glucotrol XL 10 mg

Selected Topics: Toxicology is coordinated by Kenneth Kulig,

RECEIVED: 4 December 2002; FINAL ACCEPTED: 21 September 2004

SUBMISSION RECEIVED:

MD,

of Denver, Colorado

26 August 2004; 305

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G. L. Little and K. S. Boniface

Table 1. Pharmacokinetics of Selected Sulfonylureas

Generation

Generic Name

Trade Name

First First First Second Second Second

Chlorpropamide Tolazamide Tolbutamide Glipizide Glipizide Glyburide

Third

Glimepiride

Diabinase Tolinase Orinase Glucotrol Glucotrol XL Micronase, DiaBeta, Glynase Amaryl

Time to Peak (h)

Half-life (h)

Duration of Action (h)

Metabolism

Renal Excretion of Active Metabolite

2–7 3–4 3–4 1–3 6–12 2–6

36 7 4.5–6.5 7 7 10

60 14–24 12–24 12–24 24 12–24

Hepatic Hepatic Hepatic Hepatic Hepatic Hepatic

Yes Yes Yes No No Yes

2–3

5–9

16–24

Hepatic

Yes

tablets. Only one pill was missing and the parents called the child’s pediatrician, who instructed the parents to observe the child for any change in behavior. When the child became lethargic, the parents rushed immediately to the ED. On arrival, the child was limp, and lethargic. She did respond to painful stimuli (placement of intravenous line). The initial fingerstick glucose was 39 mg/dL. A bolus of intravenous dextrose (D50 2 mL/kg) was given with improvement of mental status. The child was given graham crackers and apple juice ad lib, while being observed. An hour later the child was drowsy and a fingerstick glucose was 47 mg/dL. Another bolus of D50 was given and an intravenous solution of dextrose was initiated (D5 1/3 normal saline at 1.5 maintenance). Subsequent capillary glucose readings were maintained above 60 mg/dL. The child was admitted to the hospital for 2 days without subsequent episodes of hypoglycemia.

insulin from secretory granules within the pancreatic ␤-islet cell. Sulfonylureas also inhibit hepatic clearance of insulin, thereby inhibiting gluconeogenesis (2). There are also data to suggest that sulfonylureas indirectly decrease peripheral resistance to insulin and enhance its action (2). The mechanisms and significance of these actions are not known. Hypoglycemia is defined as a blood glucose ⬍ 60 mg/dL by serum or capillary blood sample (4,5). Defining hypoglycemia clinically can be difficult depending on the age of the child. Clearly, a lethargic or unresponsive child with low blood glucose can display classic signs of hypoglycemia. Other manifestations of decreased blood glucose in children are weakness, dizziness, change in behavior, fussiness, seizure, focal neurologic deficit, and decreased appetite. Because the clinical manifestations of early hypoglycemia can be difficult to recognize in very young children and due to the ready availability of glucometers, the blood glucose level is the best indicator to monitor.

CLINICAL MANIFESTATIONS LITERATURE REVIEW In laying the groundwork for managing sulfonylurea toxicity, it is important to understand the pharmacokinetics of these agents. It should be noted that these agents have a prolonged duration of action, are metabolized by the liver, and several are excreted by the kidneys as an active metabolite (Table 1). All of these have important implications with regard to sulfonylurea-induced hypoglycemia. Of the sulfonylureas, chlorpropamide, glyburide and the long-acting formulation of glipizide (Glucotrol XL®) are the most likely to cause prolonged hypoglycemia (⬎ 8 hours) (2,3). Sulfonylureas induce hypoglycemia by stimulating insulin secretion from the pancreas as well as enhancing insulin action on target cells. At the cellular level they inhibit an adenosine triphosphate-dependent potassium channel that results in cell membrane depolarization (2,3). This leads to calcium influx and release of stored

Although there are numerous exposures to sulfonylureas in young children reported to regional poison centers each year, there are sparse prospective data guiding the therapy of these patients. Defining the true risk of serious adverse neurologic outcomes and death is difficult in this setting. With a paucity of large prospective studies, guidelines must rely on retrospective reviews, case reports, and data from regional poison centers. Although only a handful of cases are available that demonstrate the potential for toxicity of one to two tablets of sulfonylureas, these cases raise enough concern that such instances should be taken seriously. Quadrani et al. performed a retrospective review of 93 exposures to sulfonylureas in children aged 1 to 16 years reported to a regional poison center over a 5-year period (4). Their analysis focused on 70 patients admitted to the

Sulfonylurea Exposure in Toddlers

hospital for observation and management. Twenty-five patients (36%) developed a glucose reading ⬍ 60 mg/dL. The onset of this threshold reading ranged between 0.5 and 16 hours after sulfonylurea exposure (reported for 19/25 patients). The mean onset was 4.3 hours, with a median of 2 hours post-ingestion. Although at first glance the range of onset of hypoglycemia is concerning, several points deserve mention. All four subjects with late onset of hypoglycemia (defined arbitrarily as after 8 hours) were receiving continuous glucose infusions before the onset of their low blood sugar. The patient with onset of hypoglycemia at 16 hours developed a blood glucose ⬍ 60 mg/dL soon after an intravenous infusion of 10% dextrose was discontinued. It can be argued that starting a glucose infusion can mask the onset of hypoglycemia, unnecessarily prolonging the period of observation. The elevated blood glucose levels caused by prophylactic dextrose infusions may act as an additional stimulus to insulin release, thereby compounding the toxicity of sulfonylureas and contributing to subsequent hypoglycemia. It is worth noting that the study did not include data from 18 patients who were observed for ⬍ 8 hours and discharged home, as well as from five patients who were otherwise lost to follow-up. Because this was a retrospective study, specific data were limited in many cases. For example, of the 25 patients who developed hypoglycemia, only 19 had a recorded time of onset. Despite the limitations of study design and loss of patients to follow-up, the study did provide some useful information. Of the 93 patients in the study, none suffered seizures, permanent neurologic sequelae, or death (4). A significant number were discharged home after observation without intervention. The remaining patients could be managed successfully with oral or intravenous glucose sources. Most importantly, this series of patients includes cases in which a single tablet of chlorpropamide 250 mg, glipizide 5 mg, and glyburide 2.5 mg each produced hypoglycemia in children aged 1 to 4 years. These three medications represented 95% of the sulfonylureas ingested in this series. This emphasizes the potential toxicity of a single sulfonylurea tablet in small children and reinforces the need for medical evaluation including glucose level determination. Spiller et al. performed the only prospective observational study of unintentional pediatric sulfonylurea exposures in children 12 years and younger reported to 10 regional poison centers (5). There were 185 exposures reported in children aged 10 months to 11 years (mean 2.4 years). Hypoglycemia developed in 56 patients (30%). Fifty-four of 56 were evaluated within 8 hours of exposure (2 patients arrived at the ED more than 12 hours from the time of ingestion). Fifty-three of 54 patients with hypoglycemia developed an onset of glu-

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cose ⬍ 60 mg/dL within 8 hours post-ingestion. The one patient with late-onset hypoglycemia had a single blood glucose measurement of 50 mg/dL several hours after an intravenous dextrose infusion was initiated. Of the 56 patients who developed hypoglycemia, 42 exhibited no clinical signs of hypoglycemia. However, 32 patients received intravenous glucose that may have prevented the onset of symptoms. Minor clinical symptoms (e.g., agitation, lethargy) were exhibited in the remaining 14 patients. Again, the use of intravenous glucose may have prevented any long-term effects from hypoglycemia. In both the retrospective and prospective groups of patients, no long-term adverse outcomes occurred. Also, it seems that onset of hypoglycemic action is typically within 8 hours post-exposure. The cases of delayed onset of hypoglycemia seem to occur in patients started on a prophylactic intravenous glucose infusion. A review of regional poison center data for the past 5 years confirms the findings of these previous studies, that death is unlikely in children treated appropriately. Despite approximately 1900 oral hypoglycemic poisonings in children younger than 6 years old per year reported to the AAPCC, only one death can be ascribed to a sulfonylurea medication in a young child (6). In fact, going back to data from 1990 does not reveal any additional deaths secondary to sulfonylurea poisoning in young children (6 –16). The single reported death involved a 2-year-old boy who was found playing with extended-release glipizide and benazepril (6). The child came to medical attention only after he developed seizures while sleeping. Initial blood glucose was 59 mg/dL. Despite adequate blood glucose management, the child died the next day secondary to massive cerebral edema. Although it is unclear that the sulfonylurea ingestion was causative of the cerebral edema, this case highlights the dangerous potential of sulfonylurea ingestion in small children. Szlatenyi et al. reported a case of a 2-year-old boy who ingested a single tablet of glipizide 5 mg as well as 25 mg of hydrochlorothiazide (17). His initial glucose level was ⬎100 mg/dL and he was asymptomatic, but was placed on a glucose infusion (D5 0.2%NS), treated with activated charcoal, and admitted to the hospital. Eleven hours later he developed asymptomatic hypoglycemia (49 mg/dL) that was treated with oral glucose and an increase of his glucose infusion, and he was eventually discharged without sequelae. Spiller et al. reported a case of a 6-year-old girl who ingested an unknown amount of glyburide and presented to an ED with a blood glucose of 34 mg/dL, right-sided hemiparesis, and lethargy (18). She received glucose and was admitted to the hospital. Computed tomography (CT) scan of the brain and initial laboratory values (except for serum glucose) were normal. On day 3 of ad-

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Table 2. Summary of Recommendations for the Management of Accidental Ingestion of 1-2 Sulfonylurea Tablets in Toddlers Capillary Glucose ⬎ 60 mg/dL, no symptoms ⬎ 60 mg/dL, with symptoms ⬍ 60 mg/dL, no symptoms ⬍ 60 mg/dL, with symptoms Refractory hypoglycemia

Recommendations Evaluate all patients; finger stick every 1–2 hours; access to oral glucose. Discharge home if glucose remains ⬎ 60 mg/dL for 8 hours Promote oral intake of glucose containing sources. Persistence of symptoms or borderline glucose levels requires glucose bolus (D25W 2–4 mL/kg 1–24 months; D50W 1–2 mL/kg ⬎ 24 months); with continuous infusion and admission to hospital Glucose bolus; continue access to oral glucose sources, consider continuous glucose infusion; admit to hospital Glucose bolus; continuous glucose infusion; admit to hospital Continuous glucose infusion; octreotide (4–5 ␮g/kg/day subcutaneously divided every 6 hours; max. dose 50 ␮g every 6 hours) or diazoxide (3–8 mg/kg intravenously given over 1 hour); Consider glucagon 0.1 mg/kg subcutaneously

mission the hemiparesis and mental status changes had cleared completely and she was discharged. There were no sequelae resulting from her ingestion, but this case illustrates the potential for severe symptomatic hypoglycemia in these ingestions. Although most cases will not lead to permanent neurologic sequelae or death, hypoglycemia has the potential to be very dangerous. Small children are especially vulnerable due to the non-specific signs of hypoglycemia (delaying diagnosis) and their small glycogen stores. Adverse outcomes are preventable if children receive medical attention early, if blood glucose is monitored vigilantly, and if hypoglycemia is treated aggressively.

TREATMENT There are no studies that definitively answer how nonhypoglycemic patients should be managed. Some authors suggest that the child who ingests a single tablet can safely be observed at home (19). Others recommend intravenous glucose solution empirically for all these children. For the reasons discussed earlier, we believe that the management of euglycemic patients after unintentional sulfonylurea exposure should be expectant (20,21). At a minimum, blood glucose levels should be obtained hourly. In addition, patients should have free access to oral sources of glucose while being monitored in an appropriate environment. General principles of toxicologic exposure management apply. Initial stabilization should be instituted, including oxygen, i.v. access, resuscitation, and intubation if necessary. Rapid glucose level determination is essential. Although controversial, activated charcoal may be useful in children who present to the ED for evaluation within 1 hour after sulfonylurea exposure (22,23). In symptomatic patients and those with a glucose reading ⬍ 60 mg/dL, a bolus of dextrose (1 g/kg; D25W 2– 4 ml/kg for children aged 1–24 months or D50W 1–2 mL/kg for

children aged ⬎ 2 years) should be given, with further monitoring as an inpatient. A continuous infusion of glucose can be initiated at the discretion of the treating physician. The decision should be made on a case-bycase basis, depending on the degree of hypoglycemia, the age of the child, the time of day, and the severity of symptoms. The infusion should be titrated to maintain a serum or finger stick glucose above 60 mg/dL. Occasionally, patients who are refractory to intravenous glucose therapy are encountered. The ideal therapy would be one that raises the blood glucose level without further stimulating insulin release. Specifically, an agent that inhibits the release of insulin would be optimal. Two agents, octreotide and diazoxide, satisfy these requirements. Octreotide is a synthetic peptide analogue of the endogenous human hormone somatostatin. It has been found to be a potent inhibitor of insulin secretion, in addition to its effects on numerous other hormones (24,25). One study compared the efficacy of octreotide to dextrose or diazoxide in treating glyburide overdose (24). The authors found that dextrose infusion requirements were lower in the octreotide group than the other treatment groups. Also, subjects treated with octreotide had significantly lower serum insulin levels than in the dextrose- and diazoxide-treated patients. In a retrospective chart review of 9 patients (age range 20 – 65 years) with sulfonylurea overdose, there were no side effects or adverse events after treatment with octreotide (25). After octreotide therapy, the number of hypoglycemic events and the number of ampules of 50% dextrose needed were reduced significantly. Treatment of refractory sulfonylurea toxicity with octreotide has not been studied extensively in children. In one case report, a 5-year-old boy with status epilepticus and hypoglycemia after glipizide overdose was treated with lorazepam, intravenous dextrose, and octreotide, with prompt improvement of glucose level and rapid weaning of dextrose (26). Diazoxide, a direct arteriolar vasodilatator, is an in-

Sulfonylurea Exposure in Toddlers

travenous anti-hypertensive used in hypertensive emergencies. It also directly decreases ␤-islet cell insulin secretion (27). A retrospective review of 40 sulfonylurea overdoses during a 10-year period revealed 6 patients (age range 14 –28 years) successfully treated with diazoxide for recurrent hypoglycemia, despite repeated glucose treatments (28). Similar results are reported in multiple case reports using diazoxide in the therapy of sulfonylurea overdose (26,29 –32). In current practice, octreotide is generally preferred so diazoxide is rarely used. In theory, glucagon is an attractive therapeutic option in sulfonylurea-induced hypoglycemia. The advantage of glucagon is that it can be used in patients without intravenous access or the ability to take glucose orally (33). However, glucagon has no direct inhibitory effect on sulfonylurea-induced insulin release and hyperglycemia generated by glucagon could act as a further stimulus to insulin secretion in an already primed state (33,34). Table 2 summarizes treatment recommendations.

RECOMMENDATIONS AND SUMMARY On average, 1900 exposures to hypoglycemics are reported annually to the AAPCC in children less than 6 years of age. Although only one death has been reported in a child with a potential exposure to oral sulfonylureas, a significant percentage of patients (up to 36%) will develop hypoglycemia, which has the potential to cause significant neurologic sequelae if it is not recognized and treated promptly (4). The literature on the toxicity of sulfonylureas is often non-specific with regard to the amount ingested, but selected case reports illustrate the potential for toxicity in children who ingest only one to two tablets (4,17). Based on the currently available literature, we recommend that all children suspected of sulfonylurea ingestion be evaluated and observed in an emergency department for 8 hours with frequent monitoring of serum glucose. Until more experience with the extended release (XL) preparation of glipizide is available, a longer observation period should be considered because this dosage form exhibits a delayed time to peak compared with the other products on the market. Children treated with intravenous glucose should be monitored for several hours after the glucose infusion is discontinued to ensure that hypoglycemia does not develop.

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