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Emergency Management of Oral Hypoglycemic Drug Toxicity
Emerg Med Clin N Am 25 (2007) 347–356
Emergency Management of Oral Hypoglycemic Drug Toxicity Adam K. Rowden, DOa,*, Charles J. Fasano, DOa,b a
Department of Emergency Medicine, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA b Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107-5587, USA
Exposure to oral hypoglycemic agents is a common problem confronting the emergency physician. In 2004, there were more than 10,000 exposures to these medications reported to the American Association of Poison Control Centers (AAPCC). Of these exposures, 40% involved sulfonylureas, 40% involved metformin, and the remaining 20% involved other or unknown oral hypoglycemic agents [1]. Because of the large array of oral diabetic agents available, their diverse mechanisms of action, and large variations in the potential for adverse outcomes, the emergency physician must have knowledge of the available agents and the potential for toxicity. Oral hypoglycemic agents likely to cause hypoglycemia Sulfonylureas This class of drugs is a mainstay of treatment of type II diabetes. The sulfonylureas are separated into first- and second-generation drugs. The primary difference in this classification is that the second-generation agents have a shorter elimination half-life (t1/2) than the first-generation agents. These agents stimulate insulin secretion from pancreatic beta cells [2–4]. Most of the sulfonylureas are metabolized through the liver and excreted by the kidney. Many of the metabolites are themselves active, although to a lesser degree than the parent compound. These active metabolites likely account for the long duration of action that may be seen following overdose [3]. The extremely long t1/2 and duration of action of these medications is beneficial for glucose control and medication compliance, but can be problematic when toxicity is encountered. * Corresponding author. E-mail address: [email protected] (A.K. Rowden). 0733-8627/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.emc.2007.02.010 emed.theclinics.com
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The toxicity of sulfonylureas in overdose is an extension of their therapeutic mechanism. With toxicity, the pancreas secretes excessive insulin with a resultant decrease in blood sugar [2–4]. Because of the long duration of action, those patients who have sulfonylurea-induced hypoglycemia can have repeated episodes of hypoglycemia that can be refractory to treatment [5]. Typically, patients require glucose monitoring for 24 hours, but in rare cases hypoglycemic episodes continue as many as 27 days after the initial ingestion [6]. The management of sulfonylurea toxicity is simply repeat assessment of blood glucose levels and correction of hypoglycemia if it develops. Patients who have intentional overdoses of these agents may require more aggressive management and prolonged monitoring for hypoglycemia. Diabetic patients who take their therapeutic sulfonylurea dose and then experience hypoglycemia present a unique challenge to the emergency physician. After correction of the hypoglycemia, a search for the underlying cause of the hypoglycemia must be completed. Some common causes include drug– drug interactions, decreased drug metabolism, or decreased drug excretion [7]. The complicated nature of these problems coupled with the extended t1/2 and active metabolites of the sulfonylureas makes a compelling argument for prolonged observation or inpatient admission of these patients [3,4,8]. A child exposed, or potentially exposed, to a sulfonylurea is commonly encountered in emergency medicine. In 2004, 1400 exposures to sulfonylureas in children less than 6 years of age were reported to the AAPCC [1]. Even one pill is enough to cause clinically significant hypoglycemia in toddlers [9–11]. The onset of hypoglycemia can also be delayed with rare case reports suggesting a delay of 11 to 21 hours for specific agents [10–13]. In a large, prospective, observational series, Spiller found that no child had an onset of hypoglycemic symptoms more than 8 hours after exposure [11]. Extrapolating these data, 8 hours of euglycemia is the minimum time period that a child should be watched to predict a benign outcome. If hypoglycemia develops during that time period, however, the patient should then be admitted and observed [12,14]. Multiple cases of surreptitious or accidental poisoning by sulfonylureas are reported in the literature. Intentional surreptitious ingestion [15], pharmacy dispensing errors, [16,17] contaminated herbal products [18], and cases of Munchausen by proxy in pediatric, adult, and geriatric patients [19–22] have been described. In such cases the C-peptide test, used to differentiate endogenous from exogenous insulin, is elevated because sulfonylurea exposure results in secretion of endogenous insulin from the pancreas [15]. Assays are available to screen for sulfonylureas [23], but because of the multitude of products available, false negatives have been encountered [24,25] making more specific testing necessary in some clinical scenarios. Meglitinides Repaglinide and nateglinide are the two meglitinides available in the United States and are novel agents for type II diabetes. They have
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a mechanism similar to the sulfonylureas but with a faster onset and shorter duration of action [3]. Limited experience in overdose suggests that hypoglycemia is possible but may not be as long lasting as that caused by sulfonylureas [26,27]. In a case reported by Hirsberg [26], a patient experienced repeated episodes of hypoglycemia and was subsequently evaluated for the possibility of an insulinoma. It was later discovered that he was intentionally overdosing on repaglinide. Likewise, Nakayama [27] reported a case of hypoglycemia in a patient after intentional overdose of nateglinide. In both cases, hypoglycemia was easily treated with dextrose solutions and the duration of action was short. Hypoglycemia also has been reported following therapeutic dosing of these agents [28]. Nagai [28] reported a woman who was started on nateglinide and experienced repeated episodes of hypoglycemia during therapeutic dosing even after her initial dose was halved. The patient’s decreased creatinine clearance was speculated to be the cause along with the nateglinide. In a controlled volunteer study, Fonseca and colleagues [29] found that patients who had diabetes who were mildly hyperglycemic and were given therapeutic doses of repaglinide were more likely to experience hypoglycemia than controls. Until further data are available, treating physicians should err on the side of caution in regard to the treatment and disposition of meglitinide exposures and approach them in similar manner as the sulfonylureas. Treatment of oral hypoglycemic-induced hypoglycemia As with any poisoned patient, the initial assessment is focused on addressing airway, breathing, and circulation. After the primary survey, any patient who has altered mental status should have his or her blood glucose evaluated. After initial stabilization, preventing absorption and enhancing elimination of the causative agent and possible antidotal therapy can be considered. There is controversy regarding the effectiveness of activated charcoal in the setting of sulfonylurea overdose. With the exception of tolbutamide, the first-generation agents do not seem to be effectively bound by activated charcoal [30]. The second-generation agents seem to have higher affinity for charcoal [31]. As with any overdose, when considering gastrointestinal decontamination the risk for aspiration should be weighed against any potential benefit. Hemodialysis and charcoal hemoperfusion [32] have been attempted for sulfonylurea toxicity in case reports, but are not routinely recommended. Hypoglycemia is a common presentation to the emergency department [33]. Regardless of the cause, the emergency management of hypoglycemia includes early recognition and administration of rapidly metabolized carbohydrates in the form of oral glucose or intravenous (IV) dextrose. In patients who have altered mental status, hypoglycemia is treated with a rapid bolus of IV 50% dextrose and dextrose-containing IV fluids [34]. The initial dose of dextrose is a 50 mL bolus of 50% dextrose IV, which
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provides 25 g of glucose. This dose may be repeated as needed for persistent episodes of hypoglycemia. In children, the initial recommended dose of dextrose for the treatment of hypoglycemia is a 2 mL/kg bolus of 25% dextrose in water IV, and in infants the dose is 2 to 4 mL/kg of 10% dextrose in water IV. When the patient’s mental status is normalized after initial treatment, long-acting oral carbohydrates or a continuous intravenous infusion of dextrose may need to be administered to prevent subsequent episodes. The hypoglycemic patient who does not have IV access presents a challenge to the treating physician. These patients are often confused and combative making the placement of IV catheters difficult. Sublingual administration of dextrose has been shown to be effective in children who have hypoglycemia [35]. Glucagon is an FDA-approved agent for the treatment of hypoglycemia and should be administered if attempts at IV access are unsuccessful [36]. The treatment of sulfonylurea-induced hypoglycemia is much more complex than insulin-induced hypoglycemia. Poisoning may be refractory to the routine treatments rendered for hypoglycemia and often requires repeated supplemental glucose administration, higher concentrations of glucose, and antidotal therapy. Octreotide Octreotide is a somatostatin analog that is known to suppress insulin secretion [37]. Several case reports and one prospective study in healthy volunteers have demonstrated the safety and efficacy of octreotide administration for the treatment of sulfonylurea-induced hypoglycemia [38–41]. McLaughlin and colleagues [40] published a retrospective case series of nine patients and concluded that octreotide is safe and effective in preventing rebound hypoglycemia after sulfonylurea ingestion. Boyle and colleagues [38] showed that octreotide was superior to glucose and diazoxide in preventing recurrent hypoglycemia in eight glipizide-poisoned volunteers. Octreotide has been shown to be effective in massive sulfonylurea overdose. Case reports have demonstrated the efficacy of octreotide in intentional glyburide overdose in adults [42,43] and in accidental overdose in children [44]. The indications and dosage intervals of octreotide have not been clearly defined. Some authors recommend a single 50 to100 mg subcutaneous injection after a single hypoglycemia episode [40], whereas others recommend serial subcutaneous injections every 6 to 8 hours or constant intravenous infusion after a second hypoglycemic episode [4,42,45–47]. A recently published prospective pilot study enrolled patients who presented to the emergency department with a single sulfonylurea-induced hypoglycemic episode and randomized them to receive either standard therapy consisting of 50% dextrose IV and oral carbohydrates or standard therapy plus 50 mg subcutaneous octreotide. Preliminary data demonstrated a trend toward a decrease in frequency of hypoglycemic episodes and an increase in
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mean glucose at specified intervals in those patients receiving octreotide compared with placebo [48]. Future protocols need to be developed to further confirm the above-mentioned efficacy of octreotide and define the ideal dosage and interval [40,48,49]. Glucagon Glucagon is a polypeptide hormone approved for the treatment of hypoglycemia. Glucagon is of particular interest to emergency personnel because it is efficacious for the treatment of hypoglycemia when given subcutaneously or intramuscularly, thereby negating the need for an IV line. Numerous studies have shown the efficacy and safety of glucagon for the treatment of hypoglycemia [50–52]. Vukmir and colleagues [52] showed an approximate 100 mg/dL increase in serum glucose in 49 of 50 prehospital hypoglycemic patients who received subcutaneous glucagon. In separate studies, Howell and Guly [51] and Carstens and Sprehn [50] concluded that subcutaneous glucagon administration is a safe and efficacious treatment of hypoglycemia, and it should be strongly considered when intravenous dextrose cannot be given because of the lack of IV access. Ideally, intravenous dextrose should be used to treat hypoglycemia. If this is impossible, glucagon should be administered at the dose of 1 mg in adults (greater than 20 kg) and 0.5 mg in children (less then 20 kg) by way of subcutaneous or intramuscular injection. Several studies from Europe in the 1990s showed the safety and efficacy of intranasal glucagon for the treatment of hypoglycemia [53–55]. Glucagon should be used with caution in patients who have presumed sulfonylurea-induced hypoglycemia. Its mechanism of action involves inducing gluconeogenesis by recruiting hepatic glycogen stores. This increase in serum glucose in addition to the physiologic response of insulin released by glucagon in theory could exacerbate clinical hypoglycemia in a patient who is already in a toxin-induced hyperinsulinemic state [4]. Diazoxide Diazoxide directly inhibits insulin secretion from pancreatic beta cells. It has been shown to be an effective treatment of refractory sulfonylureainduced hypoglycemia [5]. Because of its potential for hypotension, diazoxide should be used with caution. Hypotension may be limited by slow intravenous infusion (300 mg over 30 minutes every 4 hours). Disposition Patients who are exposed to sulfonylureas or meglitinides and experience hypoglycemia should be admitted for serial monitoring of their blood glucose. Exposures (ie, an intentional overdose in an adult or a child who is found ingesting a pill) that present without hypoglycemia should be
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observed for a minimum of 8 hours. If hypoglycemia develops during that observation period, the patient should be admitted for further monitoring [8,11,47].
Oral hypoglycemic agents that do not cause hypoglycemia Biguanides Metformin is the only biguanide agent available in the United States. It controls type II diabetes by several mechanisms that have not been fully elucidated. Limiting gluconeogenesis in the liver seems to be its primary mechanism. It also increases insulin receptors in muscle tissue, thereby increasing glucose uptake into cells [3,4,8,56]. It has not been shown to increase insulin secretion from the pancreas or interfere with the hormonal regulation of insulin secretion [56,57]. It therefore does not result in hypoglycemia in either therapeutic or overdose situations. Reports of metformin-related hypoglycemia involve a combination of metformin and another antidiabetic agent [8,58–60]. Lactic acidosis is a rare but serious major complication of metformin use in overdose and therapeutic situations [8,57–60]. The incidence of lactic acidosis during therapeutic dosing is low and has been estimated 1 per 10,000 patient years [61]. The most important risk factor for developing lactic acidosis during therapeutic dosing is decreased creatinine clearance [61,62]. Because metformin-induced lactic acidosis is associated with impaired renal function, those taking metformin should abstain for 48 hours after radiologic studies using intravenous contrast [62]. In overdose, high serum lactates are reported and severe acidemia is possible [58,60,63–71]. Treatment is largely supportive because no antidotal therapy is available. Although not routinely used, it is possible to enhance the elimination of metformin by extracorporeal techniques. The clearance of metformin using traditional hemodialysis has been reported to be 68 to 150 mL/min [72]. Hemodialysis was used in several case reports, with mixed results [66,68,69,71]. Metformin is cleared by both traditional dialysis [72,73] and by continuous renal replacement therapy using continuous veno-venous hemodialysis (CVVHD) in which the clearance was reported at 50 mL/h [74]. CVVHD may provide an alternative to traditional dialysis in the hemodynamically unstable patient. CVVHD alone [67,73] and in combination with traditional dialysis [75,76] has been used in case reports with mixed outcomes. Although enhancing the elimination of metformin, these options have the added benefit of correcting the metabolic derangements typical of the severely poisoned patient. It should also be noted that most poisoned patients have favorable clinical outcomes when managed with purely supportive efforts [13,47,58]. As with all therapeutic decisions, the risks and benefits of invasive treatment modalities must be weighed in each individual case. In a retrospective case series, Spiller and Quadrani [58] found that
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patients who had severe acidosis, large anion gaps, hyperglycemia, and hemodynamic instability were more likely to have serious morbidity and mortality. These data suggest that patients who develop these findings may benefit from extracorporeal elimination techniques. Children potentially exposed to metformin do not seem to be at high risk for adverse outcomes. In a small, retrospective case series of 55 patients ingesting between 1 and 10 mg/kg, none developed hypoglycemia and all were clinically well without adverse outcomes [59]. Glitazones Despite being available for several years, there are limited data on the glitazones in overdose. Based on case reports and the mechanism of action of these medications, hypoglycemia seems unlikely. These medications act to increase insulin sensitivity in the peripheral tissues [3,8]. Like metformin, the feedback loops remain intact in regard to insulin secretion of the pancreas, and therefore hypoglycemia does not occur. This class has been associated with hepatitis and fulminant hepatic failure with therapeutic doses [3,8]. a-glucosidase inhibitors Acarbose is an a-glucosidase inhibitor that prevents the breakdown of carbohydrates in the gut slowing absorption [3]. This oral agent is extensively metabolized in the gut with little absorption [3,8,47]. The clinical experience with overdose is limited, but hypoglycemia seems unlikely based on the drug’s mechanism of action. Summary The myriad of oral agents available for the treatment of diabetes complicates the approach to assessment, treatment, and disposition of the potentially poisoned patient. After initial stabilization and assessment of blood glucose, the emergency physician must make every effort to determine what class of medication the patient may have been exposed to so that complications may be anticipated and appropriate disposition decisions made. References [1] William A. Watson, George C. Rodgers Jr, Jessica Youniss, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2005;23(5):589–666. [2] Eliasson L, Renstrom E, Ammala C, et al. PKC-dependent stimulation of exocytosis by sulfonylureas in pancreatic beta cells. Science 1996;271(5250):813–5. [3] Carlton FB Jr. Recent advances in the pharmacologic management of diabetes mellitus. Emerg Med Clin North Am 2000;18(4):745–53.
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[4] Harrigan RA, Nathan MS, Beattie P. Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment. Ann Emerg Med 2001;38(1):68–78. [5] Palatnick W, Meatherall RC, Tenenbein M. Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy. Arch Intern Med 1991;151(9):1859–62. [6] Ciechanowski K, Borowiak KS, Potocka BA, et al. Chlorpropamide toxicity with survival despite 27-day hypoglycemia. J Toxicol Clin Toxicol 1999;37(7):869–71. [7] Chelliah A, Burge MR. Hypoglycaemia in elderly patients with diabetes mellitus: causes and strategies for prevention. Drugs Aging 2004;21(8):511–30. [8] Spiller HA, Sawyer TS. Toxicology of oral antidiabetic medications. Am J Health Syst Pharm 2006;63(10):929–38. [9] Osterhoudt KC. This treat is not so sweet: exploratory sulfonylurea ingestion by a toddler. Pediatr Case Rev 2003;3(4):215–7. [10] Seltzer HS. Drug-induced hypoglycemia. A review of 1418 cases. Endocrinol Metab Clin North Am 1989;18(1):163–83. [11] Spiller HA, Villalobos D, Krenzelok EP, et al. Prospective multicenter study of sulfonylurea ingestion in children. J Pediatr 1997;131(1 Pt 1):141–6. [12] Quadrani DA, Spiller HA, Widder P. Five year retrospective evaluation of sulfonylurea ingestion in children. J Toxicol Clin Toxicol 1996;34(3):267–70. [13] Szlatenyi CS, Capes KF, Wang RY. Delayed hypoglycemia in a child after ingestion of a single glipizide tablet. Ann Emerg Med 1998;31(6):773–6. [14] Borowski H, Caraccio T, Mofenson H. Sulfonylurea ingestion in children: is an 8-hour observation period sufficient? J Pediatr 1998;133(4):584–5. [15] Waickus CM, de Bustros A, Shakil A. Recognizing factitious hypoglycemia in the family practice setting. J Am Board Fam Pract 1999;12(2):133–6. [16] Shumak SL, Corenblum B, Steiner G. Recurrent hypoglycemia secondary to drug-dispensing error. Arch Intern Med 1991;151(9):1877–8. [17] Sledge ED, Broadstone VL. Hypoglycemia due to a pharmacy dispensing error. South Med J 1993;86(11):1272–3. [18] Goudie AM, Kaye JM. Contaminated medication precipitating hypoglycaemia. Med J Aust 2001;175(5):256–7. [19] Ben-Chetrit E, Melmed RN. Recurrent hypoglycaemia in multiple myeloma: a case of Munchausen syndrome by proxy in an elderly patient. J Intern Med 1998;244(2):175–8. [20] Fernando R. Homicidal poisoning with glibenclamide. Med Sci Law 1999;39(4):354–8. [21] Owen L, Ellis M, Shield J. Deliberate sulphonylurea poisoning mimicking hyperinsulinaemia of infancy. Arch Dis Child 2000;82(5):392–3. [22] Trenque T, Hoizey G, Lamiable D. Serious hypoglycemia: Munchausen’s syndrome? Diabetes Care 2001;24(4):792–3. [23] Hoizey G, Lamiable D, Trenque T, et al. Identification and quantification of 8 sulfonylureas with clinical toxicology interest by liquid chromatography-ion-trap tandem mass spectrometry and library searching. Clin Chem 2005;51(9):1666–72. [24] Earle KE, Rushakoff RJ, Goldfine ID. Inadvertent sulfonylurea overdosage and hypoglycemia in an elderly woman: failure of serum hypoglycemia screening. Diabetes Technol Ther 2003;5(3):449–51. [25] Klonoff DC. A flaw in the use of sulfonylurea screening to diagnose sulfonylurea overdosages. Diabetes Technol Ther 2003;5(3):453–4. [26] Hirshberg B, Skarulis MC, Pucino F, et al. Repaglinide-induced factitious hypoglycemia. J Clin Endocrinol Metab 2001;86(2):475–7. [27] Nakayama S, Hirose T, Watada H, et al. Hypoglycemia following a nateglinide overdose in a suicide attempt. Diabetes Care 2005;28(1):227–8. [28] Nagai T, Imamura M, Iizuka K, et al. Hypoglycemia due to nateglinide administration in diabetic patient with chronic renal failure. Diabetes Res Clin Pract 2003;59(3):191–4. [29] Fonseca VA, Kelley DE, Cefalu W, et al. Hypoglycemic potential of nateglinide versus glyburide in patients with type 2 diabetes mellitus. Metabolism 2004;53(10):1331–5.
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[30] Kannisto H, Neuvonen PJ. Adsorption of sulfonylureas onto activated charcoal in vitro. J Pharm Sci 1984;73(2):253–6. [31] Kivisto KT, Neuvonen PJ. The effect of cholestyramine and activated charcoal on glipizide absorption. Br J Clin Pharmacol 1990;30(5):733–6. [32] Ludwig SM, McKenzie J, Faiman C. Chlorpropamide overdose in renal failure: management with charcoal hemoperfusion. Am J Kidney Dis 1987;10(6):457–60. [33] Service FJ. Hypoglycemic disorders. N Engl J Med 1995;332(17):1144–52. [34] Shorr RI, Ray WA, Daugherty JR, et al. Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med 1997;157(15):1681–6. [35] Barennes H, Valea I, Nagot N, et al. Sublingual sugar administration as an alternative to intravenous dextrose administration to correct hypoglycemia among children in the tropics. Pediatrics 2005;116(5):e648–53. [36] Muhlhauser I, Toth G, Sawicki PT, et al. Severe hypoglycemia in type I diabetic patients with impaired kidney function. Diabetes Care 1991;14(4):344–6. [37] Katz MD, Erstad BL. Octreotide, a new somatostatin analogue. Clin Pharm 1989;8(4): 255–73. [38] Boyle PJ, Justice K, Krentz AJ, et al. Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses. J Clin Endocrinol Metab 1993;76(3):752–6. [39] Crawford BA, Perera C. Octreotide treatment for sulfonylurea-induced hypoglycaemia. Med J Aust 2004;180(10):540–1 [author reply 541]. [40] McLaughlin SA, Crandall CS, McKinney PE. Octreotide: an antidote for sulfonylureainduced hypoglycemia. Ann Emerg Med 2000;36(2):133–8. [41] Schier JG, Hirsch ON, Chu J. Octreotide as antidote for sulfonylurea-induced hypoglycemia. Ann Emerg Med 2001;37(4):417–8. [42] Carr R, Zed PJ. Octreotide for sulfonylurea-induced hypoglycemia following overdose. The Annals of Pharmacotherapy 2002;36(11):1727–32. [43] Green RS, Palatnick W. Effectiveness of octreotide in a case of refractory sulfonylureainduced hypoglycemia. J Emerg Med 2003;25(3):283–7. [44] Tenenbein M. Recent advancements in pediatric toxicology. Pediatr Clin North Am 1999; 46(6):1179–88, vii. [45] Krentz AJ, Boyle PJ, Macdonald LM, et al. Octreotide: a long-acting inhibitor of endogenous hormone secretion for human metabolic investigations. Metabolism 1994; 43(1):24–31. [46] Ries NL, Dart RC. New developments in antidotes. Med Clin North Am 2005;89(6): 1379–97. [47] Spiller HA. Management of antidiabetic medications in overdose. Drug Saf 1998;19(5): 411–24. [48] Fasano CJ, O’Malley GF. A prospective trial of octreotide vs. placebo in sulfonylurea-associated hypoglycemia. Acad Emerg Med 2006;13:180. [49] Lheureux PE, Zahir S, Penaloza A, et al. Bench-to-bedside review: antidotal treatment of sulfonylurea-induced hypoglycaemia with octreotide. Crit Care 2005;9(6):543–9. [50] Carstens S, Sprehn M. Prehospital treatment of severe hypoglycaemia: a comparison of intramuscular glucagon and intravenous glucose. Prehospital Disaster Med 1998;13(2–4): 44–50. [51] Howell MA, Guly HR. A comparison of glucagon and glucose in prehospital hypoglycaemia. J Accid Emerg Med 1997;14(1):30–2. [52] Vukmir RB, Paris PM, Yealy DM. Glucagon: prehospital therapy for hypoglycemia. Ann Emerg Med 1991;20(4):375–9. [53] Rosenfalck AM, Bendtson I, Jorgensen S, et al. Nasal glucagon in the treatment of hypoglycaemia in type 1 (insulin-dependent) diabetic patients. Diabetes Res Clin Pract 1992; 17(1):43–50. [54] Slama G, Alamowitch C, Desplanque N, et al. A new non-invasive method for treating insulin-reaction: intranasal lyophylized glucagon. Diabetologia 1990;33(11):671–4.
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[55] Stenninger E, Aman J. Intranasal glucagon treatment relieves hypoglycaemia in children with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1993;36(10):931–5. [56] Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non-insulindependent diabetes mellitus. N Engl J Med 1995;333(9):550–4. [57] Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334(9):574–9. [58] Spiller HA, Quadrani DA. Toxic effects from metformin exposure. Ann Pharmacother 2004; 38(5):776–80. [59] Spiller HA, Weber JA, Winter ML, et al. Multicenter case series of pediatric metformin ingestion. Ann Pharmacother 2000;34(12):1385–8. [60] von Mach MA, Sauer O, Sacha Weilemann L. Experiences of a poison center with metformin-associated lactic acidosis. Exp Clin Endocrinol Diabetes 2004;112(4):187–90. [61] Chan NN, Brain HP, Feher MD. Metformin-associated lactic acidosis: a rare or very rare clinical entity? Diabet Med 1999;16(4):273–81. [62] Thomsen HS. How to avoid CIN: guidelines from the European Society of Urogenital Radiology. Nephrol Dial Transplant 2005;20(suppl 1):i18–22. [63] Brady WJ, Carter CT. Metformin overdose. Am J Emerg Med 1997;15(1):107–8. [64] Chang CT, Chen YC, Fang JT, et al. High anion gap metabolic acidosis in suicide: don’t forget metformin intoxication–two patients’ experiences. Ren Fail 2002;24(5):671–5. [65] Gjedde S, Christiansen A, Pedersen SB, et al. Survival following a metformin overdose of 63 g: a case report. Pharmacol Toxicol 2003;93(2):98–9. [66] Guo PY, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial 2006;19(1):80–3. [67] Harvey B, Hickman C, Hinson G, et al. Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization. Pediatr Crit Care Med 2005;6(5):598–601. [68] Heaney D, Majid A, Junor B. Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol Dial Transplant 1997;12(5):1046–7. [69] Lacher M, Hermanns-Clausen M, Haeffner K, et al. Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 2005;164(6):362–5. [70] McLelland J. Recovery from metformin overdose. Diabet Med 1985;2(5):410–1. [71] Nisse P, Mathieu-Nolf M, Deveaux M, et al. A fatal case of metformin poisoning. J Toxicol Clin Toxicol 2003;41(7):1035–6. [72] Lalau JD, Andrejak M, Moriniere P, et al. Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 1989;27(6):285–8. [73] Teale KF, Devine A, Stewart H, et al. The management of metformin overdose. Anaesthesia 1998;53(7):698–701. [74] Barrueto F, Meggs WJ, Barchman MJ. Clearance of metformin by hemofiltration in overdose. J Toxicol Clin Toxicol 2002;40(2):177–80. [75] Barquero Romero J, Perez Miranda M. Metformin-induced cholestatic hepatitis. Gastroenterol Hepatol 2005;28(4):257–8. [76] Panzer U, Kluge S, Kreymann G, et al. Combination of intermittent haemodialysis and highvolume continuous haemofiltration for the treatment of severe metformin-induced lactic acidosis. Nephrol Dial Transplant 2004;19(8):2157–8.
Emergency Management of Oral Hypoglycemic Drug Toxicity Adam K. Rowden, DOa,*, Charles J. Fasano, DOa,b a
Department of Emergency Medicine, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA b Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107-5587, USA
Exposure to oral hypoglycemic agents is a common problem confronting the emergency physician. In 2004, there were more than 10,000 exposures to these medications reported to the American Association of Poison Control Centers (AAPCC). Of these exposures, 40% involved sulfonylureas, 40% involved metformin, and the remaining 20% involved other or unknown oral hypoglycemic agents [1]. Because of the large array of oral diabetic agents available, their diverse mechanisms of action, and large variations in the potential for adverse outcomes, the emergency physician must have knowledge of the available agents and the potential for toxicity. Oral hypoglycemic agents likely to cause hypoglycemia Sulfonylureas This class of drugs is a mainstay of treatment of type II diabetes. The sulfonylureas are separated into first- and second-generation drugs. The primary difference in this classification is that the second-generation agents have a shorter elimination half-life (t1/2) than the first-generation agents. These agents stimulate insulin secretion from pancreatic beta cells [2–4]. Most of the sulfonylureas are metabolized through the liver and excreted by the kidney. Many of the metabolites are themselves active, although to a lesser degree than the parent compound. These active metabolites likely account for the long duration of action that may be seen following overdose [3]. The extremely long t1/2 and duration of action of these medications is beneficial for glucose control and medication compliance, but can be problematic when toxicity is encountered. * Corresponding author. E-mail address: [email protected] (A.K. Rowden). 0733-8627/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.emc.2007.02.010 emed.theclinics.com
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The toxicity of sulfonylureas in overdose is an extension of their therapeutic mechanism. With toxicity, the pancreas secretes excessive insulin with a resultant decrease in blood sugar [2–4]. Because of the long duration of action, those patients who have sulfonylurea-induced hypoglycemia can have repeated episodes of hypoglycemia that can be refractory to treatment [5]. Typically, patients require glucose monitoring for 24 hours, but in rare cases hypoglycemic episodes continue as many as 27 days after the initial ingestion [6]. The management of sulfonylurea toxicity is simply repeat assessment of blood glucose levels and correction of hypoglycemia if it develops. Patients who have intentional overdoses of these agents may require more aggressive management and prolonged monitoring for hypoglycemia. Diabetic patients who take their therapeutic sulfonylurea dose and then experience hypoglycemia present a unique challenge to the emergency physician. After correction of the hypoglycemia, a search for the underlying cause of the hypoglycemia must be completed. Some common causes include drug– drug interactions, decreased drug metabolism, or decreased drug excretion [7]. The complicated nature of these problems coupled with the extended t1/2 and active metabolites of the sulfonylureas makes a compelling argument for prolonged observation or inpatient admission of these patients [3,4,8]. A child exposed, or potentially exposed, to a sulfonylurea is commonly encountered in emergency medicine. In 2004, 1400 exposures to sulfonylureas in children less than 6 years of age were reported to the AAPCC [1]. Even one pill is enough to cause clinically significant hypoglycemia in toddlers [9–11]. The onset of hypoglycemia can also be delayed with rare case reports suggesting a delay of 11 to 21 hours for specific agents [10–13]. In a large, prospective, observational series, Spiller found that no child had an onset of hypoglycemic symptoms more than 8 hours after exposure [11]. Extrapolating these data, 8 hours of euglycemia is the minimum time period that a child should be watched to predict a benign outcome. If hypoglycemia develops during that time period, however, the patient should then be admitted and observed [12,14]. Multiple cases of surreptitious or accidental poisoning by sulfonylureas are reported in the literature. Intentional surreptitious ingestion [15], pharmacy dispensing errors, [16,17] contaminated herbal products [18], and cases of Munchausen by proxy in pediatric, adult, and geriatric patients [19–22] have been described. In such cases the C-peptide test, used to differentiate endogenous from exogenous insulin, is elevated because sulfonylurea exposure results in secretion of endogenous insulin from the pancreas [15]. Assays are available to screen for sulfonylureas [23], but because of the multitude of products available, false negatives have been encountered [24,25] making more specific testing necessary in some clinical scenarios. Meglitinides Repaglinide and nateglinide are the two meglitinides available in the United States and are novel agents for type II diabetes. They have
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a mechanism similar to the sulfonylureas but with a faster onset and shorter duration of action [3]. Limited experience in overdose suggests that hypoglycemia is possible but may not be as long lasting as that caused by sulfonylureas [26,27]. In a case reported by Hirsberg [26], a patient experienced repeated episodes of hypoglycemia and was subsequently evaluated for the possibility of an insulinoma. It was later discovered that he was intentionally overdosing on repaglinide. Likewise, Nakayama [27] reported a case of hypoglycemia in a patient after intentional overdose of nateglinide. In both cases, hypoglycemia was easily treated with dextrose solutions and the duration of action was short. Hypoglycemia also has been reported following therapeutic dosing of these agents [28]. Nagai [28] reported a woman who was started on nateglinide and experienced repeated episodes of hypoglycemia during therapeutic dosing even after her initial dose was halved. The patient’s decreased creatinine clearance was speculated to be the cause along with the nateglinide. In a controlled volunteer study, Fonseca and colleagues [29] found that patients who had diabetes who were mildly hyperglycemic and were given therapeutic doses of repaglinide were more likely to experience hypoglycemia than controls. Until further data are available, treating physicians should err on the side of caution in regard to the treatment and disposition of meglitinide exposures and approach them in similar manner as the sulfonylureas. Treatment of oral hypoglycemic-induced hypoglycemia As with any poisoned patient, the initial assessment is focused on addressing airway, breathing, and circulation. After the primary survey, any patient who has altered mental status should have his or her blood glucose evaluated. After initial stabilization, preventing absorption and enhancing elimination of the causative agent and possible antidotal therapy can be considered. There is controversy regarding the effectiveness of activated charcoal in the setting of sulfonylurea overdose. With the exception of tolbutamide, the first-generation agents do not seem to be effectively bound by activated charcoal [30]. The second-generation agents seem to have higher affinity for charcoal [31]. As with any overdose, when considering gastrointestinal decontamination the risk for aspiration should be weighed against any potential benefit. Hemodialysis and charcoal hemoperfusion [32] have been attempted for sulfonylurea toxicity in case reports, but are not routinely recommended. Hypoglycemia is a common presentation to the emergency department [33]. Regardless of the cause, the emergency management of hypoglycemia includes early recognition and administration of rapidly metabolized carbohydrates in the form of oral glucose or intravenous (IV) dextrose. In patients who have altered mental status, hypoglycemia is treated with a rapid bolus of IV 50% dextrose and dextrose-containing IV fluids [34]. The initial dose of dextrose is a 50 mL bolus of 50% dextrose IV, which
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provides 25 g of glucose. This dose may be repeated as needed for persistent episodes of hypoglycemia. In children, the initial recommended dose of dextrose for the treatment of hypoglycemia is a 2 mL/kg bolus of 25% dextrose in water IV, and in infants the dose is 2 to 4 mL/kg of 10% dextrose in water IV. When the patient’s mental status is normalized after initial treatment, long-acting oral carbohydrates or a continuous intravenous infusion of dextrose may need to be administered to prevent subsequent episodes. The hypoglycemic patient who does not have IV access presents a challenge to the treating physician. These patients are often confused and combative making the placement of IV catheters difficult. Sublingual administration of dextrose has been shown to be effective in children who have hypoglycemia [35]. Glucagon is an FDA-approved agent for the treatment of hypoglycemia and should be administered if attempts at IV access are unsuccessful [36]. The treatment of sulfonylurea-induced hypoglycemia is much more complex than insulin-induced hypoglycemia. Poisoning may be refractory to the routine treatments rendered for hypoglycemia and often requires repeated supplemental glucose administration, higher concentrations of glucose, and antidotal therapy. Octreotide Octreotide is a somatostatin analog that is known to suppress insulin secretion [37]. Several case reports and one prospective study in healthy volunteers have demonstrated the safety and efficacy of octreotide administration for the treatment of sulfonylurea-induced hypoglycemia [38–41]. McLaughlin and colleagues [40] published a retrospective case series of nine patients and concluded that octreotide is safe and effective in preventing rebound hypoglycemia after sulfonylurea ingestion. Boyle and colleagues [38] showed that octreotide was superior to glucose and diazoxide in preventing recurrent hypoglycemia in eight glipizide-poisoned volunteers. Octreotide has been shown to be effective in massive sulfonylurea overdose. Case reports have demonstrated the efficacy of octreotide in intentional glyburide overdose in adults [42,43] and in accidental overdose in children [44]. The indications and dosage intervals of octreotide have not been clearly defined. Some authors recommend a single 50 to100 mg subcutaneous injection after a single hypoglycemia episode [40], whereas others recommend serial subcutaneous injections every 6 to 8 hours or constant intravenous infusion after a second hypoglycemic episode [4,42,45–47]. A recently published prospective pilot study enrolled patients who presented to the emergency department with a single sulfonylurea-induced hypoglycemic episode and randomized them to receive either standard therapy consisting of 50% dextrose IV and oral carbohydrates or standard therapy plus 50 mg subcutaneous octreotide. Preliminary data demonstrated a trend toward a decrease in frequency of hypoglycemic episodes and an increase in
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mean glucose at specified intervals in those patients receiving octreotide compared with placebo [48]. Future protocols need to be developed to further confirm the above-mentioned efficacy of octreotide and define the ideal dosage and interval [40,48,49]. Glucagon Glucagon is a polypeptide hormone approved for the treatment of hypoglycemia. Glucagon is of particular interest to emergency personnel because it is efficacious for the treatment of hypoglycemia when given subcutaneously or intramuscularly, thereby negating the need for an IV line. Numerous studies have shown the efficacy and safety of glucagon for the treatment of hypoglycemia [50–52]. Vukmir and colleagues [52] showed an approximate 100 mg/dL increase in serum glucose in 49 of 50 prehospital hypoglycemic patients who received subcutaneous glucagon. In separate studies, Howell and Guly [51] and Carstens and Sprehn [50] concluded that subcutaneous glucagon administration is a safe and efficacious treatment of hypoglycemia, and it should be strongly considered when intravenous dextrose cannot be given because of the lack of IV access. Ideally, intravenous dextrose should be used to treat hypoglycemia. If this is impossible, glucagon should be administered at the dose of 1 mg in adults (greater than 20 kg) and 0.5 mg in children (less then 20 kg) by way of subcutaneous or intramuscular injection. Several studies from Europe in the 1990s showed the safety and efficacy of intranasal glucagon for the treatment of hypoglycemia [53–55]. Glucagon should be used with caution in patients who have presumed sulfonylurea-induced hypoglycemia. Its mechanism of action involves inducing gluconeogenesis by recruiting hepatic glycogen stores. This increase in serum glucose in addition to the physiologic response of insulin released by glucagon in theory could exacerbate clinical hypoglycemia in a patient who is already in a toxin-induced hyperinsulinemic state [4]. Diazoxide Diazoxide directly inhibits insulin secretion from pancreatic beta cells. It has been shown to be an effective treatment of refractory sulfonylureainduced hypoglycemia [5]. Because of its potential for hypotension, diazoxide should be used with caution. Hypotension may be limited by slow intravenous infusion (300 mg over 30 minutes every 4 hours). Disposition Patients who are exposed to sulfonylureas or meglitinides and experience hypoglycemia should be admitted for serial monitoring of their blood glucose. Exposures (ie, an intentional overdose in an adult or a child who is found ingesting a pill) that present without hypoglycemia should be
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observed for a minimum of 8 hours. If hypoglycemia develops during that observation period, the patient should be admitted for further monitoring [8,11,47].
Oral hypoglycemic agents that do not cause hypoglycemia Biguanides Metformin is the only biguanide agent available in the United States. It controls type II diabetes by several mechanisms that have not been fully elucidated. Limiting gluconeogenesis in the liver seems to be its primary mechanism. It also increases insulin receptors in muscle tissue, thereby increasing glucose uptake into cells [3,4,8,56]. It has not been shown to increase insulin secretion from the pancreas or interfere with the hormonal regulation of insulin secretion [56,57]. It therefore does not result in hypoglycemia in either therapeutic or overdose situations. Reports of metformin-related hypoglycemia involve a combination of metformin and another antidiabetic agent [8,58–60]. Lactic acidosis is a rare but serious major complication of metformin use in overdose and therapeutic situations [8,57–60]. The incidence of lactic acidosis during therapeutic dosing is low and has been estimated 1 per 10,000 patient years [61]. The most important risk factor for developing lactic acidosis during therapeutic dosing is decreased creatinine clearance [61,62]. Because metformin-induced lactic acidosis is associated with impaired renal function, those taking metformin should abstain for 48 hours after radiologic studies using intravenous contrast [62]. In overdose, high serum lactates are reported and severe acidemia is possible [58,60,63–71]. Treatment is largely supportive because no antidotal therapy is available. Although not routinely used, it is possible to enhance the elimination of metformin by extracorporeal techniques. The clearance of metformin using traditional hemodialysis has been reported to be 68 to 150 mL/min [72]. Hemodialysis was used in several case reports, with mixed results [66,68,69,71]. Metformin is cleared by both traditional dialysis [72,73] and by continuous renal replacement therapy using continuous veno-venous hemodialysis (CVVHD) in which the clearance was reported at 50 mL/h [74]. CVVHD may provide an alternative to traditional dialysis in the hemodynamically unstable patient. CVVHD alone [67,73] and in combination with traditional dialysis [75,76] has been used in case reports with mixed outcomes. Although enhancing the elimination of metformin, these options have the added benefit of correcting the metabolic derangements typical of the severely poisoned patient. It should also be noted that most poisoned patients have favorable clinical outcomes when managed with purely supportive efforts [13,47,58]. As with all therapeutic decisions, the risks and benefits of invasive treatment modalities must be weighed in each individual case. In a retrospective case series, Spiller and Quadrani [58] found that
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patients who had severe acidosis, large anion gaps, hyperglycemia, and hemodynamic instability were more likely to have serious morbidity and mortality. These data suggest that patients who develop these findings may benefit from extracorporeal elimination techniques. Children potentially exposed to metformin do not seem to be at high risk for adverse outcomes. In a small, retrospective case series of 55 patients ingesting between 1 and 10 mg/kg, none developed hypoglycemia and all were clinically well without adverse outcomes [59]. Glitazones Despite being available for several years, there are limited data on the glitazones in overdose. Based on case reports and the mechanism of action of these medications, hypoglycemia seems unlikely. These medications act to increase insulin sensitivity in the peripheral tissues [3,8]. Like metformin, the feedback loops remain intact in regard to insulin secretion of the pancreas, and therefore hypoglycemia does not occur. This class has been associated with hepatitis and fulminant hepatic failure with therapeutic doses [3,8]. a-glucosidase inhibitors Acarbose is an a-glucosidase inhibitor that prevents the breakdown of carbohydrates in the gut slowing absorption [3]. This oral agent is extensively metabolized in the gut with little absorption [3,8,47]. The clinical experience with overdose is limited, but hypoglycemia seems unlikely based on the drug’s mechanism of action. Summary The myriad of oral agents available for the treatment of diabetes complicates the approach to assessment, treatment, and disposition of the potentially poisoned patient. After initial stabilization and assessment of blood glucose, the emergency physician must make every effort to determine what class of medication the patient may have been exposed to so that complications may be anticipated and appropriate disposition decisions made. References [1] William A. Watson, George C. Rodgers Jr, Jessica Youniss, et al. 2004 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2005;23(5):589–666. [2] Eliasson L, Renstrom E, Ammala C, et al. PKC-dependent stimulation of exocytosis by sulfonylureas in pancreatic beta cells. Science 1996;271(5250):813–5. [3] Carlton FB Jr. Recent advances in the pharmacologic management of diabetes mellitus. Emerg Med Clin North Am 2000;18(4):745–53.
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[4] Harrigan RA, Nathan MS, Beattie P. Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment. Ann Emerg Med 2001;38(1):68–78. [5] Palatnick W, Meatherall RC, Tenenbein M. Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy. Arch Intern Med 1991;151(9):1859–62. [6] Ciechanowski K, Borowiak KS, Potocka BA, et al. Chlorpropamide toxicity with survival despite 27-day hypoglycemia. J Toxicol Clin Toxicol 1999;37(7):869–71. [7] Chelliah A, Burge MR. Hypoglycaemia in elderly patients with diabetes mellitus: causes and strategies for prevention. Drugs Aging 2004;21(8):511–30. [8] Spiller HA, Sawyer TS. Toxicology of oral antidiabetic medications. Am J Health Syst Pharm 2006;63(10):929–38. [9] Osterhoudt KC. This treat is not so sweet: exploratory sulfonylurea ingestion by a toddler. Pediatr Case Rev 2003;3(4):215–7. [10] Seltzer HS. Drug-induced hypoglycemia. A review of 1418 cases. Endocrinol Metab Clin North Am 1989;18(1):163–83. [11] Spiller HA, Villalobos D, Krenzelok EP, et al. Prospective multicenter study of sulfonylurea ingestion in children. J Pediatr 1997;131(1 Pt 1):141–6. [12] Quadrani DA, Spiller HA, Widder P. Five year retrospective evaluation of sulfonylurea ingestion in children. J Toxicol Clin Toxicol 1996;34(3):267–70. [13] Szlatenyi CS, Capes KF, Wang RY. Delayed hypoglycemia in a child after ingestion of a single glipizide tablet. Ann Emerg Med 1998;31(6):773–6. [14] Borowski H, Caraccio T, Mofenson H. Sulfonylurea ingestion in children: is an 8-hour observation period sufficient? J Pediatr 1998;133(4):584–5. [15] Waickus CM, de Bustros A, Shakil A. Recognizing factitious hypoglycemia in the family practice setting. J Am Board Fam Pract 1999;12(2):133–6. [16] Shumak SL, Corenblum B, Steiner G. Recurrent hypoglycemia secondary to drug-dispensing error. Arch Intern Med 1991;151(9):1877–8. [17] Sledge ED, Broadstone VL. Hypoglycemia due to a pharmacy dispensing error. South Med J 1993;86(11):1272–3. [18] Goudie AM, Kaye JM. Contaminated medication precipitating hypoglycaemia. Med J Aust 2001;175(5):256–7. [19] Ben-Chetrit E, Melmed RN. Recurrent hypoglycaemia in multiple myeloma: a case of Munchausen syndrome by proxy in an elderly patient. J Intern Med 1998;244(2):175–8. [20] Fernando R. Homicidal poisoning with glibenclamide. Med Sci Law 1999;39(4):354–8. [21] Owen L, Ellis M, Shield J. Deliberate sulphonylurea poisoning mimicking hyperinsulinaemia of infancy. Arch Dis Child 2000;82(5):392–3. [22] Trenque T, Hoizey G, Lamiable D. Serious hypoglycemia: Munchausen’s syndrome? Diabetes Care 2001;24(4):792–3. [23] Hoizey G, Lamiable D, Trenque T, et al. Identification and quantification of 8 sulfonylureas with clinical toxicology interest by liquid chromatography-ion-trap tandem mass spectrometry and library searching. Clin Chem 2005;51(9):1666–72. [24] Earle KE, Rushakoff RJ, Goldfine ID. Inadvertent sulfonylurea overdosage and hypoglycemia in an elderly woman: failure of serum hypoglycemia screening. Diabetes Technol Ther 2003;5(3):449–51. [25] Klonoff DC. A flaw in the use of sulfonylurea screening to diagnose sulfonylurea overdosages. Diabetes Technol Ther 2003;5(3):453–4. [26] Hirshberg B, Skarulis MC, Pucino F, et al. Repaglinide-induced factitious hypoglycemia. J Clin Endocrinol Metab 2001;86(2):475–7. [27] Nakayama S, Hirose T, Watada H, et al. Hypoglycemia following a nateglinide overdose in a suicide attempt. Diabetes Care 2005;28(1):227–8. [28] Nagai T, Imamura M, Iizuka K, et al. Hypoglycemia due to nateglinide administration in diabetic patient with chronic renal failure. Diabetes Res Clin Pract 2003;59(3):191–4. [29] Fonseca VA, Kelley DE, Cefalu W, et al. Hypoglycemic potential of nateglinide versus glyburide in patients with type 2 diabetes mellitus. Metabolism 2004;53(10):1331–5.
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[30] Kannisto H, Neuvonen PJ. Adsorption of sulfonylureas onto activated charcoal in vitro. J Pharm Sci 1984;73(2):253–6. [31] Kivisto KT, Neuvonen PJ. The effect of cholestyramine and activated charcoal on glipizide absorption. Br J Clin Pharmacol 1990;30(5):733–6. [32] Ludwig SM, McKenzie J, Faiman C. Chlorpropamide overdose in renal failure: management with charcoal hemoperfusion. Am J Kidney Dis 1987;10(6):457–60. [33] Service FJ. Hypoglycemic disorders. N Engl J Med 1995;332(17):1144–52. [34] Shorr RI, Ray WA, Daugherty JR, et al. Incidence and risk factors for serious hypoglycemia in older persons using insulin or sulfonylureas. Arch Intern Med 1997;157(15):1681–6. [35] Barennes H, Valea I, Nagot N, et al. Sublingual sugar administration as an alternative to intravenous dextrose administration to correct hypoglycemia among children in the tropics. Pediatrics 2005;116(5):e648–53. [36] Muhlhauser I, Toth G, Sawicki PT, et al. Severe hypoglycemia in type I diabetic patients with impaired kidney function. Diabetes Care 1991;14(4):344–6. [37] Katz MD, Erstad BL. Octreotide, a new somatostatin analogue. Clin Pharm 1989;8(4): 255–73. [38] Boyle PJ, Justice K, Krentz AJ, et al. Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses. J Clin Endocrinol Metab 1993;76(3):752–6. [39] Crawford BA, Perera C. Octreotide treatment for sulfonylurea-induced hypoglycaemia. Med J Aust 2004;180(10):540–1 [author reply 541]. [40] McLaughlin SA, Crandall CS, McKinney PE. Octreotide: an antidote for sulfonylureainduced hypoglycemia. Ann Emerg Med 2000;36(2):133–8. [41] Schier JG, Hirsch ON, Chu J. Octreotide as antidote for sulfonylurea-induced hypoglycemia. Ann Emerg Med 2001;37(4):417–8. [42] Carr R, Zed PJ. Octreotide for sulfonylurea-induced hypoglycemia following overdose. The Annals of Pharmacotherapy 2002;36(11):1727–32. [43] Green RS, Palatnick W. Effectiveness of octreotide in a case of refractory sulfonylureainduced hypoglycemia. J Emerg Med 2003;25(3):283–7. [44] Tenenbein M. Recent advancements in pediatric toxicology. Pediatr Clin North Am 1999; 46(6):1179–88, vii. [45] Krentz AJ, Boyle PJ, Macdonald LM, et al. Octreotide: a long-acting inhibitor of endogenous hormone secretion for human metabolic investigations. Metabolism 1994; 43(1):24–31. [46] Ries NL, Dart RC. New developments in antidotes. Med Clin North Am 2005;89(6): 1379–97. [47] Spiller HA. Management of antidiabetic medications in overdose. Drug Saf 1998;19(5): 411–24. [48] Fasano CJ, O’Malley GF. A prospective trial of octreotide vs. placebo in sulfonylurea-associated hypoglycemia. Acad Emerg Med 2006;13:180. [49] Lheureux PE, Zahir S, Penaloza A, et al. Bench-to-bedside review: antidotal treatment of sulfonylurea-induced hypoglycaemia with octreotide. Crit Care 2005;9(6):543–9. [50] Carstens S, Sprehn M. Prehospital treatment of severe hypoglycaemia: a comparison of intramuscular glucagon and intravenous glucose. Prehospital Disaster Med 1998;13(2–4): 44–50. [51] Howell MA, Guly HR. A comparison of glucagon and glucose in prehospital hypoglycaemia. J Accid Emerg Med 1997;14(1):30–2. [52] Vukmir RB, Paris PM, Yealy DM. Glucagon: prehospital therapy for hypoglycemia. Ann Emerg Med 1991;20(4):375–9. [53] Rosenfalck AM, Bendtson I, Jorgensen S, et al. Nasal glucagon in the treatment of hypoglycaemia in type 1 (insulin-dependent) diabetic patients. Diabetes Res Clin Pract 1992; 17(1):43–50. [54] Slama G, Alamowitch C, Desplanque N, et al. A new non-invasive method for treating insulin-reaction: intranasal lyophylized glucagon. Diabetologia 1990;33(11):671–4.
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