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Hypoglycemia and its secondary effects on the CNS (neuroglycopenia) are the most common adverse effects related to insulin and the sulfonylureas. It is essential to remember that hypoglycemia is primarily a clinical, not a numerical, disorder. Clinical hypoglycemia is the failure to maintain a plasma glucose concentration that prevents signs or symptoms of glucose deficiency. The clinical presentations of patients with hypoglycemia are extremely variable. Hypoglycemia must be considered to be the etiology of any neuropsychiatric abnormality, whether persistent or transient, focal or generalized. The cerebral cortex usually is most severely affected. These findings are categorized below115:
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Delirium with subdued, confused, or manic behavior.
Coma with multifocal brainstem abnormalities, including decerebrate spasms and respiratory abnormalities, with preservation of the oculocephalic (doll’s eyes), oculovestibular (cold-caloric), and pupillary responses.
Focal neurologic deficits simulating a cerebrovascular accident (CVA) with or without the presence of coma. During a 12-month study period, 3 of 125 (2.4%) hypoglycemic patients presented with hemiplegia.83 There are numerous reports4,135 and series128,148 of patients with focal neurologic deficits.
Solitary or multiple seizures.
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These neuropsychiatric symptoms are usually reversible if the hypoglycemia is corrected promptly. The morbidity resulting from undiagnosed hypoglycemia is related partly to the etiology and partly to the duration and severity of the hypoglycemia. Because the etiologies of hypoglycemia encompass both severe diseases such as fulminant hepatic failure and benign problems such as a missed meal by an insulin-requiring diabetic, the literature with regard to outcome is confusing. Although a study of 125 emergency department (ED) cases of symptomatic hypoglycemia reported an 11% mortality rate,83 only one death (0.8%) was attributed directly to hypoglycemia. In that same study, nine patients (7.2%) presented with seizures (focal in one case), three patients (2.4%) presented with hemiparesis, and four survivors (3.2%) suffered residual neurologic deficits. In one tertiary care medical center, 1.2% of all admitted patients had hypoglycemia (defined as a glucose concentration less than 50 mg/dL). The overall mortality was 27% for this group of 94 patients.44 The longer and more profound the hypoglycemic episode, the more likely permanent CNS damage will occur.7
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No absolute criteria available from the physical examination or history distinguish one form of metabolic coma from another. Moreover, the findings classically associated with hypoglycemia, such as tremor, sweating, tachycardia, confusion, coma, and seizures, frequently may not occur.56 The glycemic threshold is the glucose concentration below which clinical manifestations develop, a threshold that is host variable. In one study, the mean glycemic threshold for hypoglycemic symptoms was 78 mg/dL in patients with poorly controlled type 1 diabetes compared to 53 mg/dL in those without the disease.15
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Patients with well-controlled type 1 diabetes may be unaware of hypoglycemia. It appears that even in the presence of numerical hypoglycemia, diabetics with near-normal glycosylated hemoglobin concentrations maintain near-normal glucose uptake by the brain, thereby preserving cerebral metabolism and limiting the response of counterregulatory hormones. The result of this limited response is unawareness of hypoglycemia.14,15 A threshold is likely achieved below which the glucose concentration is inadequate, but this may be a concentration so close to that causing serious neuroglycopenia that patients have limited opportunity for corrective action.14 Hypoglycemia unawareness is most likely in diabetics with chronic use of hypoglycemics because of hypoglycemia-associated autonomic failure.30 Acute ingestion of hypoglycemics in nondiabetic patients likely would cause more classic signs and symptoms.
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Sinus tachycardia, atrial fibrillation, and ventricular premature contractions are the most common dysrhythmias associated with hypoglycemia.75,102 An outpouring of catecholamines, hypoglycemia itself, transient electrolyte abnormalities, and underlying heart disease appear to be the most likely etiologies. Based on their mechanisms of action, both insulin and the sulfonylureas are expected to promote the shift of potassium into cells, and hypokalemia after insulin overdose is well documented.6,139 Other cardiovascular manifestations include angina and ischemia, which rarely may be the sole manifestations of hypoglycemia.38 Both are directly related to hypoglycemia.12,112 Increased release of catecholamines during hypoglycemia increases myocardial oxygen demand and may decrease supply by causing coronary vasoconstriction.
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Hypothermia may occur in hypoglycemic patients.45,63,141 If present, hypothermia usually is mild (90°–95°F {32°–35°C}), unless coexisting conditions such as environmental exposure, infection, head injury, or hypothyroidism are present. In a study comparing two groups of patients with depressed mental status, hypothermia was almost exclusively limited to the hypoglycemic patients; of these patients, 53% with demonstrated hypoglycemia showed hypothermia.141 The central hypothalamic response to hypoglycemia stimulated by the sympathetic nervous system may actually “overshoot” normal temperatures, resulting in hyperthermia following recovery.27
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Besides decreasing glucose concentrations, the hypoglycemics can produce a number of adverse effects, both in overdose and in therapeutic doses. Older sulfonylureas, predominantly chlorpropamide, cause a syndrome of inappropriate antidiuretic hormone secretion61 and disulfiram-ethanol reactions.113 These adverse effects are exceedingly uncommon with the newer second-generation sulfonylureas.
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Hypoglycemia may not occur until 18 hours after lente insulin overdose,95 may persist for up to 53 hours after subcutaneous insulin glargine overdose,18 and may persist up to 6 days after ultralente insulin overdose.84 Death after insulin overdose cannot be correlated directly with either the dose or preparation. Some patients have died with doses estimated in the hundreds of units, whereas others have survived doses in the thousands of units.127 Mortality and morbidity may correlate better with delay in recognition of the problem, duration of symptoms, onset of therapy, and type of complications, as opposed to the absolute degree of hypoglycemia or persistence of elevated insulin concentrations. A significant correlation exists between the amount of insulin injected and either the total amount of dextrose used for treatment or the duration of dextrose infusion.139 In a retrospective study of insulin overdose, 7 of 17 cases (41%) developed recurrent hypoglycemia between 5 and 39 hours after overdose despite oral feeding and intravenous dextrose infusion ranging from 5 to 17 g of dextrose per hour.
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In a retrospective review of 40 patients with sulfonylurea overdoses, the time from ingestion to the onset of hypoglycemia, when known, was variable.105 The longest delay was 21 hours after ingestion of glyburide and 48 hours after ingestion of chlorpropamide. In a retrospective poison center review of 93 cases of sulfonylurea exposures in children, 25 patients (27%) developed hypoglycemia, with a time of onset ranging from 0.5 to 16 hours and a mean of 4.3 hours.118 In a prospective poison center study of sulfonylurea exposures in children, 56 of 185 (30%) patients developed hypoglycemia, with a time of onset ranging from 1 to 21 hours and a mean of 5.3 hours.136 Single-tablet ingestions of chlorpropamide 250 mg, glipizide 5 mg, and glyburide 2.5 mg can result in hypoglycemia in young children,118 and the hypoglycemia may be delayed.143 Hypoglycemia did not occur until 45 hours after ingestion of a 10 mg extended-release glipizide tablet in a 6 year-old child.108
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Hypoglycemia is reported in at least two cases of metformin overdose.144 In both cases, metabolic acidosis with elevated lactate was evident on initial presentation. Hypoglycemia was present initially in one of the cases but did not develop until 7 hours later in the second case. Hypoglycemia and metabolic acidosis with hyperlactatemia are reported in a case of overdose with metformin, atenolol, and diclofenac.52 Hypoglycemia is reported in a case of metformin-associated metabolic acidosis with hyperlactatemia related to therapeutic use.69 Insufficient evidence supports the concept that metformin-associated hypoglycemia can develop in a patient who is not critically ill without metabolic acidosis. Because many patients receiving metformin also take sulfonylureas, hypoglycemia should be anticipated after overdose. Phenformin is similar to metformin in that ingestion alone rarely causes hypoglycemia, in overdose or following therapeutic use.130
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The α-glucosidase inhibitors, thiazolidinediones, meglitinides, GLP-1 analogs, gliptins, and amylin analogs are xenobiotics for which overdose data are limited. Acarbose and miglitol are not likely to cause hypoglycemia based on their mechanism of action of inhibiting α-glucosidase. The most common adverse effects associated with therapeutic use of these xenobiotics are gastrointestinal, including nausea, bloating, abdominal pain, flatulence, and diarrhea. Elevated aminotransferase concentrations were noted after use of acarbose in clinical trials.57 Most patients were asymptomatic, and the aminotransferase concentrations returned to normal after the drug was discontinued. The therapeutic use of acarbose in some cases reportedly led to hepatotoxicity that resolved after the drug was discontinued.5,24
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Hypoglycemia would not be expected after thiazolidinedione overdose. The most serious adverse effect of troglitazone is the development of liver toxicity with therapeutic doses, which in some cases was severe enough to require liver transplantation.49,99 Liver toxicity related to therapeutic use of rosiglitazone3,46 and pioglitazone is also reported.82,85Therapeutic use of pioglitazone and rosiglitazone may precipitate fluid retention in patients with underlying congestive heart failure.98 A meta-analysis concluded that rosiglitazone therapy is associated with an increased risk of myocardial infarction and death from cardiovascular causes.101
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Hypoglycemia should be anticipated after repaglinide and nateglinide ingestion. Hypoglycemia is reported after nateglinide overdose,96 and a case of intentionally self-induced hypoglycemia secondary to repaglinide is reported.55 Hypoglycemia did not occur in a recently published case of intentional overdose with a total of 90 μg exenatide.29“Severe hypoglycemia” was reported in a phase III clinical trial after inadvertent administration of 10 times the normal dose of exenatide. The specific glucose concentration is not noted in the report.22 Pramlintide is used therapeutically in conjunction with insulin, and hypoglycemia in this setting is more likely than with insulin use alone.77