Hypoglycemia is the most common acute complication occurring in patients with insulindependent diabetes mellitus (IDDM). It is estimated that 4% of all deaths of patients with IDDM occur as a result of severe hypoglycemia. Approximately 10% of IDDM patients using conventional insulin therapy and 25% of patients treated with insulin experience at least one episode per year of severe hypoglycemia (defined as the occurrence of a seizure or loss of consciousness or decline in intellectual functioning preventing self-treatment and requiring the administration of glucagon or intravenous glucose).1 The occurrence of severe hypoglycemia is a major impediment to the goal of achieving normal blood glucose values in IDDM patients. In the recently completed Diabetes Contro! and Complications Trial (DCCT), there was a two- to threefold increase in severe hypoglycemia.2 Despite therapeutic advances, it is impossible to control hyperglycemia without periodically incurring hypoglycemia. Overall, patients with IDDM suffer an average of one to two episodes of hypoglycemia per week. Parents fear hypoglycemia and its consequences, and children, especially adolescents, are concerned that hypoglycemia symptoms may embarrass them and set them apart from their peers. Thus, these patients risk the potential complications related to chronic hyperglycemia in order to avoid the immediate inconvenience of symptomatic hypoglycemia.3
The diagnosis of hypoglycemia in patients with IDDM often is difficult unless blood glucose values are extremely low. Whipple's triad,4 the sine qua non for its diagnosis (ie, the occurrence of typical symptoms, low glucose concentration, and the reversal of symptoms with ingestion or injection of glucose) cannot always be relied on. In nondiabetic patients, a blood glucose value of <40 mg/dL generally has been accepted as the definition of hypoglycemia. In subjects with diabetes, clinical manifestations of hypoglycemia may occur at different blood glucose levels and also may be nonspecific, varying among individuals and from time to time in the same individual. Symptoms classically are divided into either adrenergic or neuroglycopenic (Table 1 ). In normal subjects, adrenergic symptoms usually occur at glucose concentrations of 50 to 55 mg/dL with activation of the acute glucose counterregulatory hormones (glucagon and epinephrine) occurring at slightly higher levels.5'6 Cortisol and growth hormone tend to be relatively minor in importance, having delayed effects. Typically, neuroglycopenic symptoms occur with glucose values of <40 mg/dL, but may occur at slightly higher values in some subjects.5'7
Symptoms of Hypoglycémie
Hypoglycémie or insulin reactions are classified into mild, moderate, or severe. Adrenergic symptoms, such as hunger at an unusual time, sweating, palpitations, and tremors, predominate in mild reactions. Cognitive deficits usually do not occur, and patients can treat themselves. In moderate reactions, both adrenergic and neuroglycopenic symptoms usually occur. Confusion, weakness, and incoordination may require outside assistance from others in terms of administering sugar-containing food or drinks. Severe reactions with convulsions and unconsciousness require emergency measures such as intramuscular glucagon injection or glucose given intravenously.
Glucose homeostasis depends on a dynamic balance between metabolic glucose use and glucose influx (from exogenous or endogenous sources) into the circulation. In IDDM patients, hypoglycemia usually results from excessive glucose use caused by too much insulin.
The conventional risk factors for hypoglycemia are shown in Table 2. Together with deficient counterregulatory hormone responses (often occurring after several years of diabetes and resulting in diminished glycogenolytic and hepatic glucose production), these factors account for most hypoglycémie reactions. Glucagon secretion is essential for normal recovery from insulin- induced hypoglycemia.8 Glucagon leads to an immediate increase in blood glucose level due to increased blood glucose release from the liver following glycogenolysis.
Epinephrine does not appear to play a role in glucose recovery from hypoglycemia unless glucagon deficiency is present, which occurs commonly in the first few years following diagnosis.8 Although such patients are dependent on epinephrine to correct hypoglycemia, with longstanding disease they also may have deficient epinephrine responses to declining blood glucose concentrations. A vicious cycle follows in which the absence of epinephrine secretion leads to hypoglycemia unawareness in which patients lose the warning adrenergic symptoms of developing hypoglycemia and therefore fail to react (ie, to eat or drink), resulting in progression to neuroglycopenia and severe hypoglycemia.9'10 This syndrome is associated with at least a fivefold increase in the frequency of severe hypoglycemia.11 Furthermore, patients with well-controlled diabetes may have elevated glycémie thresholds, ie, they tolerate lower blood glucose levels without symptoms. They require lower glucose concentrations to elicit symptoms and counterregulatory hormone responses, which results in recurrent, severe hypoglycemia.
Brain function depends on an adequate supply of glucose from the blood. Because of the vulnerability of the brain to prolonged hypoglycemia, glucose concentrations must be raised to normal levels as rapidly as possible. Although, ideally, hypoglycemia should be confirmed before starting therapy, sugar should be given in some form as fast as possible, even if there is uncertainty as to whether the patient is truly having a reaction. Mild reactions can be treated with the oral administration of 10 to 20 g of carbohydrate. Food such as juice without extra sugar, fresh fruit, milk, or crackers with cheese or peanut butter can be given. For moderate reactions, a source of simple sugar, such as sugared juices, instant glucose, or cake frosting, should be given. The blood sugar level should then be measured. If the level is above 80 mg/dL, the person should eat a sandwich or other longer-lasting food. If less than 80 mg/dL, more sugar should be given and the level rechecked. In severe hypoglycémie reactions when the child is unable or unwilling to take oral feedings, glucagon ( 1 mg) should be given subcutaneously or intramuscularly. Alternatively, intravenous glucose at a dose of 0.5 g/kg ( 1 mL of 50% glucose/kg) may be given. After the initial glucose rise following either glucagon or intravenous glucose administration, patients should eat to prevent recurrence of hypoglycemia because these agents have only transitory effects.
Typically, there is clinical improvement in most patients who experience mild to moderate hypoglycémie reaction within IO to 15 minutes after the blood glucose level has been raised. If it is not possible to measure blood glucose concentrations and there is no response within 15 minutes, initial therapy should be repeated. In some patients with more severe hypoglycemia, recovery is sometimes delayed. Transient blindness or diplopia due to sixth cranial nerve palsy and hemiparesis are well recognized. A mild headache may persist in some patients for several hours. A rare complication is posthypogtycemic coma, which refers to unconsciousness lasting longer than 30 minutes after the blood glucose level has been restored to normal.12 Since the development of cerebral edema has been causally implicated, both mannitol and dexamethasone have been used therapeutically. Permanent brain damage, particularly in infants and toddlers with IDDM, is an occasional consequence because of the vulnerability of the still-developing central nervous system, the inability of the very young child to recognize, communicate, or act on the early symptoms, and the probability therefore, that hypoglycemia will be unrecognized until it is severe.
Prevention of Further Episodes
Although the DCCT has shown that both the development and progression of small vessel complications of IDDM are related to blood glucose control, there is a threefold increased risk of severe hypoglycemia accompanying intensive management. Patients with tightly controlled diabetes often experience several mild episodes of hypoglycemia per week. A therapeutic compromise between the patient and the diabetes management team needs to be reached to maintain blood glucose levels as close to normal as possible without increasing significant hypoglycemia.
Anticipation and prevention of the factors likely to precipitate significant hypoglycemia (Table 2) are imperative. Particularly with tightly controlled diabetic patients, small changes in the timing of insulin injection, missing meals or snacks, or exercising in an unplanned fashion may precipitate hypoglycemia. Consequently, steps such as reducing the dose of the insulin, dispensing extra food, testing regularly, and planning ahead are all part of the solution. Should a reaction occur, however, severe reactions can be prevented in most circumstances by interrupting progression of hypoglycemia. Education of diabetic children and their families to respond promptly and adequately is imperative. Since most persons with diabetes experience symptoms, it is essential that the child (more likely to be an older child or adolescent) be educated to recognize these signs. Once these are recognized, patients must be instructed to ingest a rapid-acting carbohydrate that they should carry with them at all times.
Risk Factors for Hypoglycemia
1. Ctyer PE, Binder C, Bolli GB, et »I- Hypoglycemia in insulin dependent mei Ii tus. Diabetes. 1989;)8:1193-1199.
2. The Diabetes Control and Camflicatians Trial Research Group. The effect of intensive treatment of diabetes on [he development and progression of long-ierm complications in insulin-dependent diabetes mcllitus. N En^i } Med. 1991;329:977936.
3. Brouhard BH. Hypoglycemia. In: Travis LB, Brouhard BH, Schrierter BJ, eds. Diabeies Mefliti« in Children and Adátesenos. Philadelphia, Pa: WB Saunders Co; 1987:169-178.
4. Whipple AO The surgical therapy of hypertnsu\mism. Journal of Inlemouono! Chirurgie. 1 938; ì:2 3 7- 2 76.
5. Boyle Pf, Schiatti NS, Shah SD, Clutter WE, Cryer PE. Plasma glucose concentrations at the onset of hypoglycémie symptoms in patients with poorly controlled diabetes and nondiabetics. N En¿i Med- 1 988; Î1& 1487- 1492.
6. Schivarti NS, Clutter WE. Shah SEt Cryer PE. The glycémie thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J CIm Infest. 1987;79:777-781.
7. Mitralcou A, Ryan C, Veneman T, et al. Hierarchy of glycémie thrwholds for activation of counterreguUlory hormone secretion, initiation of symptoms, and onset irf cerebral dysfunction in normal humans. AmJ Phjíioí. ?991;2????67?74.
8. Gerich JE, Davis J, Lorenii M, et al. Hormone mechanisms of recovery from hypoglycemia in man. AmJ Physid. 1979;2Î6:Î80-Î85.
9. Cryer PE Uttogenic hypaglycemia as a cause of hypoglycetnia-aseKiated autonomie feilurc in IDDM. A vicious cycle. Piai*!«. 1992;41:25?-260.
10. Grimaldi A, Bouquet F, Ffctvidoff P, et al. Unawareness of hyptiglycemia by insulin-dependenr diabetics. Hurm Miiob Res. 1990;22t90-95.
11. Hephum ??, Patrick AW. Eadington DW, Ewing DJ, Fner BM. Unawarcncsi of hypoglycemia in insulin- 1 tea led diabetk patients: prevalence and relationship in autonomie neuropathy. Diabet Med. 1990;7:7t 1-717.
12. Kay WW. The treatment of prolonged hypoglycémie coma. Journal of Mental Saence. 1961iI07:194-2î8.
Symptoms of Hypoglycémie
Risk Factors for Hypoglycemia