Assessment and management of hypoglycemia in children and adolescents with diabetes

Hypoglycemia is the result of a mismatch between insulin dose, food consumed, and recent exercise and is rarely, if ever, a spontaneous event. A careful review of only blood glucose (BG) records will yield a retrospective prediction of the hypoglycemic event for at least 50% of events (1, 2). Because it can be accompanied by unpleasant, embarrassing, and potentially dangerous symptoms and because it causes significant anxiety and fear in the patient and their caregivers, it's occurrence is a major limiting factor in attempts to achieve near normal BG levels (3, 4). Additionally, in its extreme manifestations, hypoglycemia can lead to permanent sequelae and even death (5–8). Intensive diabetes management initially resulted in a dramatic increase in the rate of hypoglycemia in adolescents (9, 10). Greater experience with intensive therapy and use of analogue insulins decreased the rates of severe hypoglycemia to 8–30 episodes per 100 patient-years of diabetes exposure (11–15), with the exception of very low incidence (,4/100 person-years) in a Finnish study (16). Non-modifiable predictors of severe hypoglycemia are: Age (infancy and adolescence) (11, 14); Increased duration of diabetes (12, 13, 15). Modifiable predictors are: Lower hemoglobinA1c (HbA1c) and Higher insulin dose. Direct health care cost of severe hypoglycemic events is estimated at 7 400 euros per 100 patients per year in the1990s (17). Further studies are needed to update these figures and to estimate, in addition, indirect costs (e.g., lost productivity and diminished quality of life). Hypoglycemia is often accompanied by signs and symptoms of autonomic (adrenergic) activation and/ or neurological dysfunction (neuroglycopenia). Children may also exhibit behavioral or mood changes when their BG falls but remains within or above the normal range (18, 19). Autonomic signs and symptoms Trembling; Pounding heart; Cold sweatiness; Pallor. Neuroglycopenic signs and symptoms Difficulty concentrating; Blurred vision or double vision; Disturbed color vision; Difficulty hearing; Slurred speech; Poor judgment and confusion; Problems with short-term memory; Dizziness and unsteady gait; Loss of consciousness; Seizure; Death. Behavioral signs and symptoms Irritability; Erratic behavior; Nightmares; Inconsolable crying. Non-specific symptoms (associated with low, high, or normal BG) Hunger; Headache; Nausea; Tiredness. There is no consistent or agreed upon numerical definition of hypoglycemia for the child with diabetes. Nevertheless, BG values below 3.3–3.9 mmol/L (60–70 mg/dL) are generally agreed to place the individual at risk for severe hypoglycemia because BG values in this range are associated with alterations in the counterregulatory hormones essential to the spontaneous reversal of hypoglycemia (14, 20, 21). For clinical use, the value of < 3.6 mmol/L (65 mg/dL) has been most often used as the level for defining hypoglycemia in the pediatric population. However, a recent American Association (ADA) Working Group report suggested using 3.9 mmol/L (70 mg/dL) as the definition in all age groups for research purposes in evaluating therapies designed to alter frequency of hypoglycemia (21). Therefore, in the interest of avoiding hypoglycemia and maintaining consistency in reporting hypoglycemia, 3.9 mmol/L (70 mg/dL) is the recommended lower target for BG levels in children and adults with insulin-treated diabetes (14, 21). Alterations in activation of autonomic symptoms or neuroglycopenia (cognitive dysfunction) have been documented to occur at BG levels as high as 3.6 mmol/L (22). However, the absolute BG level at which signs and symptoms begin to occur may vary among individuals and within the same individual at different times and in different situations (23). Young children and their parents are not as accurate at recognizing early warning signs and symptoms of low BG, as are adults with diabetes (24). Therefore, frequent BG monitoring should be encouraged especially during times at which extreme BG levels might be anticipated (overnight, at the peak of insulin actions, during and after strenuous exercise, when insulin doses are adjusted, during stressful situations, during illnesses, etc.). The BG threshold for activation of autonomic signs and symptoms is related to activation of counterregulatory hormones and has been shown to be higher in children than in adults and to vary directly with the level of BG control (higher HbA1c, higher BG threshold) (14, 25). The BG threshold for symptoms may be affected by antecedent hypoglycemia or hyperglycemia (26). This may be accompanied by reduced intensity of symptoms over 24 h following a hypoglycemic event, leading to reduced awareness of hypoglycemia during this time. Low or moderate exercise one day may result in a decrease in symptoms of hypoglycemia and decreased hormonal reactions the next day (27). Also, the BG threshold is reduced during sleep (28, 29). The BG threshold for neuroglycopenia neither varies as much with the level of glucose control nor with antecedent hypoglycemia (14, 30–33). Therefore, neuroglycopenia may occur before autonomic activation and be associated with reduced awareness of the onset of hypoglycemia (3). This phenomenon is termed hypoglycemia unawareness and is an important cause of severe hypoglycemia, accounting for 36% of the hypoglycemia that occurred during the Diabetes Control and Complications Trial (DCCT) while subjects were awake (12). A single hypoglycemic episode can lead to significant decrease in neurohormonal counter-regulatory responses and cause an unawareness of hypoglycemia (26). The syndrome is usually associated with decreased glucagon and/or epinephrine output (24, 34). There is evidence that loss of awareness of hypoglycemia can be reversed by avoiding hypoglycemia for 2–3 wk (33, 35, 36), although this may be difficult to accomplish in young children who are less able to identify hypoglycemia. Avoidance or reversal of hypoglycemia unawareness is crucial to achieving optimal glycemic control without an unacceptable risk for hypoglycemia (36) (C). Hypoglycemia has often been described as mild, moderate, or severe based on the individual's ability to treat him/herself. However, there are no clinically important reasons to distinguish between mild and moderate hypoglycemia, and younger children will almost always need to be treated by a parent or caregiver. Therefore, mild and moderate hypoglycemia are considered together. The child or parent is aware of, responds to, and treats the hypoglycemia orally after documenting a BG level of ≤ 3.9 mmol/L (70 mg/dL). The ADA (21) has suggested using the terminology of ‘Documented Symptomatic Hypoglycemia’ for this category. Asymptomatic hypoglycemia applies when the child is not symptomatic with hypoglycemia but the BG is documented to be ≤ 3.9 mmol/L (21). The category of asymptomatic hypoglycemia, especially if < 3.6 mmol/L (65 mg/dL), is suggested because it is important to recognize the frequency of hypoglycemia unawareness or glucose values that place an individual at risk for hypoglycemia unawareness. The child is having altered mental status and cannot assist in their care, is semiconscious or unconscious, or in coma± convulsions and may require parenteral therapy (glucagon or i.v. glucose). The goal is to restore the BG level to euglycemia [BG = 5.6 mmol/L (100 mg/dL)]. It should be remembered that capillary BG estimation at low BG levels is less accurate than at higher levels, and therefore, low BG numbers should be interpreted with caution. If the BG is 3.5–3.9 mmol/L and the child does not have uncomfortable symptoms, immediate intake of most carbohydrates will raise the BG sufficiently. In adults, 20 g of carbohydrate in the form of glucose tablets raised BG by approximately 2.5–3.6 mmol/L (45-65 mg/dL) (37, 38, 39). This has been extrapolated to 0.3 g/kg in children (40). However, it is important to remember that the amount of carbohydrate required will depend on the size of the child, type of insulin therapy, proximity to recent insulin dosage, the intensity of antecedent exercise as well as other factors (37, 41). The type of carbohydrate is also important as 40 g of carbohydrate in the form of juice was needed to give approximately the same rise as 20 g in the form of glucose tablets (37), sucrose likewise requires a greater amount to provide the same increase in blood glucose (38). Milk containing 20 g of carbohydrate gave only a rise of approximately 1 mmol/L (20 mg/dL). This has been explained by delayed emptying of the stomach because of the fat content (42). Treatment of hypoglycemia should be provided promptly and should provide immediate oral, rapidly absorbed, simple carbohydrate calculated to raise BG level to 5.6 mmol/L (100 mg/dL), [1 g glucose should raise BG by approximately 0.17 mmol/L (3 mg/dL) for the average adult]. The amount of carbohydrate required will depend on the size of the child, type of insulin therapy, and proximity to recent insulin dosage as well as the vigorousness of the immediate antecedent exercise, if any (41). To increase the BG approximately 3-4 mmol/L (55-70 mg/dL) give glucose tablets/sugar lumps or a sweet drink (glucose/sucrose drinks, cola etc.), approximately 10 grams of glucose is needed for a 30 kg child and 15 grams for a 30 kg child. If sucrose or fructose are used, slightly higher amounts are required compared to pure glucose (38, 37). Chocolate, milk and other foods containing fat will cause the sugar to be absorbed more slowly and should be avoided as the initial treatment of hypoglycemia (37, 43). After treatment, wait 10–15 min, retest BG, if no response or an inadequate response, then repeat oral intake as above. Retest the BG in another 20–30 min to confirm that target glucose has been maintained and not exceeded (E). For initially lower glucose values, as symptoms improve or euglycemia is restored, the next meal or snack may be ingested (e.g., fruit, bread, cereal, and milk) to prevent recurrence of hypoglycemia. Additional recommendations are given in the exercise section and in the International Society for Pediatric and Adolescent Diabetes (ISPAD) Guidelines for Exercise. Retesting to document normalization of glucose is essential to ensure adequate, and not excessive, treatment. Urgent treatment is required. Severe hypoglycemia with loss of consciousness ± convulsions (particularly if there is vomiting) is most safely and rapidly reversed by injection of glucagon 0.5 mg for age < 12 yr, 1.0 mg for ages > 12 yr, or 10–30 mcg/kg body weight (44). Glucagon is given intramuscularly or subcutaneously. In a hospital setting, i.v. glucagon may be given. if glucagon is unavailable or recovery is inadequate. Intravenous dextrose should be administered slowly by trained personnel over several minutes, e.g., dextrose 10–30% at a dose of 200–500 mg/kg (dextrose 10% is 100 mg/mL) to reverse the hypoglycemia. Rapid administration, or excessive concentration, i.e., dextrose 50%, may result in an excessive rate of osmotic change. When glucagon is not available, a common practice is to administer a rapid acting source of glucose (e.g. glucose gel or honey) into the buccal pouch (E). However, the efficacy of this practice is anecdotal and there is no scientific evidence for absorption of glucose from the buccal mucosa. On the contrary, there is one study in adults showing no buccal absorption of glucose (45). In the recovery phase after treatment of severe hypoglycemia, close observation and BG monitoring is essential because vomiting is common and recurrent hypoglycemia may occur. Should recurrent hypoglycemia occur, the child will require additional oral carbohydrate and/or i.v. infusion of glucose, e.g., dextrose 10%, 2–5 mg/kg/min (1.2–3.0 mL/kg/h). To fully categorize a patient's frequency of hypoglycemia, it should be recognized that individuals with diabetes may not always document an episode of hypoglycemia but may treat the event resulting in resolution of symptoms. These events should be recognized and may be categorized as probable symptomatic hypoglycemia(21). In addition, an event may occur when symptoms typical of hypoglycemia occur and are relieved by treatment but the BG value is > 3.9 mmol/L. This may occur if the BG level falls rapidly or may occur in patients with chronically poor glycemic control (46). This is termed relative hypoglycemia(21). There is no evidence of any neurocognitive harm from relative hypoglycemia but, without appropriate patient education, it may become a barrier to achievement of more optimal glycemia. Families should receive education about the times when hypoglycemia is more likely to occur so that more frequent glucose monitoring may be initiated. Hypoglycemia occurs more frequently: when the treatment regimen is altered (more insulin, less food, and more exercise); in younger children; with lower HbA1c levels [The relation between severe hypoglycemia and lower HbA1c had been extensively explored (33), especially in children (11, 17, 35, 47, 48).]; when there are frequent low BG levels (25); when awareness of autonomic symptoms is reduced (49); during sleep (14, 28); after the ingestion of alcohol (50). Alcohol suppresses gluconeogenesis (51) and may induce hypoglycemia unawareness (52). In addition, alcohol ingestion acutely improves insulin sensitivity. In combination with exercise, drinking can lead to severe hypoglycemia, which may occur 10–12 h after the exercise or alcohol ingestion (53). The comorbidities of celiac disease, present in 4–10% of children with type 1 diabetes, and Addison's disease, present much less commonly (54), may also increase the risk for hypoglycemia (55, 56). The introduction of a gluten-free diet and appropriate treatment of Addison's Disease may reduce the frequency of hypoglycemia (57, 58). The risk for hypoglycemia is increased during, immediately after, as well as 2–12 h after exercise. This effect is variable and depends on many factors including duration and intensity of exercise, type of insulin, and site of injection (41, 59, 60). that BG levels below mmol/L mg/dL), to exercise in the is associated with a high of hypoglycemia within min insulin infusion therapy for to h during exercise may to prevent hypoglycemia exercise, 15 g of carbohydrate will raise the BG by approximately 1 mmol/L for a child to the therefore, g of oral carbohydrate may be required to prevent hypoglycemia for a 30 kg child and grams for kg child, additional carbohydrate will usually be required if exercise occurs at the peak of insulin carbohydrate will be lower if the to the exercise is or if the exercise occurs several after the meal has been given. In many a of the insulin dose after exercise should be considered to prevent hypoglycemia. hypoglycemia is often does not sleep and may be studies hypoglycemia in of children treated with the combination of and insulin When glucose monitoring was for had at least one episode of low glucose It should be if BG is low, and/or or occur during the or if altered or are on has shown that counterregulatory responses to low BG may be during sleep hypoglycemia is not on the of a BG level and can only be by BG at during the or glucose monitoring A snack containing carbohydrate as well as fat and may be in hypoglycemia, but this should not be at the of high BG in the snack to provide from hypoglycemia than simple carbohydrates However, one study in adults that the of with not give hypoglycemia h after the snack slowly absorbed carbohydrate at may be especially following strenuous exercise in the or and insulin and insulin infusion therapy may decrease risk for hypoglycemia glucose monitoring has been in the frequency and duration of hypoglycemia have shown an between hypoglycemia and decrease in in children with type 1 diabetes before the age of the of diabetes and hyperglycemia to decrease in very young children has increased On a episodes of hypoglycemia, even if have important for and well These dysfunction reduced awareness of low BG, or and significant fear of hypoglycemia, resulting in in insulin glucose levels and increased HbA1c episodes of hypoglycemic in young children may cause permanent changes and studies that hypoglycemia and hyperglycemia cause changes in the and of lead to significant in and ability to and The may be even after mild hypoglycemia However, in one severe hypoglycemia not have on in during when with children without severe hypoglycemia Severe hypoglycemia in children may result in were in of children with a of severe hypoglycemia compared with only of without and of control children However, intensive insulin treatment in the at while the incidence of hypoglycemia, has not to a significant of or during the as well as after into the This observation may be evidence that the effect of severe hypoglycemia on is age However, there is evidence that hyperglycemia may be to the of the The in with of age to at and HbA1c but not to hypoglycemia A study in type 1 patients with duration of and diabetes that higher HbA1c levels and severe hypoglycemic events were associated with lower of in for and blood glucose levels early in may the and the more to any other that occurs in the Severe hypoglycemia can also lead to increased poor hospital excessive of insulin dose, and of glycemic control with severe hypoglycemia also lower quality of Hypoglycemia is a significant factor in in patients with diabetes recent in therapy, among children has not for and a recent report a increase in in death in young with type 1 diabetes has been described and is as the in syndrome It to be for about of in patients below 40 hypoglycemia has been as the cause for these consistent with of counterregulatory response during sleep the high frequency of hypoglycemia by the and more recent studies using glucose monitoring severe hypoglycemia can lead to and death Hypoglycemia is potentially because its occurrence is because it is often associated with significant may be the that it can in lead to permanent sequelae and is potentially education for their and other should be given to children and their to recognize the early warning signs of hypoglycemia and treat low BG immediately and To reverse hypoglycemia patients and their parents should be trained to their diabetes care if hypoglycemia is documented without symptoms or if the symptoms are of and not autonomic symptoms hypoglycemia hypoglycemic episode should be to its cause evaluating the insulin of insulin administration, peak insulin and intensity of insulin recent food intake and amount of carbohydrates and peak BG effect of recent recent and To if changes in the treatment regimen are additional should signs and symptoms of early the of of meal insulin if a BG was at the of the hypoglycemic symptoms and after treatment These in the are especially for adolescents who may not be in or their insulin doses or to signs of hypoglycemia. After insulin should be given to using insulin that have been shown to reduce the occurrence of hypoglycemia including insulin infusion and and The most consistent of rapid acting and analogue insulins has significant decrease in hypoglycemic studies have not been to a in severe events but have documented a in mild to moderate events and in hypoglycemic events intake and should be so that glycemic are more to insulin and may need to be to the meal especially in younger children or if insulin is the meal insulin dose for the BG value and the carbohydrate content of the meal may be in the risk for hypoglycemia The and intensity of exercise should be so that food intake and insulin dose can prevent in BG and may be required. A carbohydrate snack of g to exercise in has been shown to decrease hypoglycemia, as has of rate during exercise, but if exercise occurs at the peak of insulin, or is additional carbohydrates may be required Additional recommendations for carbohydrate intake during exercise are given in a review by and the BG may need to be in patients with recurrent hypoglycemia and/or hypoglycemia unawareness BG can be in several (28, and in the Guidelines on BG with to levels, is one of the most important to mild hypoglycemia and prevent and severe glucose monitoring has that hypoglycemia may occur during the and this to a significant in and of hypoglycemia of glucose monitoring have given to that glycemic control may not lead to increased risk of hypoglycemia when this is used The goal remains the of a or an with and to control insulin (E). The of diabetes treatment should be to BG levels above 3.9 mmol/L while to achieve the glycemic control without the occurrence of severe hypoglycemia. about the risk factors for hypoglycemia should be given to patients and to as to times and situations when increased glucose monitoring is required and when treatment need to be Hypoglycemia should be because its occurrence is and it is often associated with significant more it can in lead to permanent sequelae and may be potentially should be given to and other to recognize the early warning signs of hypoglycemia and treat low BG immediately and Children and adolescents with diabetes should form of or of their diabetes (E). immediate source of glucose or sucrose always be immediately to young with diabetes for BG be to all children with diabetes for immediate and management of hypoglycemia Glucagon should be to all parents and caregivers, especially when there is a high risk of severe hypoglycemia. on of glucagon is essential (E). Treatment of hypoglycemia should increase the BG approximately 3-4 mmol/L (55-70 mg/dL). This can be by glucose tablets/sugar lumps or a sweet drink (glucose/sucrose drinks, cola etc.), approximately 10 grams of glucose is needed for a 30 kg child and 15 grams for a 30 kg child If sucrose or fructose are used, slightly higher amounts are required compared to pure milk and other foods containing fat will cause the sugar to be absorbed more slowly and should be avoided as the initial treatment of hypoglycemia. treatment BG should be min, if no response or inadequate response, repeat intake as above. Retest the BG in 20–30 min to confirm that target glucose has been maintained and not BG monitoring should be to exercise, and carbohydrates should be based on the BG level and the intensity and duration of the exercise. and their parents should be trained to their diabetes care if hypoglycemia is documented without symptoms or if the symptoms are of and not autonomic symptoms hypoglycemia glucose may need to be in patients with recurrent hypoglycemia and/or hypoglycemia unawareness. If hypoglycemia is for celiac and Addison's should be