Module 204.1 en_0

Editor's Notes

1. In this presentation we will review hypoglycaemia – the causes, signs and symptoms, treatment, and prevention. We will also discuss unawareness of hypoglycaemia and hypoglycaemia in special situations.
2. Hypoglycaemia, which literally means “low blood glucose” can arise from many causes, and can occur at any age. The most common forms of moderate and severe hypoglycaemia occur as a complication of treatment of diabetes with insulin or oral medications. Endocrinologists typically consider the following criteria (known as Whipple's triad) as indicating that a person’s symptoms can be attributed to hypoglycaemia: The presence of symptoms known to be caused by hypoglycaemia Low glucose at the time the symptoms occur Reversal or improvement of symptoms when glucose levels are restored to normal. For practical purposes and for teaching, a blood glucose level of 4 mmol/L (~72 mg/dl) or below is considered hypoglycaemia. Cryer, P.E., Davis, S.N., Shamoon, H. (2003). Hypoglycemia in diabetes. Diabetes Care, 26(6),1902-1912.
3. It is important to stress that hypoglycaemia is preventable most of the time if a person knows how to correct medication doses and make appropriate food choices. There are many possible causes for hypoglycaemia. The obvious risks include: Consuming too little carbohydrate Missing a meal or eating a meal later than the usual time Taking excessive doses of insulin or blood glucose-lowering medicines Physical activity may also provoke low levels of glucose at the time of the activity. Hypoglycaemia can occur many hours after an activity – up to about 12 hours, especially after prolonged and/or intensive exercise. People should monitor blood glucose frequently after exercise and learn how to adjust their food intake and insulin doses accordingly. The crucial time for carbohydrate intake is within the first two hours after exercising. After prolonged or intensive exercise, the liver and muscle tissue may be depleted of glucose stores. It will take some time to replenish these stores; during this time the person is at risk of hypoglycaemia.
4. Severe hypoglycaemia is more common following a previous episode of hypoglycaemia. This is because the normal subsequent counter-regulatory responses are blunted. It may also be that a person did not consume adequate carbohydrate in response to the initial hypoglycaemia. People who have frequent mild to moderate hypoglycaemic reactions may also have blunted glucagon response putting them at risk for severe hypoglycemia. Overcorrection of elevated blood glucose levels is a very common cause of hypoglycaemia. It is difficult to predict the effect of stress on blood glucose levels. In some people, the stress of an exam might raise blood glucose levels; in others it may lead to hypoglycaemia. Women with type 1 diabetes in their first trimester of pregnancy – particularly during weeks eight to 12 – often experience wide swings in blood glucose levels, including many low levels. Breastfeeding women are also at higher risk. Safety is a major concern; they should always eat before driving, for instance, and always test before feeding or bathing the baby. Comorbidities such as gastroparesis, liver disease or kidney failure may increase the risk of hypoglycaemia. Gastroparesis results in delayed gastric emptying and therefore delays the uptake of glucose. If medication has been taken, this may work before the glucose reaches the blood. Liver or kidney disease may alter the clearance of medicines and provoke prolonged action or build up of glucose-lowering medicines.
5. If people with diabetes do not have the symptoms or fail to recognize the symptoms of hypoglycemia because they are distracted or sleeping the blood glucose levels will continue to fall putting them at risk for a severe reaction. Alcohol intake may increase the risk of hypoglycaemia. People should be cautioned to eat carbohydrate when consuming alcohol (see slide 25 for more on alcohol). It is important to note that in 50% of cases there does not appear to be a reason for the hypoglycaemia. Therefore, when talking to people about a recent hypoglycaemic event, the healthcare provider should avoid making judgments or comments that place “blame’’ on the person with diabetes.
6. As blood glucose levels drop, a counter-regulatory response is provoked in all of us. In people without diabetes, the normal counter-regulatory responses are as above. It is important to note that in people with diabetes these thresholds shift to higher levels when glucose levels have been higher than normal and to lower levels in those with blood glucose levels consistently in the lower target range. When the blood glucose level is about 4.5 mmol/L (81 mg/dl) the secretion of endogenous insulin is suppressed. This does not happen in type 1 diabetes because injected insulin (exogenous) cannot be suppressed. At about 3.6 - 3.9 mmol/L (65-70 mg/dl) the secretion of glucagon is increased – releasing stored glucose. This is followed by increases in epinephrine, cortisol and growth hormone. All these hormones are in effect trying to raise blood glucose. At about 3.2 mmol/L (57.6 mg/dl) autonomic (adrenergic) symptoms appear: Tremors Palpitations Sweating Anxiety Ravenous hunger Nausea Tingling, especially around lips At about 2.8 – 3.0 mmol/L (50-55 mg/dL), the brain no longer receives enough glucose and temporary cognitive impairment occurs. This shortage of glucose (glycopenia) in the brain is called neuroglycopenia. Prolonged neuroglycopenia can result in permanent damage to the brain. People experience: Difficulty concentrating Confusion Weakness Drowsiness Vision changes Headache Tiredness There is a wide variation in the symptoms that people experience at various levels of blood glucose. Cryer P.E. Davis, S.N. Shamoon, H. Hypoglycemia in diabetes. Diabetes Care, 26(6):1902-1912 (2003) Zammitt, N.N., Frier, B.M. Hypoglycemia in type 2 diabetes. Diabetes Care, 28(12):2948-2961, (2005)
7. Physiology forms the basis for definitions of low levels of blood glucose as “mild’’, “moderate’’ and “severe’’. It is important to assess hypoglycaemia in terms of incidence, realistic prevention goals and treatment. We should hope to prevent all severe hypoglycaemia. However, some mild-to-moderate hypoglycaemia must be expected given the current available diabetes treatments. If people with diabetes tell you that they never experience symptoms of hypoglycaemia, this may indicate that their blood glucose levels are above target or that they are unaware of their hypoglycaemia. If a person reports no hypoglycaemia, ask how often they have blood glucose levels of lower than 4 mmol/L (72 mg/dL). If people, following tests, know that their levels are below 4 mmol/L (72 mg/dL), they are probably unaware that they are experiencing hypoglycaemia.
8. Of the counter-regulatory hormones, glucagon is the first line. Low blood glucose is the stimulus to the alpha cells to release glucagon (glycogenolysis). Released from the alpha cells of the pancreas, it acts only in the liver. The role of glucagon is to increase levels of glucose. It does this by: Releasing stored glycogen from the liver (glyconeogenolysis) Activating the production of new glucose from proteins (gluconeogenesis) Stimulating the production of ketones in the liver Fowler, M.J. (2008). Hypoglycemia. Clinical Diabetes, 26(4),170-173.
9. In the absence of effective glucagon, epinephrine takes on the role of the first line counter-regulatory hormone. Epinephrine (or adrenalin) is secreted by the adrenal medulla. When released into the blood, epinephrine binds to multiple receptors and has numerous effects throughout the body. It increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the skin and gut while dilating arterioles in leg muscles. Epinephrine elevates the blood sugar level by increasing the hydrolysis of stored glycogen to glucose in the liver, and at the same time begins the breakdown of lipids in adipocytes – cells in adipose tissue that are specialized in storing energy as fat. The effect epinephrine is similar to that of glucagon, stimulating the release of stored glycogen from the liver, but it does this at a slower rate. It also stimulates production of new glucose from protein (gluconeogenesis) and reduces the uptake of glucose at the periphery. In people without diabetes, the release of epinephrine also suppresses insulin production. Fowler, M.J. (2008). Hypoglycemia. Clinical Diabetes, 26(4),170-173.
10. Cortisol is a corticosteroid hormone that is produced by the adrenal cortex and is involved in people’s response to stress. Growth hormone is a polypeptide hormone that is synthesised and secreted by the anterior pituitary gland to stimulate growth and cell reproduction. These are the last of the counter-regulatory hormones to be released – only if hypoglycaemia is severe and prolonged. They predominantly decrease the peripheral uptake of glucose and stimulate the breakdown of proteins (muscle) and body fat for the formation of new glucose and ketones. Cryer, P.E., Davis, S.N., Shamoon, H. (2003). Hypoglycemia in diabetes. Diabetes Care, 26(6),1902-1912.
11. People with diabetes, their families and healthcare providers fear hypoglycaemia. Their fears are justified: hypoglycaemia has social and health implications. People with diabetes who are hypoglycaemic may act “inappropriately’’ or appear drunk. The treatment of hypoglycaemia may also cause embarrassment. (Cryer, 2003) Presenting symptoms of hypoglycaemia are very troubling and frightening. Moreover, hypoglycaemia can lead to injury, such as falling and fracturing bones; an accident while driving – possibly resulting in loss of driving license as well as any physical consequences; cognitive impairment; and on rare occasions death. Hypoglycaemia, severe hypoglycaemia in particular, may be a major limitation to achieving desired goals of blood glucose control. Cryer P.E. Davis, S.N. Shamoon, H. (2003). Hypoglycemia in diabetes. Diabetes Care, 26(6),1902-1912 Saleh M., Grunberger, G. (2001). Hypoglycemia: A cause for poor glycemic control. Clinical Diabetes, 19(4), 161-167.
12. Note to the educator: Ask groups of participants to write their advice to people for the treatment of each of the levels of hypoglycaemia. Ask the first group to share with the others their recommendations for mild hypoglycaemia; ask the others if they agree, disagree or wish to add anything. Do the same for each level.
13. Hypoglycaemia must be treated quickly. If possible, blood glucose levels should be measured with a meter to confirm hypoglycaemia. Do not delay treatment. If a meter is not available, treat the symptoms. People taking acarbose (a gluco-disaccharide inhibitor) must treat hypoglycaemia with glucose. After treatment, wait 15 minutes before testing again. If blood glucose remains lower than 4 mmol/L (72 mg/dL), glucose should be consumed. Through fear or impatience, people have a tendency to over-treat hypoglycaemia. People with diabetes and healthcare professionals should learn not to over-treat; the blood glucose may get too high. This is known as rebound hyperglycemia. This slide shows examples of treatment of mild or moderate hypoglycaemia. The recommended measures are: Glucose tablets or glucose gel if available 1/2 (125 mls) cup fruit juice 150 mls soft drink 3 teaspoons sugar or honey 1 cup of milk Glucose should be given in a quickly absorbed form – that is as “straight’’ sugar.
14. It is not advisable to repeat the glucagon; after a single dose, the person with diabetes will usually be able to take further glucose orally. If not, an ambulance should be called or the person transported to a hospital. In people with severe hypoglycaemia, when confusion or loss of consciousness prevents self-management, it is imperative to ensure their airway is clear before administering a form of glucose. If there is no glucagon available, and the person is not able to take fluids, honey or sugar substance could be smeared on the buccal mucosa. This has been shown not to work very well but when there is no other option it is worth trying.
15. Ideally, all people with type 1 diabetes ought to have a relative or friend who knows how to use and administer glucagon if necessary – to learn how to do this, the person would need instruction. Once glucagon is injected and the person affected by hypoglycaemia begins to come round, he or she may be nauseated. It is therefore important not to give food immediately; slow sips of a sweet drink are sufficient. Glucagon has a short shelf life; people with diabetes should learn to check the expiry date. After a severe hypoglycaemic event people may develop a severe headache. This headache does not generally respond to normal analgesic medications; once blood glucose levels are stabilised, people should be encouraged to sleep for a couple of hours. If glucagon is not available, intravenous dextrose can be used. Caution should be shown when injecting the dextrose. Dextrose can cause phlebitis if the dextrose goes into tissue instead of into a vein. After a severe hypoglycaemic episode, the liver may have used its store of glucose. People should therefore be warned that after an event, they are at increased risk of further hypoglycaemic events. If blood glucose levels rise significantly after the treatment, it may not be advisable to inject extra insulin as this may start the person swinging from highs to lows. Insulin may in fact need to be reduced over the next day to prevent another episode. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. (2008). Canadian Diabetes Association 2008. Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Canadian Journal of Diabetes, 32(suppl 1).
16. Treatment should be followed by the planned snack or meal. If the usual meal or snack is not planned for another hour or more, a snack consisting of carbohydrate (15-20 g) and protein may be needed. In mild to moderate hypoglycaemia, the next dose of diabetes medication or insulin is usually given. However, this should be individually assessed depending on the cause of the hypoglycaemia and the severity of the episode. After a severe episode, the next dose of insulin would likely be omitted or reduced by an amount predetermined by the health professional – by about 20% for 24 or 48 hours, for example. Although the causes of 50% of hypoglycaemic events are unknown, people with diabetes should be encouraged to try to determine the cause of hypoglycaemia and adjust treatment or lifestyle accordingly to prevent this occurring in the future.
17. For people who experience frequent hypoglycaemia, certain strategies might help. Long-acting insulin analogues, if available, are long-acting insulins without the peak that characterises intermediate-acting insulin. These insulins have been shown in several studies to result in significantly less hypoglycaemia – especially nocturnal hypoglycaemia – at the same level of glycaemic control, when compared to basal insulin (Garg 2004, Rosenstock 2005). Rapid acting analogues are much shorter lasting and can sometimes be given after a meal when it is known how much was eaten. Particularly useful in children. An insulin pump is sometimes used to provide the required basal amount of insulin, while avoiding the peaks of intermediate insulin. Changing the injection site may help. People should not inject in a limb that will be used in exercise; the insulin will be absorbed more quickly. This might also occur immediately after a hot bath or shower. Garg, S.K., Gottlieb, P.A., Hisamoti, M.E., D’Souza, A., Walker, A.J., Izuora, K.E., et al. (2004). Improved glycemic control without an increase in severe hypoglycemic episodes in intensively treated patients with type 1 diabetes receiving morning, evening, or split doses insulin glargine. Diabetes Res Clin Pract, 66(1), 49-56. Garg, S.K., Paul, J.M., Karsten, J.I., Menditto, L., Gottlieb, P.A. (2004). Reduced severe hypoglycemia with insulin glargine in intensively treated adults with type 1 diabetes. Diabetes Technol Ther, 6(5), 589-95. Rosenstock, J., Dailey, G., Massi-Benedetti, M., Fritsche, A., Lin, Z., Salzman, A. (2005). Reduced hypoglycemia risk with insulin glargine: A meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care, 28(4), 950-5.
18. Relative hypoglycaemia occurs when blood glucose levels have consistently remained high over a period of time. This might occur in a person who does not know he/she had diabetes or in a person with inadequately managed diabetes. As treatment is initiated and the blood glucose level is lowered, the person may feel the symptoms of hypoglycaemia at levels higher than 4 mmol/L (72 mg/dL). The symptoms should be treated; people will feel better when their levels increase. Teach people that as the body adjusts to target-range blood glucose levels, the symptoms of hypoglycaemia will not be felt until blood glucose reaches the usual levels.
19. Raised fasting glucose levels in the early morning may occur as a “rebound’’ effect of nighttime hypoglycaemia - around 2 to 4 am. When a person with diabetes on insulin presents with elevated fasting glucose, there should be an attempt to determine the cause before treatment is changed. The person should be asked to test for their blood glucose level at about 3 am to check for hypoglycaemia.
20. If high blood glucose levels in the morning occur as a result of overnight lows, various treatment options can be considered. These include: Decreasing evening doses of intermediate-acting insulin Moving dinner-time intermediate-acting insulin to bedtime – this delays the peak in the action of insulin until later in the morning to coincide with the dawn rise in glucose Changing to a long-acting insulin analogue – shown to reduce nocturnal hypoglycaemia by around 35% Increasing the bedtime snack (Rosenstock, 2005) In order to reduce risk of weight gain, consideration should be given, when using this later option, to the energy value of the snack. Rosenstock, J., Dailey, G., Massi-Benedetti, M., et al. (2005). Reduced hypoglycemia risk with insulin glargine: A meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care, 28(4), 950-5.
21. It is imperative that people with diabetes receive our support in their efforts to reduce the incidence of even mild-to-moderate lows. While as many as half of all hypoglycaemic events go unrecognised, recognised hypoglycaemia occurs around twice a week. An increased frequency of hypoglycaemic events (four or more times a week) may decrease a person’s counter-regulatory response and their awareness. (Cryer, 2003) Episodes of asymptomatic nocturnal low blood glucose often last more than 4 hours. One study involving adolescents with type 1 diabetes demonstrated that counter-regulatory hormone responses were blunted during sleep. This would explain asymptomatic nocturnal hypoglycaemia (Jones 1998). Approximately 50% of severe hypoglycaemia occurs at night. Frier suggests that severe hypoglycaemia during the night may result in death. (Frier, 2003) Cryer, P.E., Davis, S.N., Shamoon, H. (2003). Hypoglycemia in diabetes. Diabetes Care, 26(6),1902-1912. Frier AKV, (2003) Nocturnal Hypoglycemia: clinical manifestations and therapeutic strategies toward prevention. Endocr Pract 9(6), 530-43. Jones, T.W., Porter, P., Sherwin, R.S., Davis, E.A., O’Leary, P., Frazer, F., Byrne, G., Stick, S., et al. (1998). Decreased epinephrine responses to hypoglycaemia during sleep. N Eng J Med, 338, 1657-62.
22. Why does this phenomenon occur? The glucagon response to hypoglycaemia in people with established type 1 diabetes is lost. If a person has repeated hypoglycaemic episodes, the action of epinephrine may be blunted or delayed. The adrenergic symptoms of hypoglycaemia are thus also blunted or delayed. It therefore becomes increasingly important for people to recognise neuroglycopenic symptoms.
23. It is important for people with diabetes to know that hypoglycaemia unawareness is reversible. Management to overcome this debilitating disorder should ensure that the person has no hypoglycaemic episodes for a period of several weeks (average six weeks). This usually entails increasing target blood glucose levels to above normal – possibly a period at 8-12 mmol/L (144-216 mg/dL). Strict avoidance of lows (up to three months) has been shown to improve counter-regulation and awareness. It is possible that the person does have some signal to alert them of low blood glucose levels but they have not identified it. Extra attention and training for recognition of signals may be useful. Blood glucose awareness training teaches people to recognize unusual symptoms as warnings of impending hypoglycaemia (Cox 2001). If people have “hypoglycaemic unawareness”, they should learn to test before engaging in any activity that might put themselves or others at risk – such as driving a car. People who are hypoglycaemia-unaware should carry appropriate identification and ensure that family members and friends are aware of how to manage hypoglycaemia. If a person lives alone, safety strategies should be set in place, for instance a sugar source left by the bed, regular checks by family and friends.. Amiel,S. (2009). Hypoglycemia: from the laboratory to the clinic. Diabetes Care,32,1364-1371. Cox, D.J., Gonder-Frederick, L., Polonsky. W., Schlundt, D., Kovatchev, B., Clarke, W. (2001). Blood glucose awareness training (BGAT-2): Long-term benefits. Diabetes Care, 24(4), 637-42. Leiter, L.A., Yale, J.F., Chiasson J.L., Harris, S.B., Kleinstiver, P., Sauriol, L. (2005). Assessment of the impact of fear of hypoglycemic events. Can J Diabetes,29(3),186-192. Thomas, R.M., Aldibbiat A., Griffin, W., Cox, M.A., Leech, N.J., Shaw, J.A. (2007). A randomized pilot study in type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous avoidance with insulin analogue therapy, CSII or education alone. Diabetic Medicine, 24(7),778-83.
24. In the Diabetes Control and Complications Trial (DCCT) study, a direct relationship was demonstrated between glycaemic control and the frequency of hypoglycaemia. As control improved, the number of severe hypoglycaemic events increased. The people in the intensive treatment group had a three-fold increased risk of hypoglycaemia compared with those in the control group. However it needs to be pointed out that in the DCCT rapid acting analogue insulins were not available. Since the rapid acting insulins are available and are now used more frequently in intensive therapy, the incidence of hypoglycaemia may be lower. In the United Kingdom Prospective Diabetes Study (UKPDS), people in the intensive treatment group experienced more hypoglycaemia than those in the conventional group. The rates of major hypoglycaemic episodes were: 0.7% in the conventional group 1.0% with chlorpropamide 1.4% with glibenclamide 1.8% with insulin Some research has shown that using insulin analogues together with close blood glucose monitoring and education in strategies to avoid hypoglycaemia, good control can be achieved and may reduce the risk of hypoglycaemia. DCCT. (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Eng J Med, 329(14),977-86. UKPDS. (1998). Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 352(9131), 837-53.
25. Consuming excessive alcohol can be a major cause of severe hypoglycaemia. Alcohol increases the risk of hypoglycaemia especially overnight or early in the morning in type 1 diabetes. (Turner, 2001) Excessive alcohol is often accompanied by additional exercise such as a night out drinking and dancing and can lead to severe hypoglycaemia several hours after the outing. It is important to teach people to eat adequate carbohydrate when drinking alcohol. We also have to be realistic and teach young people how to drink safely. Suggestions for safe drinking include: Drinking juice between alcohol drinks Having a late evening meal Testing blood glucose levels before sleep or reducing bedtime insulin Reinforce the need to wear an ID bracelet or necklace. When drinking, a hypo might be mistaken for a state of inebriation, particularly if the episode is severe. Turner, B.C., Jenkins, E., Kerr, D., Sherwin, R.S., Cavan, D.A. (2001). The effect of evening alcohol consumption on next-morning glucose control in type 1 diabetes. Diabetes Care, 24(11), 1888-93.
26. Hypoglycaemia in older people may result in an increased risk of falls. In some situations, blood glucose target levels will need to be raised and diets revised. Avoid using long-acting sulphonylureas, which can lead to profound, prolonged hypoglycaemia that does not respond to the usual treatment. Use of repaglinide (short action time) or acarbose or DPP-IV inhibitors which do not cause hypoglycemia may be a better choice for the elderly. For elders on insulin using premixed insulins or insulin pens may reduce dosing errors. Johnson, E.L., Brosseau, J.D., Sobule, M., Kolberg, J. (2008). Treatment of diabetes in long-term care facilities: A primary care approach. Clinical Diabetes, 26(4), 152-156.
27. All people with diabetes should be given guidelines for driving. They should check their blood glucose levels before driving and have a treatment with them at all times. People who have hypoglycaemia unawareness are at risk of losing their license. People with diabetes should not drive when blood glucose is in the range of 4.0 to 5.0 mmol/L (72-90 mg/dL). Preventive action (eating something) should be taken first. (Cox, 2000) Cox, D.J., Gonder-Frederick, L.A., Kovatchev, B.P., Julian, D.M., Clarke, W.L. (2000). Progressive hypoglycaemia's impact on driving simulation performance. Occurrence, awareness and correction. Diabetes Care, 23(2), 163-70.
28. Moderate and severe hypoglycemic reactions are a risk to people’s physical and psychological health. They are frightening for people with diabetes and their family. Recurrent hypo is a failure of diabetes treatment and education. The remedy lies in assessing the cause and improving treatment and education. The goal is to minimize the incidence and the severity of hypoglycaemic reactions.