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Diabetic Emergencies: Hypoglycemia Caused by Insulin, Part 3

Dec 3, 2012

Consequences of acute hypoglycemia






Acute hypoglycemia can lead to health damage either directly (from deleterious effects of low blood glucose supply to the brain) or indirectly, usually via trauma due to loss of consciousness or seizures. As an example, hypoglycemia may occur during driving and may obviously cause road traffic accidents….


In the vast majority of cases, recovery from a severe hypoglycemic event, even if it manifests with seizures or coma, is complete. Sometimes, neurologic abnormalities can be observed immediately after recovery of consciousness and improve afterwards. Hypoglycemic hemiplegia is an uncommon condition that has been described as a hemiparetic state, presenting in the morning when the patient awakens after a nocturnal hypoglycemic event. The episode typically resolves after a few minutes or hours and may recur. 28 Permanent neurologic damage and death have been reported rarely, 29 especially after massive insulin overdose and delayed restoration of normoglycemia. 30

Another possible mechanism of acute health damage, including sudden death, due to hypoglycemia is via the induction of cardiovascular events. Hypoglycemia has been implicated in the so-called "dead-in-bed syndrome," the unexpected death of a young person with Type 1 diabetes found dead in an undisturbed bed. 29 It has also been suggested that the increased total mortality risk observed in the intensive glycemic control arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study might be due to the high rate of hypoglycemic events. 18 However, this insinuation has not been verified in post hoc analysis of the trial data. 31

It has been shown that hypoglycemia, especially in patients with pre-existing cardiovascular disease, induces multiple proarrhythmic changes, mainly increasing pre-existent QT prolongation, producing intracellular Ca2+ overload, and decreasing serum K+.32 As a consequence, hypoglycemia is considered a state that may lead to sudden death (as a result of cardiac arrhythmia). Whereas the evidence supporting this view is strong from a basic science perspective, no large clinical studies have yet definitively confirmed it.32 Epidemiological confirmation of a causal association between hypoglycemia and arrhythmic events is difficult to prove due to the fact that firm postmortem evidence of hypoglycemia is virtually impossible to obtain. A recent extensive review of the possible link between hypoglycemia and ischemic cardiac events concluded that although small observational studies suggest an association between hypoglycemia and such events, there is currently no evidence for causality. 33 

A severe hypoglycemic event is an annoying and unpleasant experience that can also be embarrassing from a social point of view. Hence, such an event may be associated with adverse psychological consequences including fear of hypoglycemia, high levels of anxiety, and deterioration of glycemic control.13

Consequences of chronic recurrent hypoglycemia

The existence of a link between recurrent severe hypoglycemic events and impaired cognitive function is an issue of debate. There is some evidence to suggest that severe hypoglycemia is associated with a decline of the intelligence quotient (IQ) in patients with Type 1 diabetes.34 However, large, well-designed and controlled studies of the impact of recurrent hypoglycemia on cognitive performance in patients with diabetes are sparse and inconclusive. It has been shown prospectively (up to 18 years of follow-up) that intensified insulin therapy does not lead to cognitive impairment despite its association with a high rate of hypoglycemic events.35 Interestingly, it has been recently shown in rats that recurrent moderate hypoglycemia preconditions the brain and protects neurons against damage induced by severe hypoglycemia.36 The situation is probably different in the developing brain. In children with Type 1 diabetes, some aspects of attention are adversely affected by a history of seizures from hypoglycemia.37

A longitudinal cohort study of nearly 17,000 patients with a mean age of 65 years and Type 2 diabetes indicated an association between severe hypoglycemic episodes and a higher risk of dementia.38

Summary box
It is extremely important to avoid episodes of severe hypoglycemia in young children, in whom slightly higher glycemic targets might be more appropriate. Similarly, elderly patients might also be at increased risk of brain damage from recurrent episodes of hypoglycemia.
Management of hypoglycemia caused by insulin treatment 

Management includes the following steps:

  • Restoration of normal plasma glucose levels
  • Prevention of relapse in the short term
  • Prevention of recurrent episodes in the long term.
Restoration of normal plasma glucose levels
(Figure 4.2)

In non-severe hypoglycemia, the oral consumption of carbohydrates is usually adequate to restore plasma glucose levels above the lower limit of the normal range. Patients starting insulin for the treatment of their diabetes should be taught to recognize the symptoms of hypoglycemia and how to react in case of a hypoglycemic event. Self-monitoring blood glucose (SMBG) is strongly recommended for these patients.27 If hypoglycemia is suspected, a blood glucose measurement using a portable glucose meter is recommended in order to confirm low plasma glucose, although this option is not always feasible. Therefore, in clinical practice, many mild hypoglycemic episodes are classified as "probable symptomatic hypoglycemia" (see Classification of hypoglycemia). On the other hand, patients with hypoglycemia unawareness typically discover mild hypoglycemia during routine self-monitoring. Such events are classified as "asymptomatic hypoglycemia" and should be treated as promptly as symptomatic ones.



Summary box
It is mandatory that patients do not delay self-treatment of mild episodes, since they could rapidly evolve to severe life-threatening hypoglycemia.
Rapidly-absorbed simple carbohydrates are preferred over complex ones, since the latter might fail to promptly correct blood glucose. Glucose tablets (usually provided as 5 g each) are effective and often preferred, especially by well-educated patients with Type 1 diabetes. Alternatively, glucose-or sucrose-containing beverages such as non-diet soft drinks or sweetened fruit juice are also quite effective and usually readily available. 39 In patients being treated with insulin in combination with an α-glucosidase inhibitor (acarbose or miglitol), pure glucose-containing tablets or beverages are prescribed, since these drugs delay the degradation of disaccharides (such as sucrose and fructose).

Summary box

Severe hypoglycemia is a potentially life-threatening condition and should be treated immediately.


Severe hypoglycemia is defined as hypoglycemia that is not possible to self-manage (see Classification of hypoglycemia). If a patient is able to receive oral carbohydrates with the help of a third person, then this method constitutes the preferred way to correct low plasma glucose. The same rules as for mild episodes can be followed, although higher amounts of simple carbohydrates should likely be administered (40-50 g instead of 20 g). In comatose patients or those who are severely confused or refusing to collaborate, parenteral therapy is recommended. This can be administered either as glucagon injection or intravenous glucose solution.

Summary box

Glucagon is preferred when the hypoglycemic episode occurs during everyday activity and a third person (family member, close friend, roommate, school personnel, child care provider, etc.) has been educated to recognize such an event and act appropriately.


If a glucose meter is available, blood glucose measurement is highly recommended in order to confirm low plasma glucose levels. Glucagon 1 mg should then be administered intramuscularly or subcutaneously. The glucagon kit should be readily available and the patient’s relatives or friends should know how to mix the glucagon powder with the diluent, draw it from the vial, and give the injection. Some glucagon kits contain a syringe prefilled with the diluent, which is then inserted into the vial, mixed with the glucagon powder, and redrawn in the same syringe. Successful glucagon therapy requires that the glucagon kit be readily accessed and that the rescuer remain calm while properly preparing and administering the injection. If a glucose meter is not available, glucagon should still be given to the unconscious patient. Although coma might be due to marked hyperglycemia (with or without ketoacidosis) rather than hypoglycemia, the latter will be corrected, whereas no particularly deleterious effect will be produced if blood glucose concentration is high. It should be noted that hyperglycemic coma occurs progressively, usually over several hours or even days. In contrast, hypoglycemia evolves within a few minutes. In addition, in contrast to marked hyperglycemia, in hypoglycemia the skin is wet, deep tendon reflexes are increased, and there is mydriasis.

Recovery of consciousness and restoration of normal plasma glucose levels are expected in about 10-15 minutes. At this time the patient may have nausea or vomiting, a common side effect of glucagon administration. These symptoms, however, if present, last only a few minutes.

If a glucagon injection is not available (and there is no access to intravenous glucose), is there any other option for the unconscious hypoglycemic patient while awaiting emergency personnel? Some experts recommend family members or friends to squeeze and rub a sucrose-containing substance (such as white sugar, honey, syrup, or glucose gel) between the teeth and buccal mucosa, while keeping the patient’s head tilted to the side. No data exist to support or reject this. Nevertheless, if such an instruction is given to patients’ relatives, attention should be paid to avoid aspiration, which might have more deleterious consequences than hypoglycemia itself.

If there is no response to glucagon, intravenous glucose should be administered. Since glucagon acts by stimulating glycogenolysis, its administration may not be effective in case of heavy alcohol consumption, prolonged fasting, or hepatic failure. In addition, because glucagon stimulates insulin secretion as well, its administration may be less useful in Type 2 diabetes.13


Summary box

In the medical emergency setting, severe hypoglycemia should be treated by intravenous glucose infusion.


No specific guidelines, based on the results of clinical trials, exist regarding the optimal way to treat severe hypoglycemia at the emergency room. Some experts recommend the intravenous administration of 20-50 ml of 50% glucose solution as a bolus, providing 10-25 g of glucose.13,40 Others suggest that a higher amount (75-200 ml) of a more dilute glucose solution (10-20%) should be preferred, given that the 50% solution might be tissue-toxic if extravasated. 30 We usually administer 50 ml of a 35% glucose solution, providing 17.5 g of glucose, as a bolus. This is sufficient to restore plasma glucose and lead to recovery of consciousness in the vast majority of cases. We have never observed any severe tissue necrosis due to extravasation.

According to some recommendations, bolus glucose administration should be followed by continuous infusion of a 10-20% glucose solution at a rate of 50-200 ml/h, depending on the degree of hypoglycemia and the patient’s response to treatment. Plasma glucose should be re-measured 10-15 minutes after the initial glucose administration and a bolus infusion repeated if hypoglycemia persists. If plasma glucose has been restored but consciousness is still disturbed, the glucose infusion should be continued at a slow rate. Although other causes of impairment of consciousness should be considered, clinicians should be aware that occasionally full recovery of brain function might take several minutes or even hours. In rare cases of sustained neurological manifestations solely attributed to hypoglycemia, some experts recommend the administration of dexamethasone.40

Prevention of relapse in the short term

Restoration of plasma glucose levels after an acute hypoglycemic event usually follows quickly after the administration of carbohydrates, either orally or intravenously, or after a glucagon injection. It is very important, however, to keep in mind that hypoglycemia tends to relapse in some cases, this tendency depending on the etiology of the initial decline in plasma glucose (Box 4.1).


Summary box

Follow-up after immediate plasma glucose correction is a cornerstone in the overall management of any hypoglycemic episode.


In mild self-treated hypoglycemia, patients are advised to re-measure their plasma glucose levels 15 minutes after carbohydrate ingestion and repeat treatment in case of relapse or tendency towards relapse. If the next meal is scheduled more than one hour later, it is wise to consume a small amount of complex carbohydrates (e.g., a sandwich or a couple of pieces of fruit) in order to avoid recurrence of hypoglycemia.

In severe hypoglycemia treated with glucagon, it is recommended that immediately after regaining consciousness patients should receive oral carbohydrates providing 20-40 g of glucose in order to restore hepatic glycogen and prevent relapse of hypoglycemia. We advise patients recovering from severe hypoglycemia treated with glucagon to monitor their plasma glucose frequently (every half an hour) for the next few hours.

In severe hypoglycemia treated at the emergency room, a continuous infusion of a 10-20% glucose solution is generally recommended after the initial administration of bolus glucose, accompanied by frequent monitoring of capillary blood glucose. The decision on whether and when the patient should be discharged depends on response to treatment as well as on factors related to the cause of the hypoglycemic event, the age of the patient, and the presence of co-morbidities (Box 4.1).

Identification of the cause of the severe hypoglycemic event is crucial. As stated above, iatrogenic hypoglycemia occurs when circulating insulin exceeds actual patient needs, while, at the same time, counter-regulatory mechanisms fail to prevent the decline of blood glucose levels. The most common causes of hypoglycemia in insulin-treated patients are misjudgment of insulin dose, a missed/delayed meal, or increased, usually unplanned, physical activity. Other factors that should be taken into account in the evaluation of a severe hypoglycemic episode are listed in Box 4.1. In a 12-month survey of all attendances with hypoglycemia at the emergency department at two district general hospitals in the UK, only 11% of patients were admitted to hospital, 83% of patients were discharged, and 6% self-discharged.23 Four out of the 10 admitted patients had co-morbidities, 4 had a decreased Glasgow coma scale, 2 were above 80 years old, one had alcohol intoxication, and one was homeless. In another retrospective study from the UK, of 54 patients admitted to the hospital with a primary diagnosis of hypoglycemia, 9 had a relapse during the first 24 hours of hospitalization. The mortality rate was 7.4% (4 deaths) but only one was attributable to hypoglycemia itself, in a 63-year-old patient suffering from several co-morbidities.41


Summary box

Insulin-treated patients with iatrogenic hypoglycemia can be safely discharged from the emergency department if their level of functioning has returned to baseline, they are able to eat, their plasma glucose levels are constantly above 100 mg/dl (5.6 mmol/L) for at least 1 hour after discontinuation of glucose infusion, and no major co-morbidities are present.


As an extra precaution, some experts recommend that patients at extremes of age should be observed for 24 hours. Patients who receive oral antidiabetic drugs in combination with insulin might also require further observation (see Chapter 5). Every case, however, should be carefully examined as criteria for admission are individualized. 

Prevention of recurrent episodes in the long term

Recurrent hypoglycemia requires a thorough evaluation of diabetes management and should be an indication for referral to a diabetologist/endocrinologist. The circumstances before and during hypoglycemia, as well as the factors listed in Box 4.1, should be carefully examined in order to prevent further severe hypoglycemic episodes. Special consideration should be paid to diagnose the presence of HAAF and hypoglycemia unawareness, since these two conditions are significant risk factors for severe hypoglycemia. A careful history is usually adequate to identify hypoglycemia unawareness. In other cases, careful follow-up with frequent SMBG or even the use of a glucose sensor for continuous subcutaneous glucose monitoring may be recommended. The evaluation of patients with recurrent hypoglycemia and the management of hypoglycemia unawareness are beyond the scope of this book and the reader is referred to recent extensive reviews on these topics.8,42


13. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care 2003; 26: 1902-12.

14. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Prolonged nocturnal hypoglycemia is common during 12 months of continuous glucose monitoring in children and adults with Type 1 diabetes. Diabetes Care 2010; 33: 1004-8.

15. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-86.

16. Pedersen-Bjergaard U, Pramming S, Heller SR, et al. Severe hypoglycemia in 1076 adult patients with Type 1 diabetes: Infl uence of risk markers and selection. Diabetes Metab Res Rev 2004; 20: 479-86.

17. United Kingdom Prospective Diabetes Study Group. 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 1998; 352: 837-52.

18. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-59.

19. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-72.

20. Duckworth W, Abraira C, Moritz T, et al. Intensive glucose control and complications in American veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-39.

21. Leese GP, Wang J, Broomhall J, et al, the DARTS/MEMO Collaboration. Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: A population-based study of health service resource use. Diabetes Care 2003; 26: 1176-80.

22. Donnelly LA, Morris AD, Frier BM, et al, the DARTS/MEMO Collaboration. Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population based study. Diabet Med 2005; 22: 449-55.

23. Brackenridge A, Wallbank H, Lawrenson RA, et al. Emergency management of diabetes and hypoglycaemia. Emerg Med J 2006; 23: 183-5.

24. McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. Diabet Med 2001; 18: 690-705.

25. Deary IJ, Hepburn DA, MacLeod KM, et al. Partitioning the symptoms of hypoglycaemia using multi-sample confi rmatory factor analysis.Diabetologia 1993; 36: 771-7.

26. Liatis S. Treatment of diabetes with insulin. In: Katsilambros N, Diakoumopoulou E, Ioannidis I, Liatis S, Makrilakis K, Tentolouris N, Tsapogas P (ed), Diabetes in Clinical Practice, Questions and Answers from Case Studies, West Sussex, England: John Wiley & Sons Ltd, 2006: 371-408.

27. American Diabetes Association. Clinical practice recommendations 2010. Diabetes Care 2008; 33 (Suppl 1): S11-61.

 28. Shintani S, Tsuruoka S, Shiigai T. Hypoglycaemic hemiplegia: A repeat SPECT study. J Neurol Neurosurg Psychiatry 1993; 56: 700-1.

29. Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med 1991; 8: 49-58.

30. Amiel SA. Iatrogenic hypoglycemia. In: Kahn R, King GL, Moses AC, Weir GC, Jacobson AM, Smith RJ (ed), Joslin ‘ s Diabetes Mellitus, 14 th edn, Philadelphia, USA: Lippincott Williams & Wilkins, 2005: 671-86.

31. Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010; 340: b4909.

32. Nordin C. The case for hypoglycaemia as a proarrhythmic event: Basic and clinical evidence. Diabetologia 2010; 53: 1552-61.

33. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care 2010; 33: 1389-94.

34. Deary IJ, Crawford JR, Hepburn DA, et al. Severe hypoglycemia and intelligence in adult patients with insulin-treated diabetes. Diabetes 1993; 42: 341-4.

35. The Diabetes Control and Complications Trial Research Group.Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. Ann Intern Med 1996; 124: 379-88.

36. Puente EC, Silverstein J, Bree AJ, et al. Recurrent moderate hypoglycemia ameliorates brain damage and cognitive dysfunction induced by severe hypoglycemia. Diabetes 2010; 59: 1055-62.

37. Rovet J, Alvarez M. Attentional functioning in children and adolescents with IDDM. Diabetes Care 1997; 20: 803-10.

38. Whitmer RA, Karter AJ, Yaffe K, et al. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009; 301: 1565-72.

39. Georgakopoulos K, Katsilambros N, Fragaki M, et al. Recovery from insulin-induced hypoglycemia after saccharose or glucose administration. Clin Physiol Biochem 1990; 8: 267-72.

40. Heller S. Hypoglycemia and diabetes. In: Pickup JC, Williams G (ed), Textbook of Diabetes Mellitus, 3 rd edn, Oxford, UK: Blackwell Publishing, 2003:33. 1-19.

41. Hart SP, Frier BM. Causes, management and morbidity of acute hypoglycaemia in adults requiring hospital admission. QJM 1998; 91: 505-10.

42. de Galan BE, Schouwenberg BJ, Tack CJ, et al. Pathophysiology and management of recurrent hypoglycaemia and hypoglycaemia unawareness in diabetes. Neth J Med 2006; 64: 269-79.


Next Excerpt: Hypoglycemia/Case Studies

Nikolaos Katsilambros, MD, PhD, FACP
SCOPE Founding Fellow
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Athens, Greece

Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Athens, Greece

Stavros Liatis, MD
Consultant in Internal Medicine and Diabetology
Laiko General Hospital

Konstantinos Makrilakis, MD, MPH, PhD
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Athens, Greece

Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
Athens, Greece

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Diabetic Emergencies: Diagnosis and Clinical Management provides emergency room staff, diabetes specialists and endocrinologists with highly practical, clear-cut clinical guidance on both the presentation of serious diabetic emergencies like ketoacidosis, hyperosmolar coma and severe hyper- and hypoglycemia, and the best methods of both managing the emergencies and administering appropriate follow-up care.

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