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  1. 1. HYPOGLYCEMIA Prepared by : Ahmed Rawhi Dabour
  2. 2. HYPOGLYCEMIA Hypoglycemia: is a clinical syndrome with diverse causes in which low plasma glucose concentrations lead to symptoms and signs, and there is resolution of the symptoms/signs when the plasma glucose concentration is raised . In patients with Diabetes, hypoglycemia is defined as : All episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm.
  3. 3. The diagnosis of hypoglycemia is not based on an absolute blood glucose level; it requires fulfillment of the Whipple triad: I ) Signs and symptoms consistent with hypoglycemia 2) Associated low glucose level 3) Relief of symptoms with supplemental glucose
  4. 4. People with diabetes should become concerned about the possibility of hypoglycemia at a self-monitored blood glucose (SMBG) level ≤70 mg/dL (3.9 mmol/L). This cut-off value has been debated, with some favoring a value of <63 mg/dL . While this value is higher than the value used to diagnose hypoglycemia in people without diabetes ≤55 mg/dL . The primary task in a patient without diabetes is to make an accurate diagnosis, whereas the primary task in a patient with diabetes is to alter or adjust therapy in an attempt to minimize or eliminate hypoglycemia .
  5. 5. Epidemiology Hypoglycemia is common in type 1 diabetes, especially in patients receiving intensive therapy, in whom the risk of severe hypoglycemia is increased more than threefold. They suffer an average of two episodes of symptomatic hypoglycemia per week, thousands of such episodes over a lifetime of diabetes, and one episode of severe, at least temporarily disabling hypoglycemia per year. • Incidence : • 3.14% in the intensive treatment group • 1.03% in the standard group • Increased risk among women, African Americans, those with less than high school education, aged participants .
  6. 6. Hypoglycemia is less frequent in type 2 diabetes than it is in type1. Hypoglycemia was reported in 38% of patients with T2DM who added a sulfonylurea or meglitinide to metformin therapy. Over time, the frequency of hypoglycemia in patients with type 2 diabetes approaches that in type 1 diabetes as patients with type 2 diabetes approach the insulin deficient end of the spectrum of the disease and require aggressive treatment with insulin. In contrast to patients with diabetes, hypoglycemia is uncommon in individuals who do not have drug-treated diabetes mellitus.
  7. 7. Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus The brain uses glucose as its preferred fuel. When a person's plasma glucose level is less than 70 mg/dL (3.9 mmol/L), signals are sent from the brain to the pancreas, liver, and adrenal glands that collectively raise the plasma glucose level. The hormones involved are insulin, glucagon, epinephrine, norepinephrine, Cortisol, and growth hormone .
  8. 8. RESPONSE TO HYPOGLYCEMIA IN NORMAL SUBJECTS As plasma glucose levels decline within the physiologic range in the fasting state, pancreatic beta-cell insulin secretion decreases, thereby increasing hepatic glycogenolysis and hepatic (and renal) gluconeogenesis. Low insulin levels also reduce glucose utilization in peripheral tissues, inducing lipolysis and proteolysis, thereby releasing gluconeogenic precursors. Thus, a decrease in insulin secretion is the first defense against hypoglycemia.
  9. 9. As plasma glucose levels decline just below the physiologic range, counterregulatory (plasma glucose–raising) hormones are released Among these, pancreatic α-cell glucagon, which stimulates hepatic glycogenolysis, plays a primary role. Glucagon is the second defense against hypoglycemia. Adrenomedullary Epinephrine , which stimulates hepatic glycogenolysis and gluconeogenesis, renal gluconeogenesis), is not normally critical. However, it becomes critical when glucagon is deficient. Epinephrine has similar hepatic effects as glucagon. It also increases the delivery of gluconeogenic substrates from the periphery, inhibits glucose utilization by several tissues ,and inhibits insulin secretion.
  10. 10. As with glucagon, a normally functioning liver is necessary for an adequate response. Epinephrine is the third defense against hypoglycemia. When hypoglycemia is prolonged beyond 4 hours, cortisol and growth hormone also support glucose production and limit glucose utilization. As plasma glucose levels fall to lower levels, symptoms prompt the behavioral defense against hypoglycemia, including the ingestion of food.
  11. 11. RESPONSE TO HYPOGLYCEMIA IN DIABETES Insulin : The protective response to hypoglycemia is impaired in many diabetic patients . The first defense, the ability to suppress insulin release, cannot occur in patients with absolute beta-cell failure ( those with type 1 diabetes and long-standing type 2 diabetes). Therefore, inhibition of hepatic glucose production continues. Thus, the main defense against hypoglycemia is increased release of counter regulatory hormones (glucagon and epinephrine), which raise plasma glucose concentrations by stimulating glucose production and by antagonizing the insulin- induced increase in glucose utilization.
  12. 12. Glucagon :The glucagon response to hypoglycemia, although normal at the onset of diabetes, is lost in parallel with that of insulin in type 1 diabetes and more slowly in type 2 diabetes . This may be the result of beta-cell failure and subsequent loss of the hypoglycemia-induced decline in intra islet insulin that normally signals increased glucagon secretion during hypoglycemia . Epinephrine : In the setting of absent insulin and glucagon responses, patients are dependent upon epinephrine to protect against hypoglycemia. However, the epinephrine response to hypoglycemia also becomes attenuated in many patients, at least in part because of recent antecedent hypoglycemia .
  13. 13. Hypoglycemia-Associated Autonomic Failure (HAAF) The concept of hypoglycemia-associated autonomic failure (HAAF) in type 1 diabetes and long-standing (absolute endogenous insulin deficient) type 2 diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness and thus a vicious cycle of recurrent hypoglycemia . It does so by shifting the glycemic threshold for the sympathoadrenal response to subsequent hypoglycemia to a lower plasma glucose concentration. This shift causes defective glucose counterregulation by reducing epinephrine responses in the setting of absent insulin and glucagon responses at a given level of hypoglycemia.  It also causes hypoglycemia unawareness by reducing neurogenic symptom responses.
  14. 14. • Mechanism — The precise mechanism(s) of the key feature of HAAF, the attenuated sympathoadrenal response to falling plasma glucose concentrations, is unknown . 1) One hypothesis is that hypoglycemic episodes lead to up regulation of glucose transport in the brain, resulting in the maintenance of glucose uptake and therefore the prevention of warning symptoms of hypoglycemia. 2) Another is that an increase in cortisol during hypoglycemia causes a reduced sympathoadrenal response to subsequent hypoglycemia. 3) A third is that hypoglycemia-induced alterations in hypothalamic functions, or even a cerebral network, reduce the sympathoadrenal response to subsequent hypoglycemia.
  15. 15. Classifications of Hypoglycemia • In diabetes mellitus the hypoglycemia is classified as : 1) Severe hypoglycemia 2) Documented symptomatic hypoglycemia 3) Probable symptomatic hypoglycemia 4) Asymptomatic hypoglycemia(or hypoglycemic Unawareness) 5) Relative hypoglycemia • Without diabetes mellitus the hypoglycemia is classified as: 1) reactive(sometimes called "postprandial") 2) and nonreactive(sometimes called "fasting").
  16. 16. Severe hypoglycemia: which requires the assistance of another person to administer a carbohydrate (preferably glucose sublingually or intravenously) or subcutaneous glucagon Documented symptomatic hypoglycemia : which occurs when a patient feels typical hyperadrenergic hypoglycemic symptoms and verifies the blood glucose level is less than 70 mg/dL (3.9 mmol/L) before self treating with 15 grams of a carbohydrate Probable symptomatic hypoglycemia : Typical hypoglycemia symptoms not accompanied by plasma glucose determination but likely caused by plasma glucose ≤70 mg/dL (≤3.9 mmol/L)
  17. 17. Asymptomatic hypoglycemia (or hypoglycemic unawareness): in which a patient does not develop typical hyperadrenergic symptoms but has a measured plasma glucose level of less than 70 mg/dL (3.9mmol/L).  this situation occurs most often in type 1 diabetes in patients striving for excellent glycemic control (hemoglobin A1c value <7.0%) who have chronic, frequent episodes of hypoglycemia. The body's ability to recognize hypoglycemia and secrete counterregulatory hormones in response to hypoglycemia deteriorates and leaves these patients vulnerable to further episodes of severe hypoglycemia. In diabetic patients, if severe neuropathy is present, the autonomic response (epinephrine) to hypoglycemia is not activated. This leads to neuroglycopenic symptoms.
  18. 18. Relative hypoglycemia: in which a patient experiences hyperadrenergic hypoglycemic symptoms but has a measured plasma glucose level greater than 70 mg/dL (3.9 mmol/L). • this situation occurs most often in patients who have had months (or longer) of hyperglycemia (plasma glucose levels >200 mg/dL [11.1mmol/L] at all times) whose plasma glucose levels are then lowered by medication or lifestyle changes closer to the normal range. • Hyperadrenergic hypoglycemic symptoms can occur when the plasma glucose level in these patients is 120 mg/dL (6.7 mmol/L) or even higher. • If these patients continue to keep their plasma glucose level substantially less than 200 mg/dL (11.1 mmol/L), the threshold at which they manifest hypoglycemic symptoms will fall to more typical levels (<70 mg/dL [3.9mmol/L]).
  19. 19. Reactive or postprandial hypoglycemia : develops in response to a nutrient challenge. see it in some post-GI surgical patients, when gastric contents get dumped into the small intestine too quickly. • Idiopathic reactive hypoglycemia requires fulfillment of the Whipple triad to be a true diagnosis. • Some patients have symptoms but normal blood glucoses; they need no further workup, in spite of their insistence.
  20. 20. Nonreactive or fasting hypoglycemia can be further subdivided into: 1) iatrogenic (most common overall cause) 2) and fasting/factitious. • In the fasting/factitious type, the patient is unable to maintain glucose levels with fasting. • Most common causes: alcohol abuse, drugs (oral hypoglycemics, pentamidine), sepsis, and renal failure.
  21. 21. CAUSES OF HYPOGLYCEMIA • Drugs are the most common cause of hypoglycemia , Hypoglycemia is common in type 1 diabetes, especially in patients receiving intensive therapy in whom the risk of severe hypoglycemia is increased more than threefold. • Less commonly, hypoglycemia may also affect patients with type 2 diabetes who take either insulin secretagogues or insulin. • In contrast, hypoglycemia is uncommon in individuals who do not have drug-treated diabetes mellitus. • In such patients, hypoglycemia may be caused by a variety of other drugs, including : alcohol, and common critical illnesses such as hepatic, renal, or cardiac failure, sepsis, or inanition. It may be due to adrenal insufficiency, an insulinoma, or an IGF-secreting tumor. In addition, hypoglycemia can be factitious, accidental, or even malicious
  22. 22. Hypoglycemia in Diabetes  Exogenous insulin and insulin secretagogue (eg, Glyburide , Glipizide , Glimepiride , Repaglinide , Nateglinide ) stimulated endogenous insulin secretion suppress hepatic (and renal) glucose production and stimulate glucose utilization and, thus, can cause hypoglycemia, particularly in the setting of compromised defenses. Even in the setting of intact defenses, these drugs can cause hypoglycemia when given in sufficient doses.  Among the commonly used sulfonylureas, Glimepiride and Glyburide (Glibenclamide) are more often associated with hypoglycemia than glipizide because of the longer duration of actions..
  23. 23. Among the drugs used to treat type 2 diabetes early in its course, insulin sensitizers ( metformin , Glitazones), glucosidase inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase IV inhibitors should not cause hypoglycemia. These drugs rely on residual endogenous insulin secretion for efficacy, and insulin secretion should decrease appropriately as plasma glucose concentrations decline into the normal range. However, all of these drugs can increase the risk of hypoglycemia when combined with administration of insulin secretagogues or insulin.
  24. 24. Hypoglycemia in patients without Diabetes • Drugs : In addition to insulin, sulfonylureas, and meglitinides, other drugs, including alcohol, may also cause hypoglycemia. • Excluding drugs used to treat diabetes and alcohol 164 different drugs were associated with hypoglycemia . • The drugs most commonly associated with hypoglycemia were quinolones, pentamidine , quinine , beta blockers, angiotensin- converting enzyme inhibitors, and IGF-1.
  25. 25. Ethanol: inhibits gluconeogenesis but not glycogenolysis. Thus alcohol-induced hypoglycemia typically follows a several day alcohol binge with limited ingestion of food resulting in hepatic glycogen depletion. Sepsis: is a relatively common cause of hypoglycemia. Cytokine accelerated glucose utilization and induced inhibition of gluconeogenesis in the setting of glycogen depletion .  chronic kidney disease: The mechanism of hypoglycemia is less clear. It likely involves impaired gluconeogenesis, reduced renal clearance of insulin, and reduced renal glucose production.
  26. 26. severe liver failure: gluconeogenesis and glycogenolysis are impaired. cardiac failure: The mechanism of hypoglycemia is unknown, It may involve hepatic congestion and hypoxia. Malnourishment: Malnutrition can cause hypoglycemia as a result of substrate limitation of gluconeogenesis and glycogenolysis in the setting of glycogen depletion. Hypoglycemia has been reported in patients with anorexia nervosa Hormone deficiencies :Cortisol deficiency (adrenal insufficiency ) growth hormone deficiency (hypopituitrism).
  27. 27. Nonislet cell tumors hypoglycemia(NICTH) : usually large tumors of mesenchymal or epithelial cell types (hepatomas, adrenocortical carcinomas, carcinoids). Hypoglycemia usually occurs as a result of tumor production of incompletely processed insulin-like growth factor II IGF-II . but insulin secretion is suppressed appropriately. During hypoglycemia plasma IGF-II to IGF-I ratios are high and free IGF-II levels and levels of pro-IGF-II are elevated. Curative surgery is seldom possible, but reduction of tumor bulk may ameliorate hypoglycemia. Therapy with a glucocorticoid, growth hormone, or both has also been reported to alleviate hypoglycemia.
  28. 28. Endogenous hyperinsulinism: is more likely in an otherwise overtly well individual with no clinical clues to the common causes of hypoglycemia. • In adults, hypoglycemia due to endogenous hyperinsulinism can be caused by the following : 1) A beta cell secretagogue, such as a sulfonylurea 2) A beta cell tumor (Insulinoma) 3) A functional beta cell disorder, often termed nesidioblastosis, that can occur as a feature of the noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) 4) Insulin autoimmune hypoglycemia an antibody to insulin or to the insulin receptors
  29. 29. Accidental, surreptitious, or malicious hypoglycemia: should be considered when the cause of a hypoglycemic disorder is not apparent . • Hypoglycemia can result from medical, pharmacy, or patient errors, such as the mistaken use of a hypoglycemic tablet by the elderly spouse of a patient with diabetes. It may also occur after ingestion of herbal products contaminated with sulfonylureas or after covert self-administration of a hypoglycemic tablet or insulin by a patient with or without diabetes. Malicious hypoglycemia : Involves administration of an insulin secretogogue or insulin to another person with the intent to cause hypoglycemia.
  30. 30. SYMPTOMS AND SIGNS OF HYPOGLYCEMIA  Symptoms of hypoglycemia have been classified into two major groups:  Autonomic Symptoms (Adrenergic And Cholinergic).  Neuroglycopenic Symptoms.  Autonomic symptoms are recognized at a threshold of approximately 60 mg/dL  Neuroglycopenic symptoms occurs at a threshold of approximately 50 mg/dL
  31. 31. Autonomic symptoms Neurogenic (or autonomic) symptoms of hypoglycemia are the result of the perception of physiologic changes caused by the CNS-mediated sympathoadrenal discharge triggered by hypoglycemia. 1. adrenergic symptoms (mediated largely by norepinephrine released from sympathetic postganglionic neurons but perhaps also by epinephrine released from the adrenal medullae) such as palpitations, tremor, and anxiety are usually experienced first. 2. cholinergic symptoms (mediated by acetylcholine released from sympathetic postganglionic neurons) such as sweating, hunger, and paresthesias.
  32. 32. Neuroglycopenic symptoms  Neuroglycopenic symptoms of hypoglycemia are the direct result of central nervous system (CNS) glucose deprivation.  They include behavioral changes, confusion, fatigue, loss of consciousness , cognitive impairment, somnolence, dizziness, slurred speech .  If these signs and symptoms are not recognized and treated and the plasma glucose level continues to decrease , the patient may develop focal neurologic signs such as hemiparesis, or have seizures and death
  33. 33. Signs of hypoglycemia • Common signs of hypoglycemia include : 1. diaphoresis and pallor. 2. Heart rate and systolic blood pressure are typically increased but may not be raised in an individual who has experienced repeated, recent episodes of hypoglycemia. 3. Transient focal neurologic deficits occur occasionally. 4. Permanent neurologic deficits are rare.
  34. 34. SIGNS-SYMPTOMS-Physical-Exam 1) General : confusion, lethargy 2) HEENT: diplopia 3) CVS : tachycardia 4) Neurologic: tremulousness, weakness, paresthesias , stupor, seizure, or coma 5) Mental status: irritability, inability to concentrate, or short-term memory loss 6) Skin: pale, diaphoresis
  35. 35. Who should be evaluated? • Only those patients in whom Whipple's triad is documented require evaluation and management of hypoglycemia. • In patients with symptoms of hypoglycemia but normal plasma glucose concentrations at the same time, no further evaluation is needed.
  36. 36. Clinical Evaluation The first step is to review the patient's history in detail, including the nature and timing of symptoms (particularly in relationship to meals), existence of underlying illnesses or conditions, surgical history ,medications taken by the individual and by family members, and social history. In a patient with documented hypoglycemia, the cause may be apparent from the history and physical examination. In a seemingly well individual, the cause is less apparent and may be due to hyperinsulinism or factitious hypoglycemia. When the cause of hypoglycemia is not evident, detailed laboratory evaluation is needed.
  37. 37. Fasting evaluation: There are patients in whom symptoms occur after only a short period of food withdrawal. Plasma glucose should be measured repeatedly during the period of observation. • If symptoms occur and hypoglycemia is documented (plasma glucose <55 mg/dL [3 mmol/L]), the other tests should be performed( Insulin, C-peptide,Beta-hydroxybutyrate,Proinsulin Sulfonylurea and meglitinide screen) • If this approach causes neither symptoms nor hypoglycemia and if clinical suspicion remains high, the patient should undergo a 72-hour fast.
  38. 38. Postprandial evaluation: If symptoms of hypoglycemia typically occur within five hours after eating, patients should be evaluated in the postprandial state (mixed meal test).  mixed meal diagnostic test: the patient consumes a meal that usually leads to symptoms and is then observed for up to five hours . • Samples are collected for plasma glucose, insulin, C-peptide, and proinsulin prior to ingestion of the meal and every 30 minutes thereafter for five hours.
  39. 39. • If severe symptoms occur prior to five hours, samples for the above lab tests should be collected before the administration of carbohydrates (to assess for correction of symptoms). All glucose samples are sent for analysis. • The samples for insulin, C-peptide, and proinsulin should be analyzed only in those samples in which plasma glucose is <60 mg/dL (3.3 mmol/L). • If Whipple's triad is demonstrated, sulfonylureas, meglitinides, and antibodies to insulin should also be measured.
  40. 40.  72-hour fast : • Normal subjects do not have symptomatic hypoglycemia after a prolonged fast because of a hormonally mediated increase in glucose production. • Gluconeogenesis accounts for approximately 50% of glucose production after an overnight fast and for almost all glucose production after 42 hours or more of fasting . • The prolonged fast will result in hypoglycemia only if there is a defect in the ability to maintain normoglycemia due, for example, to an excess of insulin.
  41. 41. Protocol : 1) Date the onset of the fast at the time of the last intake of calories. Discontinue all nonessential medications. 2) Allow the patient to drink beverages that are calorie and caffeine free. 3) Ensure that the patient is active during waking hours. 4) Collect blood specimens for measurement of plasma glucose, insulin, C-peptide, proinsulin, and beta hydroxybutyrate (BHOB) every six hours until the glucose concentration is below 60 mg/dL (3.3 mmol/L); at this point, the frequency of sampling should be increased to every one to two hours.  Although blood is collected repeatedly, we measure insulin, C- peptide, and proinsulin only in those specimens in which the plasma glucose concentration is ≤60 mg/dL (3.3 mmol/L).
  42. 42. Test end points and duration : 1) when the plasma glucose concentration is ≤45 mg/dL 2) the patient has symptoms or signs of hypoglycemia, 3) 72 hours have elapsed, 4) or when the plasma glucose concentration is ≤55 mg/dL if Whipple's triad was documented on a prior occasion Ending the fast: Three steps are performed at the end of the fast: 1) Collect samples for plasma glucose, insulin, C-peptide, proinsulin, BHOB, and oral hypoglycemic agents 2) 1 mg of glucagon is given intravenously and the plasma glucose measured 10, 20, and 30 minutes later 3) The patient is fed
  43. 43. Laboratory tests 1) CBC 2) Glucose 3) Insulin 4) C-peptide 5) Beta-hydroxybutyrate 6) Proinsulin 7) Antibodies for insulin and its receptors 8) Sulfonylurea and meglitinide screen 9) Electrolytes, BUN/Cr, UA 10) liver function tests, cortisol and thyroid levels , growth hormone level 11) Other tests: ECHO, ECG, CXR , CT and MRI
  44. 44. Management of Hypoglycemia The management of hypoglycaemia can be divided into three phases: 1. acute intervention to prevent and minimize neurological damage . 2. maintenance therapy to prevent recurrence of hypoglycemia . 3. subsequent measures to search for and treat the underlying cause .
  45. 45. Acute intervention it is important if possible to obtain a blood sample for laboratory glucose measurement before glucose administration and to save serum for more sophisticated investigation if the cause of hypoglycaemia is not obvious (i.e. hypoglycaemia in a seemingly healthy, nondiabetic patient). If the patient has a history of malnutrition or chronic alcohol abuse, intravenous (IV) thiamine at a bolus dose of 12 mg/kg should be given before initiation of glucose treatment, to avoid precipitating Wernicke’s encephalopathy.
  46. 46. The treatment for all hypoglycaemia events is the administration of glucose. The route and amount of administration will depend on the glucose level as well as the patient’s level of consciousness and available access. Where possible an oral carbohydrate load should be administered urgently, followed by careful blood glucose monitoring. Consider the ‘rule of 15s’ during therapy (i.e. 15 g of carbohydrate will raise the glucose level about 15 mg/dl in about 15 minutes).  If the oral route is not possible, such as in cases of impaired consciousness or an uncooperative patient, IV glucose intramuscular (IM) or subcutaneous (SC) glucagon can be considered
  47. 47. Oral carbohydrate is ideally provided in the form of 15-20 g (or 20-30 g if blood glucose 50 mg/dl) glucose tablets. However, any form of carbohydrate that contains glucose can be used.  This dose of glucose will typically maintain euglycaemia for up to 2 hours, and therefore a complex carbohydrate (e.g. snack or meal) should be administered as soon as it is safe to do so. Failure of the hypoglycaemia to correct within 15 minutes following one dose of glucose should lead to administration of a second dose, and occasionally a third, But failure thereafter should prompt the clinician to consider other interventions ?? The patient should be warned not to drive for at least 45 minutes after correction of hypoglycaemia.
  48. 48. Oral treatments are clearly inappropriate in the unresponsive patient or those who are unable to take oral medications.  In this situation, the presence of IV access allows 25-50 ml (i.e.12.5-25 g) 50% dextrose (D50) to be administered and is adequate in most circumstances. D50 is highly irritating and should be administered through a large gauge needle into a large vein if possible and followed by a saline flush. Larger volumes of less concentrated dextrose in IV infusions (e.g. 125 ml of 20% dextrose D20 or 250 ml of 10% dextrose [D10]) may be used to minimize irritation. For inpatients with hypoglycaemia, D50 mixed with equal parts of water can also be given through a feeding tube if available.
  49. 49. If IV access is not available, or is delayed, glucagon 1mg IM (or SC) can be administered, but its action is short lived. However, glucagon may not be effective in cases where gluconeogenesis is defective, such as in cases of extreme fasting, liver failure, alcohol induced hypoglycaemia or adrenal insufficiency because of glycogen depletion. Glucocorticoid replacement (after plasma is saved for cortisol testing) is required for patients with suspected adrenal insufficiency. Owing to these various issues, IV glucose remains the treatment of choice for severe hypoglycaemia.
  50. 50. Maintenance therapy The clinical response of hypoglycaemia to IV glucose administration should be rapid and dramatic. Patients with hypoglycaemic coma are expected to regain consciousness and become coherent within 5-10 minutes. However, complete cognitive recovery may be delayed for 30-60 minutes after restoration of normoglycaemia. If there is no obvious improvement in symptoms or consciousness within 10-15 minutes, alternative diagnoses (e.g. stroke or drug overdose) should be reconsidered.
  51. 51. A common mistake is to assume that once the glucose has been corrected, it will maintain itself.  Depending on the initial cause for hypoglycaemia, a concurrent source of glucose may need to be administered for some time. As the effect of IV glucose is relatively transient, patients should receive an additional form of glucose along with protein (e.g. milk, cheese and crackers) to replenish hepatic glycogen stores. If the hypoglycaemic episode is expected to be prolonged or recurrent (e.g. due to long acting insulin or sulfonylurea), an IV infusion of 5-10% dextrose (D5 or D10) should be commenced and continued as necessary.
  52. 52.  For example sulfonylurea-induced hypoglycaemia, which due to long duration of action can cause prolonged hypoglycaemic events (especially in the elderly or in patients with renal impairment). Octreotide, a synthetic somatostatin analogue, inhibits insulin release and has been used to treat hypoglycaemia in this context. Various regimens are described but 50 mcg 6-8 hourly administered IV or SC are commonly used The use of this agent should be considered in any situation where endogenous hyperinsulinaemia is apparent.
  53. 53. Subsequent Measures After initial stabilization, subsequent management should be directed at searching for the underlying etiology of hypoglycemia and preventing further attacks . Once the underlying cause is established, definitive therapy should be offered. Repeated hypoglycemia in an otherwise stable diabetic patient should alert the healthcare provider of the onset of nephropathy, concomitant Addison’s disease, hypothyroidism, hypopituitarism or interfering medications
  54. 54. Treatment of Non-Diabetes Related Hypoglycemia Non diabetic hypoglycemia definitive management depends on the underlying etiology. Hypoglycemia induced by medications improves promptly once the medication is removed. Correction of sepsis and improvement in hepatic and renal function improves hypoglycemia of the critical illness. Deficiencies of counterregulatory hormones can be corrected with replacement of relevant hormone.
  55. 55. Dietary changes are importance in the context of hyperinsulinaemic hypoglycemia, and the frequency and severity of episodes can be significantly reduced with frequent smaller volume meals. Complex carbohydrates such as bread, rice and pasta should be consumed frequently. Wherever possible, surgery to remove an insulinoma should be employed, although patient preference and significant comorbidities may preclude the use of surgery. In these cases and in the context of NIPHS (where partial pancreatectomy can also be offered if diet and/or medical treatment fails, although may be ineffectual if diffuse nesidioblastosis is present), medical therapies should be used in the knowledge that each has significant limitations or side effects
  56. 56. Diazoxide is a potassium channel activator, first developed as an antihypertensive agent, but now more commonly used in the context of hypoglycaemia due to inhibition of insulin secretion. It is administered at a dose of 5 mg/kg/day (with higher doses in refractory cases up to 15 mg/kg/day) in two or three divided oral doses (e.g. 200-1200 mg/day) . somatostatin inhibits insulin production, and analogues can be used in any state of chronic hyperinsulinaemia. Octreotide therapy is effective in reducing hypoglycaemia in over 50% of patients with an insulinoma and can be administered as a long-acting formulation.  Octreotide is commenced at a dose of 50 mcg three times daily by SC injection, and can be titrated to a maximum dose of 500 mcg three times daily.
  57. 57. Many other medications have been used in the management of hyperinsulinaemic hypoglycemia including: 1. verapamil (i.e. because calcium influx is required for insulin secretion, calcium channel blockers have been tried for treatment of hyperinsulinaemia), 2. a-glucosidase inhibitors (e.g. acarbose or miglitol) and glucocorticoids, but evidence supporting their efficacy is based primarily on case reports only 3. Glucocorticoid and/or GH therapy have been used with some success in patients with NICTH, for tumors which cannot be resected completely.
  58. 58. Treatment Of Diabetes Related Hypoglycemia Evaluation of hypoglycemia in a diabetic patient is focused on intensity of glycemic control and the treatment regimen.  If hypoglycemic agents (e.g. insulin, sulfonylureas or meglitinides) are prescribed, adjustments may be required to prevent further episodes. Patient education is vital with respect to diet, exercise, timing of medications, insulin injection sites and frequent self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM), to try to avoid hypoglycemia.
  59. 59. The patient should be concerned about the possibility of developing hypoglycaemia when the SMBG is falling rapidly or is ≤70 mg/dl. In the UK, it has been recommended that ‘four is the floor’ for blood glucose targets in order to limit hypoglycaemia frequency. For non critically ill patients, glycemic goals are premeal and random blood glucose levels <140 mg/dl and<180 mg/dl respectively If intensive insulin therapy is used in ICU patients a target blood glucose range of 140-200 mg/dl
  60. 60. Summary Of Management Obtain blood glucose concentration as soon as possible (usually with a meter and strips, if available): For symptomatic patient known to have diabetes and with a low glucose value, <70 mg/dL, administer treatment. If a glucose test cannot be performed, do not delay. Treat as if hypoglycemia has been confirmed. If the glucose is low (<55 mg/dL) and the patient is a not a diabetic, draw blood for glucose, insulin, C-peptide, and an oral hypoglycemic agent screen and then treat Do not delay treatment if symptomatic hypoglycemia is suspected but rapid blood glucose measurement is not available or blood for diagnostic studies cannot be collected
  61. 61. If the patient is conscious and able to drink and swallow safely (ie, alert enough to do so and with gag reflex intact), administer a rapidly- absorbed carbohydrate (eg, 3 to 4 glucose tablets or a tube of gel with 15 grams, 4 to 6 oz. fruit juice or non-diet soda, or a teaspoon of honey or table sugar). If the patient has altered mental status, is unable to swallow, or does not respond to oral glucose administration within 15 minutes, give an IV bolus of 12.5 to 25 g of glucose (25 to 50 mL of 50 percent dextrose). Measure a blood glucose 10 to 15 minutes after the IV bolus. Readminister 12.5 to 25 grams of glucose as needed to maintain the blood glucose above 80 mg/dL. If glucose cannot be given by parenteral or oral routes, give glucagon 1 mg IM or SQ. Response may be transient and should be followed by careful glucose monitoring and oral or intravenous glucose administration
  62. 62. • Give additional maintenance glucose by mouth or IV. IV dextrose infusion should ensure delivery of 6 to 9 mg/kg per minute of glucose. • Amounts needed vary depending upon the cause and severity of the symptomatic hypoglycemia. Once the patient is able to ingest carbohydrate safely, providing a mixed meal (including carbohydrates, such as a sandwich) is the preferred means of maintaining glucose levels. • Measure a blood glucose 10 to 15 minutes after the initial IV bolus and monitor every 30 to 60 minutes thereafter until stable (minimum of 4 hours).
  63. 63. PATIENT-CONSIDERATIONS-Admission-Criteria 1) Any doubt of cause 2) Expectation of prolonged hypoglycemia (e.g., caused by sulfonylurea drug) 3) Inability to drink or eat 4) Treatment has not resulted in prompt sensory recovery. 5) Seizures, coma, or altered behavior (e.g., ataxia, disorientation, unstable motor coordination, dysphasia) secondary to documented or suspected hypoglycemia 6) recurrent hypoglycemia during observation PATIENT-CONSIDERATIONS-Discharge-Criteria 1. Normoglycemia and risk of severe hypoglycemia is negligible.
  64. 64. Differential Diagnosis • Neurologic: CVA/TIA, seizure disorder • Drug/alcohol intoxication • Psychosis, depression
  65. 65. Complications 1-recurrent/persistent psychosocial morbidity(Emotional liability , irritability, depression). 2-Fear of hypoglycemia-barrier for diabetic control. 3-Seizure 4-permanent neurologic deficit (including cognitive impairment) 5-Coma 6-Death
  66. 66. THANK YOU

Editor's Notes

  • In a retrospective review of 37,898 non-diabetic, non-critical care hospital admissions, the estimated frequency of hypoglycemia (≤55 mg/dL [3.0 mmol/L]) was 36 per 10,000 admissions .
  • Sleep and prior exercise can cause a similar phenomenon
  • Treatment for this hypoglycemic unawareness is to reduce the insulin dosage and eat more carbohydrates both at meals and between meals to ensure a blood glucose level of 150 to 200 mg/dL (8.3-11.1 mmol/L) at all times for several weeks.
  • . Never order an OGTT to work up this entity
  • and thereby raises blood glucose in 5-10 minutes
    Glucagon in these situations may paradoxically aggravate the hypoglycaemia by stimulating insulin secretion.

  • The response to IM (or SC) glucagon is slightly slower, with an average time difference of 2-3 minutes when compared with IV glucose.
  • Diazoxide has numerous side effects including peripheral oedema, nausea, vomiting, hypotension and arrhythmias.
    Of concern, particularly to females, is the tendency for diazoxide to promote hypertrichosis, whilst pancytopaenia is
    occasionally seen in an idiosyncratic manner. Thiazide diuretics synergise the hyperglycaemic effect of diazoxide as well as reduce the fluid retention, and can be used in addition.
    However, a paradoxical fall in blood glucose levels can occur in approximately 50% of patients because of suppression of counterregulatory hormones such as glucagon.
    Patients are usually stabilized with short-acting octreotide for 10-28 days before converting them to long acting somatostatin analogues.
    Sandostatin LAR, administered as an IM depot, given at an initial dose of 20mg every 4 weeks and adjusted after 3 months to a maximal dose of 40 mg every 4 weeks
    Lanreotide LA, administered as an IM depot 30mg every 2 weeks and can be increased to 30 mg every 7 days
    Lanreotide Autogel, administered as a deep SC injection of 60mg every 4 weeks and increased after 3 months to 120mg every 4 weeks if needed