Hypoglycemia.pptx

Hypoglycemia

1. Presenter; Dr Shahana MK Moderator; Dr Radhika B V

2. HYPOGLYCEMIA Introduction Definition and classification Symptoms and clinical signs Physiology of hypoglycemia Hypoglycemia in DM HAAF( hypoglycemia -associated autonomic failure) Hypoglycemia unawareness Hypoglycemia without DM Approach to patient management

3. INTRODUCTION India is the capital for DM Newer drugs and intensive glycemic control causes frequent hypoglycemia in DM Incresed mortality in DM –severe hypoglycemia Need adequate control measures against this life threatning complication Early recognition ,regular self monitoring ,appropriate treatment, educational program

4. DEFINITION According to ADA 2018 hypoglycemia defined as blood glucose < 70mg/dl It is a clinical syndrome with diverse causes in which low plasma glucose concentrations lead to symptoms /signs, and there is resolution of the symptoms /signs when the plasma glucose concentration is raised The diagnosis of hypoglycemia is not based on an absolute blood glucose level It requires fulfilment of the whipple triad

5. classification level Glycemic criteria description Hypoglycemia alert value (level 1) <70mg/dl Needs rx with fast acting carbohydrate and dose adjustment of glucose lowering therapy Clinically significant hypoglycemia (level2) <54mg/dl Clinically important hypoglycemia Severe hypoglycemia (level 3) No specific glucose thrshold Associated with severe cognitive impairment and need external assistance for recovery

6. Reactive hypoglycemia- hypoglycemia after 3-5 hrs after a rich meal due to inappropriate secretion of insulin in persons whose fasting sugars were in normal range Post gastrostomy, gastrojejunostomy , pyloroplasty or vagotomy Also called elementary hypoglycemia or elementary hyper insulinemia .

7. Relative or pseudo hypoglycemia – occurence of symptoms of hypoglycemia in persons with normal blood sugar . It is usally due to rapid fall in blood sugar levels (from 500mg/dl to 150mg/dl)

8. PHYSIOLOGY OF HYPOGLYCEMIA Glucose is an obligate metabolic fuel for the brain under physiologic conditions . The brain cannot synthesize glucose or store more than a few minutes and therefore requires a continuous supply of glucose from the arterial circulation

9. As the arterial plasma glucose concentration falls below the physiologic range , blood-to-brain glucose transport becomes insufficient to support brain energy metabolism and function . multiple integrated glucose counterregulatory mechanisms normally prevent or rapidly correct hypoglycemia . Hormones involved are insulin ,glucagon, epinephrin,nor epinephrin,cortisol and GH

10. Hepatic glycogen stores are usually sufficient to maintain plasma glucose levels for ~8 h This period can be shorter if glucose demand is increased by exercise or if glycogen stores are depleted by illness or starvation.

11. INSULIN a decrease in insulin secretion is the first defense against hypoglycemia . Glycogenolysis,gluconeogenesis Reduce glucose utilization in peripheral tissues Lipolysis,proteolysis-gluconeogenic precursors

12. Glucagone is the second defence against hypoglycemia EPINEPHRINE – glycogenolysis,gluconeogenesis Epinephrine becomes critical when glucagon is deficent Epinephrine has similiar hepatic effects as glucagon Epinephrine is the third defence against hypoglycemia

13. When hypoglycemia is prolonged beyond 4 h, cortisol and growth hormone also support glucose production and restrict glucose utilization to a limited amount As Plasma glucose Levels fall to lower levels ,symptoms prompt the behavioural defense against hypoglycemia , including ingestion of food

14. Glucose Homeostasis ↓ blood glucose ↑ blood glucose

15. Glucose Homeostasis

16. SYMPTOMS AND SIGNS EARLY ADRENERGIC SYMPTOMS NEUROGLYCOPENIC SIGNS Diaphoresis Pallor Tachycardia Shakiness Hunger Irritability Anxiety Dizziness headache Confusion Uncontrolled behaviour Slurred speech Extreme fatigue Disorientation Seizures Pupillary sluggishness Loc Decresed response to noxious stimuli

17. Hypoglycemia

18. Hypoglycemia activates pro-inflammatory, pro-coagulant and pro- atherothrombotic responses in T1DM , T2DM, and non-diabetic individuals . These responses increase platelet aggregation, reduce fibrinolytic balance (↑ plasminogen activator inhibitor-1), and increase intravascular coagulation . Hypoglycemia also reduces protective nitric oxide-mediated arterial vasodilator mechanisms in healthy, T1DM, and T2DM individuals.

19. HYPOGLYCEMIA IN DIABETES Hypoglycemia is common in type 1DM especially in patients receiving intensive therapy - >3fold chance for severe hypoglycemia Hypoglycemia was reported in 38% of pts with type 2 DM with sulfonylurea or meglitinides In contrast to pts with DM , hypoglycemia is uncommon in individuals who do not have drug treated DM. Insulin, sulfonylureas, or glinides can cause hypoglycemia in T2DM. Metformin, thiazolidinediones , α- glucosidase inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase IV (DPP-IV) inhibitors do not cause hypoglycemia

20. Conventional Risk Factors insulin (or insulin secretagogue ) doses are excessive , ill-timed, or of the wrong type the influx of exogenous glucose is reduced (e.g., during an overnight fast, periods of temporary fasting, or after missed meals or snacks ) insulin-independent glucose utilization is increased (e.g., during exercise ) sensitivity to insulin is increased (e.g., with improved glycemic control, in the middle of the night, late after exercise, or with increased fitness or weight loss ) endogenous glucose production is reduced (e.g., after alcohol ingestion ) insulin clearance is reduced (e.g., in renal failure).

21. Insulin - the ability to suppress insulin release cannot occur in pts with absoulute beta cell failure .there fore ,inhibition of hepatic glucose production continues. Thus the main defence against hypoglycemia is incresed release of counter regulatory hormones (glucagon and epinephrine)

22. Glucagon - normal response at the onset of DM , I s lost in parallel with that of insulin in type 1 DM and more slowly in type 2 DM this may be the result of beta cell failure and susequent loss of the hypoglycemia induced decline in intra islet insulin that normally signals increased glucagon secretion during hypoglycemia

23. Epinephrine -in the setting of absent insulin and glucagon responses,pts are dependent upon epinephrine to protect against hypoglycemia The epinephrine response also becomes attenuated in many patients (recent antecedent hypoglycemia )

24. Hypoglycemia-Associated Autonomic Failure (HAAF) Concept of HAAF in type 1DM and long standing T2 DM ,that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation and hypoglycemia un awareness Shifting the glycemic threshold for the sympathoadrenal response to subsequent hypoglycemia to a lower plasma glucose concentration. Hypoglycemia unawareness by reducing neurogenic symptom responses

25. Hypoglycemia unawareness HU is defined as the onset of neuroglycopenia symptoms before the appearance of autonomic symptoms HU is seen in 40% of T1DM, and is less frequently observed in T2DM HU is more common in On tight glycemic control Longer duration of DM Old age History of recent and recurrent hypoglycemic events F>M

26. HAAF CAUSES Catecholamines - Blunted catecholamine response Sleep –sleep is a mediator of HAAF,which is linked with catecholamine response , significantly decresed epinephrine response to hypoglycemia during sleep Increase in cortisol –reduced sympathoadrenal response to susequent hypoglycemia Up regulation of glucose transport in the brain Hypoglycemia induced alteration in hypothalamic functions or even a cerebral network reduce sympathoadrenal response to susequent hypoglycemia.

27. additional risk factors for hypoglycemia in diabetes ( 1 ) absolute insulin deficiency , indicating that insulin levels will not decrease and glucagon levels will not increase as plasma glucose levels fall (2) a history of severe hypoglycemia or of hypoglycemia unawareness, implying recent antecedent hypoglycemia , as well as prior exercise or sleep, indicating that the sympathoadrenal response will be attenuated ( 3) impaired renal function resulting in reduced clearance of exogenous and endogenous insulin ( 4) classical diabetic autonomic neuropathy (5) lower hemoglobin A1C (HBA1C), or lower glycemic goals even at elevated HBA1C levels (8–10%), as they represent an increased probability of recent antecedent hypoglycemia .

28. Hypoglycemia Risk Factor Reduction The glycemic maintenance goals have been modified to lie between 140 and 180 mg/ dL . Pancreatic transplantation (both whole-organ and islet-cell) has been used in part as a treatment for severe hypoglycemia The use of continuous glucose monitors,either alone or in combination with continuous subcutaneous infusion via a wearable pump a portable wearable “artificial pancreas” incorporating continuous glucose sensor modulation of either insulin alone or bi-hormonal delivery of both insulin and glucagon has been established

29. stem cell-derived β-cells also offer promise of novel therapeutic interventions to reduce hypoglycemia . Other interventions to stimulate counterregulatory responses, such as selective serotonin-reuptake inhibitors, β- adrenergic receptor antagonists, opiate receptor antagonists, and fructose, remain experimental

30. HYPOGLYCEMIA WITHOUT DIABETES Drugs- Insulin and insulin secretagogues Ethanol blocks gluconeogenesis but not glycogenolysis . Thus, alcohol-induced hypoglycemia typically occurs after a several-day ethanol binge during which the person eats little food, with consequent glycogen depletion.

31. Other drugs angiotensin -converting enzyme inhibitors and angiotensin receptor antagonists β- adrenergic receptor antagonists quinolone antibiotics indomethacin quinine sulfonamides.

32. Critical Illness renal hepatic cardiac failure sepsis

33. Rapid and extensive hepatic destruction (e.g., toxic hepatitis) causes fasting hypoglycemia because the liver is the major site of endogenous glucose production Sepsis is a relatively common cause of hypoglycemia . Increased glucose utilization is induced by cytokine production in macrophage-rich tissues such as the liver, spleen, and lung Cytokine-induced inhibition of gluconeogenesis in the setting of nutritional glycogen depletion Hypoglycemia can be seen with starvation.

34. Hormone Deficiencies hypoglycemia can occur with prolonged fasting in patients with primary adrenocortical failure ( Addison’s disease) or hypopituitarism . Growth hormone deficiency can cause hypoglycemia in young children.

35. Non-beta-Cell Tumors Fasting hypoglycemia, often termed non– islet cell tumor hypoglycemia , occurs occasionally in patients with large mesenchymal or epithelial tumors (e.g., hepatomas , adrenocortical carcinomas, carcinoids) insulin secretion is suppressed appropriately during hypoglycemia . hypoglycemia is due to overproduction of an incompletely processed form of insulin-like growth factor II (“big IGF-II”) plasma ratios of IGF-II to IGF-I are high, and free IGF-II levels are elevated

36. 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 . Hypoglycemia attributed to ectopic IGF-I production has been reported but is rare

37. Endogenous Hyperinsulinism a primary β- cell disorder — typically a β- cell tumor ( insulinoma ), sometimes multiple insulinomas , or a functional β- cell disorder with β- cell hypertrophy or hyperplasia an antibody to insulin or to the insulin receptor a β- cell secretagogue such as a sulfonylurea ectopic insulin secretion , among other very rare mechanisms

38. diagnostic strategy To measure plasma glucose, insulin, C-peptide, proinsulin , and β- hydroxybutyrate concentrations And to screen for circulating oral hypoglycemic agents during an episode of hypoglycemia To assess symptoms during the episode and seek their resolution following correction of hypoglycemia by IV injection of glucagon (i.e., to document Whipple’s triad)

39. Diagnostic plasma insulin concentration ≥3 μ U/ mL (≥18 pmol /L ) a plasma C-peptide concentration ≥0.6 ng / mL (≥0.2 nmol /L ) and a plasma proinsulin concentration ≥5.0 pmol /L when the plasma glucose concentration is <55 mg/ dL (<3.0 mmol /L) with symptoms of hypoglycemia.

40. A low plasma β- hydroxybutyrate concentration (≤2.7 mmol /L) and an increment in plasma glucose level of >25 mg/ dL (>1.4 mmol /L) after IV administration of glucagon (1.0 mg) indicate increased insulin (or IGF) actions.

41. Insulinomas uncommon with an estimated yearly incidence of 1 in 250,000. >90% of insulinomas are benign they are a treatable cause of potentially fatal hypoglycemia . The median age at presentation is 50 years in sporadic cases, but the tumor usually presents in the third decade when it is a component of multiple endocrine neoplasia type 1 More than 99% of insulinomas are within the substance of the pancreas, And the tumors are usually small (<2.0 cm in diameter in 90% of cases ). Therefore , they come to clinical attention because of hypoglycemia rather than mass effects . CT or MRI detects ~70–80% of insulinomas .

42. metastases in the roughly 10% of patients with a malignant insulinoma . Transabdominal ultrasound often identifies insulinomas , and endoscopic ultrasound has a sensitivity of ~90 %. Somatostatin receptor scintigraphy is thought to detect insulinomas in about half of patients.

43. Surgical resection of a solitary insulinoma is generally curative . Diazoxide , which inhibits insulin secretion, or the somatostatin analogue octreotide can be used to treat hypoglycemia in patients with unresectable tumors ; everolimus , an mTOR (mammalian target of rapamycin ) inhibitor, is promising.

44. ACCIDENTAL, SURREPTITIOUS, OR MALICIOUS HYPOGLYCEMIA Should be considered when the cause of hypoglycemic disorder is not apparent Can result from medical , pharmacy,patient errors Malicious hypoglycemia - admn of an insulin secretogogue or insulin to another person with the intent to cause hypoglycemia

45. INBORN ERRORS OF METABOLISM CAUSING HYPOGLYCEMIA Cases in adults can be classified into those resulting in fasting hypoglycemia postprandial hypoglycemia and exercise-induced hypoglycemia

46. fasting hypoglycemia glycogen storage disease (GSD) of types 0, I, III, and IV and Fanconi -Bickel syndrome Patients with GSD types I and III characteristically have high blood lactate levels before and after meals, respectively. Both groups have hypertriglyceridemia, but ketones are high in GSD type III.

47. Defects in fatty acid oxidation also result in fasting hypoglycemia . (1) defects in the carnitine cycle (2) fatty-acid β- oxidation disorders (3) electron transfer disturbances (4) ketogenesis disorders. Finally , defects in gluconeogenesis (fructose-1, 6-biphosphatase ) have been reported to result in recurrent hypoglycemia and lactic acidosis.

48. Postprandial Hypoglycemia (1) glucokinase , SUR1, and Kir6.2 potassium channel mutations ( 2) congenital disorders of glycosylation (3) inherited fructose intolerance.

49. Exercise-Induced Hypoglycemia Exercise, It results in hyperinsulinemia caused by increased activity of monocarboxylate transporter 1 in β cells

50. APPROACH TO THE PATIENT RECOGNITION AND DOCUMENTATION Convincing documentation of hypoglycemia requires the fulfillment of Whipple’s triad. Blood should be drawn, whenever possible, before the administration of glucose to allow documentation of a low plasma glucose concentration.

51. plasma insulin, C-peptide, proinsulin , and β- hydroxybutyrate levels screening for circulating oral hypoglycemic agents And assessment of symptoms before and after the plasma glucose concentration is raised.

52. DIAGNOSIS OF THE HYPOGLYCEMIC MECHANISM hypoglycemic mechanism can often be deduced from the history, physical examination, and available laboratory data

53. Management of hypoglycemia Acute intervention -to prevent and minimise neurological damage Maintence therapy –to prevent recurrence of hypoglycemia Subsequent measures –to search for and treat the underlying cause

54. URGENT TREATMENT If the patient is able and willing, oral treatment with glucose tablets or glucose-containing fluids, candy, or food is appropriate.

55. Oral Carbohydrates Glucose 15-20 g orally – preferred initial treatment in conscious individual with hypoglycemia Examples of 15 g of carbohydrates: 4 ounces of juice 8 ounces of skim milk 3-4 glucose tablets 5-6 Life Savers candies After treatment, eat snack with protein/fat to prevent recurrence Clinical Diabetes 2012 Jan;30(1):38

56. If the patient is unable or unwilling (because of neuroglycopenia ) to take carbohydrates orally, parenteral therapy is necessary . IV administration of glucose (25 g) should be followed by a glucose infusion guided by serial plasma glucose measurements. If the patient has a history of malnutrition or c/c alcoholic , IV thiamine at a bolus dose of 12mg/kg should be given before initiating glucose treatment,to avoid precipitating wernickes encephalopathy

57. If IV therapy is not practical, SC or IM glucagon (1.0 mg in adults) can be used, particularly in patients with T1DM . Because it acts by stimulating glycogenolysis , glucagon is ineffective in glycogen-depleted individuals (e.g., those with alcohol-induced hypoglycemia ) Glucagon also stimulates insulin secretion and is therefore less useful in T2DM.

58. Glucagon Dose: 1 mg IV/IM/SQ, may repeat in 15 mins IV dextrose should be administered as soon as it is available; if patient fails to respond to glucagon, IV dextrose must be given. Role: patients without IV access (especially severe hypoglycemia, unconscious patients Glucagon Emergency Kit Glucagon HypoKit

59. The somatostatin analogue octreotide can be used to suppress insulin secretion in sulfonylurea-induced hypoglycemia . These treatments raise plasma glucose concentrations only transiently , and patients should therefore be urged to eat as soon as is practical to replete glycogen stores.

60. Octreotide Somatostatin analogue Provides more potent inhibition of growth hormone, glucagon, and insulin as compared to endogenous somatostatin May reduce recurrent hypoglycemia as with dextrose-alone therapy Should be used with IV dextrose/oral carbohydrates Dose: (ideal dose not well established) IV: up to 125 mcg/hour has been used SC 50mcg q8h daily

61. Octreotide Warnings/precautions: Cholelithiasis – may inhibit gallbladder contractility Hypothyroidism – may suppress TSH secretion Pancreatitis – may change absorption of fats Adverse effects : bradycardia, dizziness, hyperglycemia, diarrhea, constipation Sandostatin [prescribing information].

62. Diazoxide Antidote for hypoglycemia due to hyperinsulinemia Opens ATP-dependent K + channels on pancreatic beta cells  hyperpolarization of the beta cell  inhibition of insulin release Binds to a different site on the potassium channel than the sulfonylureas Dose: 3-8 mg/kg/day PO in divided doses Q8H Starting dose 3 mg/kg/day PO divided in 2-3 doses

63. Diazoxide Contraindications : hypersensitivity to diazoxide or to other thiazides Warnings/precautions: Heart failure – antidiuretic actions Gout – may cause hyperuricemia Renal dysfunction Adverse effects : hypotension, hyperglycemia Diazoxide [prescribing information].

64. PREVENTION OF RECURRENT HYPOGLYCEMIA Prevention of recurrent hypoglycemia requires an understanding of the hypoglycemic mechanism. Offending drugs can be discontinued or their doses reduced . Hypoglycemia caused by a sulfonylurea can persist for hours or even days . Underlying critical illnesses can often be treated. Cortisol and growth hormone can be replaced if levels are deficient . Surgical, radiotherapeutic , or chemotherapeutic reduction of a non–islet cell tumor can alleviate hypoglycemia even if the tumor cannot be cured;

65. Surgical resection of an insulinoma is curative; medical therapy with diazoxide or octreotide can be used if resection is not possible The treatment of autoimmune hypoglycemia (e.g., with glucocorticoid or immunosuppressive drugs) is problematic, but these disorders are sometimes self-limited.

66. frequent feedings and avoidance of fasting may be required . Administration of uncooked cornstarch at bedtime An overnight intragastric infusion of glucose may be necessary for some patients

67. Admission criteria Any doubt of cause Prolonged hypoglycemia . Inability to eat and drink Treatment has not resulted in prompt sensory recovery Seizures,coma or altered behaviour Recurrent hypoglycemia during observation

68. D/D Neurologic – CVA/TIA , seizure disorder Drug /alcohol intoxication Psychosis , depression

69. complications Recurrent/persistent psychosocial morbidity Fear of hypoglycemia Seizure Permanant neurological deficit Coma Death

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