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Divisi Endokrin-MetabolikDepartemen Ilmu Penyakit Dalam FK USU/ RSUP H Adam Malik Medan.H Y P O G L Y C E M I A

*What is Hypoglycemia?Hypoglycemia is an abnormally low plasma glucose level that leads to symptoms of sympathetic NS stimulation or of CNS dysfunction.

The Merck Manual of Diagnosis and TherapySeventeenth Edition (1999)

*Review of Blood Glucose controlNormal BG 60-100 mg/dLHypoglycemia: BG

*PHYSIOLOGY OF GLUCOSECOUNTERREGULATIONCharacteristic sequence:

insulin secretion as glucose concentrations decline within the physiological range (72108 mg/dl /4.06.0 mmol/l).

glucagon and epinephrine secretion, glucose concentrations fall just below the physiological range (6570 mg/dl (3.63.9 mmol/l).

3. Neurogenic and neuroglycopenic symptoms, and cognitive impairments in range (5055 mg/dl (2.8 3.0 mmol/l).

Liver glucose output responds to multiple hormonal signals

*Hypoglycemia Risk FactorsMissed or delayed mealEating less food at a meal than plannedVigorous exercise without carbohydrate compensationTaking too much diabetes medicine (e.g., insulin, insulin secretagogues, and meglitinides)Drinking alcohol

*CausesFasting hypoglycemiaResult of a serious medical conditionInsulinomas (most are benign)*Pancreatic tumors-secrete insulinOther tumors (breast, cervix, adrenal glands)*Secrete insulin-like growth factors (IGF)Glucose production by liver inhibited; increased uptake in peripheral tissuesExtensive liver disease*Le Roith, Derek. (1999). Tumor-induced hypoglycemia. The New England Journal of Medicine, 341, 10.

*CausesPostprandial (reactive)2-5 hrs after eatingEarly insulin release with excess secretion in response to the hyperglycemiaAlimentaryIn patients w/GI procedures (gastrectomy, pyloroplasty, gastrojejunostomy)Idiopathic alimentaryRARE; over-diagnosedHealthy young-adults2-4 hrs after meal or after a missed meal

*Various CausesAlcoholic hypoglycemiaIngestion of alcohol after a long fast

Factitious hypoglycemiaInsulin & sulfonylureasPrimarily in health care worker and relatives of diabeticsDistribution of incorrect drugs to patients**Robinson, Irving, et. Al. (1994) Closet Hypoglycemia. Journal of Family Practice, 38, 1.

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*Hormones in the response to hypoglycemia:(counterregulatory hormone)

Glucagon (glycogenolysis and gluconeogenesis). Epinephrine (glycogenolysis and gluconeogenesis and limits glucose utilization) growth hormone (reduce glucose utilization and support its production).Cortisol (reduce glucose utilization and support its production)

play less important roles in the control of glucose flux during normal physiologic circumstances, except in critically ill

*Counter Regulation Respons to Hypoglycemia

*SymptomsBG level at which symptoms develop varies from person to person

AdrenergicSweating, trembling, anxiety, nausea, pallor, faintness, palpitations, hunger

Neuroglycopenic (CNS manifestations)Confusion, fatigue, difficulty speaking, headache, dizziness, inability to concentrate, inappropriate behavior, stupor, coma

*SYMPTOMS OF HYPOGLYCEMIANeurogenic (autonomic) Neuroglycopenictrembling difficulty concentratingpalpitations confusionsweating weaknessanxiety drowsinesshunger vision changesnausea difficulty speakingtingling headache dizziness tiredness

*Signs of HypoglycemiaMild Hypoglycemia:Pallor, Diaphoresis, Tachycardia, Palpitations, Hunger, Paresthesias, ShakinessIndividual is able to self-treatModerate HypoglycemiaInability to Concentrate, Confusion, Slurred Speech, Irrational or uncontrolled behavior, slowed reaction time, blurred vision, somnolence, extreme fatigueIndividual is able to self-treat

*Signs of HypoglycemiaSevere HypoglycemiaCompletely automated/disoriented behaviorLoss of ConsciousnessInability to arouse from sleepSeizuresIndividual requires assistance of another person

*Requirements for DiagnosisWhipples TriadSymptoms of hypoglycemiaBlood glucose levels

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*Management of HypoglycemiaLifestyle:5-6 small meals/day (CHO, PRO, FAT)Spread out intake of CHO evenly (2-4/meal)Avoid foods w/large amounts of CHORestrict/avoid coffee & alcoholDecrease fat intake (moderate intake

*TreatmentTwo components:Relief of symptoms by restoring blood glucose levels within normal rangesCorrecting the underlying causeImmediate:Eat foods/beverages containing CHOIV glucose may be required

*TREATMENTGOALS: To detect and treat a low blood glucose level and provides a rapid rise is blood glucose to a safe leveleliminating the risk of injury, and relieving symptoms quickly. 15 g of glucose will usually increase blood glucose by 2.1 mmol/L within 20 minutes with adequate symptom relief for most people. 20 g will usually increase blood glucose by 3.6 mmol/L within 45 minutes.

*TREATMENTMild to moderate hypoglycemia15 g of oral carbohydrate (CHO), preferably as glucose or sucrose tablets or solution. Retest blood glucose in 15 minutes; repeat treatment if BG still < 4.0 mmol/L

Severe hypoglycemia, conscious20 g of oral CHO (glucose tablets or equivalent); retest in 15 minutes, repeat treatment if BG still < 4.0 mmol/L

Severe hypoglycemia, unconscious adult1 mg glucagon subcutaneously or intramuscularly or 10 to 25 g of glucose intravenously (20 50 cc of D50W)

*Preventing HypoglycemiaIf blood glucose is < 70 mg/dl, give 1520 g of quick-acting carbohydrate (12 teaspoons of sugar or honey, 1/2 cup of regular soda, 56 pieces of hard candy, glucose gel or tablets as directed, or 1 cup of milk).

Test blood glucose 15 minutes after treatment. If it is still < 70 mg/dl, re-treat with 15 g of additional carbohydrate.

If blood glucose is not < 70 mg/dl but it is > 1 hour until the next meal, have a snack with starch and protein (crackers and peanut butter, crackers and cheese, half of a sandwich, or crackers and a cup of milk).

*HYPOGLYCEMIA- RECOMMENDATIONSIn hospitalized patients, efforts must be made to ensure that patients using insulin have ready access to an appropriate form of glucose at all times, particularly when NPO or during diagnostic procedures [Grade D, Consensus].In adults, mild to moderate hypoglycemia should be treated by the oral ingestion of 15 g of carbohydrate, preferably as glucose or sucrose tablets or solution. These are preferable to orange juice and glucose gels [Grade B, Level 2]. To wait 15 minutes, retest BG and retreat with another 15 g of carbohydrate if BG level remains < 4.0 mmol/L. In smaller children (< 5 years of age or < 20 kg), 10 g of carbohydrate may be used initially [Grade D, Consensus].

*HYPOGLYCEMIA- RECOMMENDATIONSSevere hypoglycemia in a conscious adult, should be treated by the oral ingestion of 20 g of carbohydrate, preferably as glucose tablets or equivalent. Patients should be encourage to wait 15 minutes, retest BG and retreat with another 15 g of glucose if the BG level remains < 4.0 mmol/L [Grade D, Consensus].Severe hypoglycemia in an unconscious individual 5 years of age, in the home situation, should be treated with 1 mg of glucagon subcutaneously or intramuscularly. In children < 5 years of age, a dose of 0.5 mg of glucagon should be given. Caregivers or support persons should call for emergency services and the episode should be discussed with the diabetes healthcare team as soon as possible [Grade D, Consensus].

*HYPOGLYCEMIA- RECOMMENDATIONSIn the home situation, support persons should be taught how to administer glucagon by injection [Grade D, Consensus].For severe hypoglycemia with unconsciousness in adults, when intravenous (IV) access is available, glucose 10 to 25 g (20 to 50 cc of D50W) should be given over 1 to 3 minutes. The pediatric dose of glucose for IV treatment is 0.5 to 1 g/kg [Grade D, Consensus].

*HYPOGLYCEMIA- RECOMMENDATIONSIn hospitalized patients, a PRN order for glucagon should be considered for any patient at risk for severe hypoglycemia (i.e. requiring insulin and hospitalized for concurrent illness) when IV access is not readily available [Grade D, Consensus].

To prevent repeated hypoglycemia, once the hypoglycemia has been reversed, the person should have the usual meal or snack that is due at that time of day. If a meal is > 1 hour away, a snack (including 15 g of carbohydrate and a protein source) is recommended in the absence of complicating factors [Grade D, Consensus].

*ConclusionsHypoglycemia is rareshould not automatically suspect it on basis of reported symptomsDue to past over-diagnosis, Whipples Triad most important determinant of hypoglycemiaIn those with diagnosed hypoglycemia, serious underlying medical conditions must be consideredTesting for medications in blood important in ruling out insulinomas

*HYPOGLYCEMIA IN DIABETES

*CLINICAL RISK FACTORS FOR HYPOGLYCEMIA IN DIABETESAbsolute or relative insulin excess occurs when

1. doses Insulin (or insulin secretagogue or sensitizer) 2. Exogenous glucose delivery.3. Endogenous glucose production 4. Glucose utilization 5. Sensitivity to insulin 6. Insulin clearance

*Sulfonylureas : hypoglycemic riskTolbutamideGliclazideRepaglinideGlipizideGlimepirideGlibenclamide 11 - 2(2)1 - 22(1)3 - 4(3)5(1)RR 1) Ferner 1988(2) Teisse, Diab Med,1994(3) Dills, Horm Metab Res,1996

*Hypoglycemic riskGlibenclamide has greatest risk for hypoglycemia (less so when given 2-3 times a day in smaller portions)

Repaglinide (3 times a day) seems to have smallest risk, but needs more confirmation on its efficacy in severe DM.Although different receptor-binding explains this difference, the small doses used is crucial.

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HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE

counterregulatory hormone responses (type 1 diabetes) - insulin levels do not decline as glucose levels fall (first defense lost) - glucagon response diminishes (the second defense lost) - the epinephrine response reduced (third defense lost)

(2) hypoglycemia unawareness. a loss of the warning symptomsthe first manifestation of hypoglycemia

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*PreventionKnow the signs and symptoms of hypoglycemiaTry to eat regular mealsCarry a source of CHOPerform SMCBG regularly Use regular insulin 30 minutes before eatingSchedule exercise appropriately, adjust meal times, calorie intake, insulin dosingCheck blood glucose before sleeping

*TreatmentGoal is to normalize the plasma glucose level as quickly as possibleMild Hypoglycemia: 3 glucose tablets, cup fruit juice, 2 tablespoon rains, 5 lifesavers candy, to cup regular soda, 1 cup milkModerate Hypoglycemia: Larger amount of CHO that are rapidly absorbedSevere Hypoglycemia: IV glucose or Glucagon (1mg), Glucose gel, Honey, syrup, jelly

*Interventions

Mildcarbohydrate 10-15 gramModerate20-30 gram of carbsGlucagon, 1 mg SC or IM

Severe50% dextrose 25 g IVGlucagon 1 mg IM or IV

*Somogyi EffectRebound hyperglycemiaCounterregulatory hormones activate gluconeogenesis and glycogenolysisHormones supress insulin 12-48 hoursAlso influenced by excessive carb intake

*Somogyi Effect

*Insulin secreted by beta-cells allows glucose into cells (doesnt regulate glucose in the brain)*Glucagon secreted by alpha-cells, stimulates release of stored liver glycogen to glucose*Brain responds to low BS by stimulating adrenal glands to release epinephrine which in turn stimulates liver to release glucose into blood*Cortisol & GHnormal counter regulatory response to hypoglycemia (but do not help to correct hypoglycemia)*Our body maintains BG levels w/in narrow range under many conditions*Sometimes simply