ACUTE COMPLICATION OF DIABETESACUTE COMPLICATION OF DIABETES

Dharma Lindarto

Div. Endokrinologi-Metabolik

Dep. Ilmu Penyakit Dalam FK USU/RSUP H Adam Malik Medan

ACUTE COMPLICATION OF DIABETES

� Diabetic ketoacidosis (DKA)

� Hyperosmolar nonketotic (HONK)� Hyperosmolar nonketotic (HONK)

� Hypoglycemia

Diabetic Ketoacidosis

� Diabetic Ketoacidosis (DKA) is a complication arising from Diabetes Mellitus

� DKA typically affects Type 1 diabetics, but Type 2 diabetics can also be at risk

1-2% mortality rate� 1-2% mortality rate

� Most common cause of death in pediatric diabetes

� Combination of hyperglycemia, ketonemia, and acidemia

� Hyperglycemia > 250 mg%

� Anion gap acidosis� (Na + K) – (Cl + Bicarb) >12

� Bicarbonate <15 mEq/L

Diabetic Ketoacidosis

� pH <7.3

� Urine ketones and serum ketones

� Hyperosmolarity

Common Precipitating Factors

Include:

� Infection- UTI, URTI, gastroenteritis

� poor patient compliance with medication, or not � poor patient compliance with medication, or not increasing insulin when needed

�myocardial infarction, CVA

� thromboembolic disorders

Symptoms of DKA

� External signs� Warm, dry skin� Rapid, deep respirations� Sweet, fruity odor of breath

� Internal indications� Internal indications� Blood sugar < 600� Low Na+� Severe metabolic acidosis (pH < 7.3)

Comparison of Diabetic Emergencies.

Diabetic Ketoacidosis

Hyperglycaemic non-ketotic coma.

Diabetic history Known type 1 or new diabetic

Mild or new type 2 diabetes

Age Young OldAge Young Old

Onset Days Days to weeks

Change in LOC o/+ ++

Acidosis +++ o/+

Fluid Loss ++ +++

Blood Sugar ++ +++

Diabetes Spectrum Volume 15, Number 1, 2002

Signs & Symptoms DKA

• Fruity breath

• Dehydration� hot/dry skin, dry mucous membranes,

rapid weak pulse, thirst, restless

Danger from dehydration and coma• Danger from dehydration and coma� BG > 250 mg/dl

Treatment DKA

• re-hydration

• insulin injection

• Correction electrolit imbalance• Correction electrolit imbalance

Hyperosmolar Non-Ketotic coma

(HONK)

� Glucose >600 mg/dl

� Sodium� Normal, elevated or low

� Potassium� Potassium� Normal or elevated

� Bicarbonate >15 mEq/L

� Osmolality >320 mOsm/L

Diabetic Hyper-osmolar State

• 40% of all diabetic fatalities

• most common in Type 2 diabetes (overweight)

renal absorption of glucose impaired• renal absorption of glucose impaired• dehydration, cerebral edema

Signs & Symptoms HONK

• Dehydration

. hot/dry skin, dry mucous membranes, rapid weak pulse, thirst, restless

. hot/dry skin, dry mucous membranes, rapid weak pulse, thirst, restless

• Danger from dehydration and coma

• BG > 600 mg/dl

• 40-70 % mortality

Treatment HNK

• re-hydration

• insulin injection

• Correction electrolit imbalance• Correction electrolit imbalance

Fluids

� Fluid deficit due to � Osmotic diuresis due to glucosuria� GI losses

� Average fluid deficitDKA 3-6L� DKA 3-6L

� HONK 8-10 L

Fluids

� For every 1L of fluid lost, will lose 70 mEq of

Na and K

� Isosmotic fluid Na=154 mEq

� Enhanced loss of water compared to solute � Enhanced loss of water compared to solute

leads to hyperosmolality

� Hyperosmolality=presenting neurologic

symptoms

Potassium

� Deficit due to urine losses and GI losses

� But may be normal or elevated level on

presentation.

� Initially thought due to acidosis causing K � Initially thought due to acidosis causing K

extrusion from cells

� Now: insulin deficiency and hyperosmolality

Potassium Therapy

� These patients have substantial potassium losses.

� Insulin therapy causes potassium to move into the cell.

� Potassium has to be monitored and � Potassium has to be monitored and replaced at appropriate levels.

� A rate of between 5 to 10 mmol/hour is often required with continuous ECG monitoring.

Bicarbonate

� Is it best choice to resolve acidosis?

� Insulin will allow resolution of acidosis as

metabolism of ketoacid anions produces

bicarbbicarb

Other therapy

� Treat underlying problem- consider antibiotics if sepsis

Thromboembolic prophylaxis� Thromboembolic prophylaxis

� Refer to diabetic team for longer term care.

Summary

� DKA and HONK are diseases on a continuum

� Pathophysiology dictates treatment approach

� Understanding it will help prevent treatment

from causing harmfrom causing harm

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.”dysfunction.”

The Merck Manual of Diagnosis and Therapy

Seventeenth Edition (1999)

Blood Glucose

� Normal Blood Glucosa 60-100 mg/dL

� Hypoglycemia: BG <50 mg/dL in men;

<45 mg/dL in women<45 mg/dL in women

SYMPTOMS OF HYPOGLYCEMIA

Neurogenic (autonomic) Neuroglycopenic

trembling difficulty concentrating

palpitations confusion

sweating weakness

anxiety drowsinessanxiety drowsiness

hunger vision changes

nausea difficulty speaking

tingling headache

dizziness

tiredness

Signs of Hypoglycemia

� Mild Hypoglycemia:� Pallor, Diaphoresis, Tachycardia, Palpitations,

Hunger, Paresthesias, Shakiness� Individual is able to self-treat

� Moderate HypoglycemiaModerate Hypoglycemia� Inability to Concentrate, Confusion, Slurred Speech,

Irrational or uncontrolled behavior, slowed reaction time, blurred vision, somnolence, extreme fatigue

� Individual is able to self-treat

� Severe Hypoglycemia� Completely automated/disoriented behavior� Loss of Consciousness� Inability to arouse from sleep� Seizures� Individual requires assistance of another person� Individual requires assistance of another person

Hormones in the response to hypoglycemia:(counterregulatory hormone)

1. Glucagon (glycogenolysis and gluconeogenesis).

2. Epinephrine (glycogenolysis and gluconeogenesis and limits glucose utilization)

3. growth hormone (reduce glucose utilization and support its production).production).

4. 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

Liver glucose output responds to multiple hormonal signals

Antonio Vidal-Puig & Stephen O'rahilly (2001) Nature 413, 125 – 126.

PLASMA GLUCOSE

Adrenal medullaEPINEPHRINE SECRETION

PLASMA EPINEPHRINE

ACTIVITY OF SYMPATHETIC NERVESTO ADIPOSE TISSUE AND LIVER

SYMPATHETIC RESPONSE IN HYPOGLYCEMIA

PLASMA EPINEPHRINE

Skeletal muscleGLYCOGENOLYSIS

LiverGLYCOGENOLYSISGLUCONEOGENESIS

Adipose TissueLIPOLYSIS

PLASMA GLUCOSE, FATTY ACIDS, GLYCEROL

Hypoglycemia Risk Factors

1. Missed or delayed meal

2. Eating less food at a meal than planned

3. Vigorous exercise without carbohydrate compensation

4. Taking too much diabetes medicine,(e.g., insulin, insulin 4. Taking too much diabetes medicine,(e.g., insulin, insulin secretagogues, and meglitinides)

5. Drinking alcohol

C a u s e s1. Fasting hypoglycemia

Result of a serious medical condition

� Insulinomas (most are benign)*

Pancreatic tumors-secrete insulin

Other tumors (breast, cervix, adrenal glands)*� Other tumors (breast, cervix, adrenal glands)*

Secrete insulin-like growth factors (IGF)Glucose production by liver inhibited; increased uptake in peripheral tissues

� Extensive liver disease

*Le Roith, Derek. (1999). Tumor-induced hypoglycemia. The New England Journal of Medicine, 341, 10.

2. Postprandial (reactive)

2-5 hrs after eating

Early insulin release with excess secretion in response to the hyperglycemia

� Alimentary

� In patients w/GI procedures (gastrectomy, pyloroplasty, gastrojejunostomy)

� Idiopathic alimentary

� RARE; over-diagnosed� Healthy young-adults� 2-4 hrs after meal or after a missed meal

Other Causes

1. Alcoholic hypoglycemia

� Ingestion of alcohol after a long fast

Factitious hypoglycemia2. Factitious hypoglycemia

� Insulin & sulfonylureas

� Primarily in health care worker and relatives of diabetics

� Distribution of incorrect drugs to patients*

*Robinson, Irving, et. Al. (1994) Closet Hypoglycemia. Journal of Family Practice, 38, 1.

Requirements for Diagnosis

� Whipple’s Triad� Symptoms of hypoglycemia� Blood glucose levels <50 mg/dL in men or

<45 mg/dL in women<45 mg/dL in women� Alleviation of symptoms after correction of

the low BG levels (ingestion of sugar)

Management of Hypoglycemia

� Lifestyle:� 5-6 small meals/day (CHO, PRO, FAT)� Spread out intake of CHO evenly (2-4/meal)� Avoid foods w/large amounts of CHO� Avoid foods w/large amounts of CHO� Restrict/avoid coffee & alcohol� Decrease fat intake (moderate intake <30% of total

kcal)� Moderate (upper range) PRO intake

Treatment

� Two components:� Relief of symptoms by restoring blood glucose levels

within normal ranges� Correcting the underlying cause

� Immediate:Eat foods/beverages containing CHO� Eat foods/beverages containing CHO

� IV glucose may be required

TREATMENT

GOALS:

� To detect and treat a low blood glucose level and provides a rapid rise is blood glucose to a safe level

� eliminating 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.

TREATMENT

Mild to moderate hypoglycemia

� 15 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, consciousSevere hypoglycemia, conscious

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

Severe hypoglycemia, unconscious adult

� 1 mg glucagon subcutaneously or intramuscularly or 10 to 25 g of glucose intravenously (20 – 50 cc of D50W)

Preventing Hypoglycemia

� If blood glucose is < 70 mg/dl, give 15–20 g of quick-acting carbohydrate (1–2 teaspoons of sugar or honey, 1/2 cup of regular soda, 5–6 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).

Conclusions

� Hypoglycemia is rare—should not automatically suspect it on basis of reported symptoms

� Due to past over-diagnosis, Whipple’s Triad most important determinant of hypoglycemia

� In those with diagnosed hypoglycemia, serious underlying medical conditions must be consideredIn those with diagnosed hypoglycemia, serious underlying medical conditions must be considered

� Testing for medications in blood important in ruling out insulinomas

HYPOGLYCEMIA IN DIABETES

CLINICAL RISK FACTORS FOR HYPOGLYCEMIA

IN DIABETES

Absolute 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 4. ↑ Glucose utilization 5. ↑ Sensitivity to insulin 6. ↓ Insulin clearance

Sulfonylureas : hypoglycemic riskSulfonylureas : hypoglycemic risk

TolbutamideTolbutamide

GliclazideGliclazide

RepaglinideRepaglinide

11

1 1 -- 22(2)(2)

1 1 -- 22

RRRR

GlipizideGlipizide

GlimepirideGlimepiride

GlibenclamideGlibenclamide

22(1)(1)

3 3 -- 44(3)(3)

55(1)(1)

1) Ferner 1988(2) Teisse, Diab Med,1994(3) Dills, Horm Metab Res,1996

Hypoglycemic risk

� Glibenclamide 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 � 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.

HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE

(1) ↓ 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)- epinephrine response reduced (third defense lost)

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

Prevention

� Know the signs and symptoms of hypoglycemia

� Try to eat regular meals

� Carry a source of CHO

� Perform SMCBG regularly

� Use regular insulin 30 minutes before eating� Use regular insulin 30 minutes before eating

� Schedule exercise appropriately, adjust meal times, calorie intake, insulin dosing

� Check blood glucose before sleeping

Treatment

Goal: to normalize the plasma glucose level as quickly as

possible

� Mild Hypoglycemia:

3 glucose tablets, ½ cup fruit juice, 2 tablespoon rains, 5 lifesavers candy, ½ to ¾ cup regular soda, 1 cup milk

� Moderate Hypoglycemia:

Larger amount of CHO that are rapidly absorbed

� Severe Hypoglycemia:

IV glucose or Glucagon (1mg), Glucose gel, Honey, syrup, jelly)

Somogyi Effect

� Rebound hyperglycemia� Counterregulatory hormones activate

gluconeogenesis and glycogenolysis� Hormones supress insulin 12-48 hours� Also influenced by excessive carb intake� Also influenced by excessive carb intake

Somogyi Effect