ACUTE 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) 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 Most common cause of death in pediatric diabetes Combination of hyperglycemia, ketonemia, and acidemia

Diabetic Ketoacidosis
Hyperglycemia

> 250 mg% Anion gap acidosis

(Na + K) (Cl + Bicarb) >12
Bicarbonate

<15 mEq/L

pH

<7.3 Urine ketones and serum ketones Hyperosmolarity

Common Precipitating Factors

Include: Infection- UTI, URTI, gastroenteritis 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 Blood sugar < 600 Low Na+ Severe metabolic acidosis (pH < 7.3)

Comparison of Diabetic Emergencies.

Diabetic Ketoacidosis Diabetic history Age Onset
Known type 1 or new diabetic

Hyperglycaemic nonketotic coma.

Mild or new type 2 diabetes

Young Days

Old Days to weeks

Change in LOC Acidosis

Fluid Loss Blood Sugar

o/+ +++
++ ++

++ o/+
+++ +++

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 BG > 250 mg/dl

Treatment DKA

re-hydration insulin injection Correction electrolit imbalance

Hyperosmolar Non-Ketotic coma (HONK)

Glucose
Sodium

>600 mg/dl

Normal, elevated or low 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 dehydration, cerebral edema

Signs & Symptoms HONK

Dehydration

. 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

Fluids
Fluid

deficit due to Osmotic diuresis due to glucosuria GI losses Average fluid deficit 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 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 extrusion from cells Now: insulin deficiency and hyperosmolality

Potassium Therapy
These

losses. Insulin therapy causes potassium to move into the cell. 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.

patients have substantial potassium

Bicarbonate
Is

it best choice to resolve acidosis? Insulin will allow resolution of acidosis as metabolism of ketoacid anions produces bicarb

Other therapy
Treat

underlying problem- consider antibiotics if sepsis prophylaxis

Thromboembolic Refer

care.

to diabetic team for longer term

Summary
DKA

and HONK are diseases on a continuum Pathophysiology dictates treatment approach Understanding it will help prevent treatment from causing harm

H YPOGLYCEMIA

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 Therapy Seventeenth Edition (1999)

Blood Glucose
Normal

Blood Glucosa 60-100 mg/dL BG <50 mg/dL in men; <45 mg/dL in women

Hypoglycemia:

SYMPTOMS OF HYPOGLYCEMIA
Neurogenic (autonomic) Neuroglycopenic trembling difficulty concentrating palpitations confusion sweating weakness anxiety drowsiness hunger vision changes nausea difficulty speaking tingling headache dizziness tiredness

Hormones in the response to hypoglycemia: (counterregulatory hormone)

1.
2.

3.

4.

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

Liver glucose output responds to multiple hormonal signals

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

SYMPATHETIC RESPONSE IN HYPOGLYCEMIA

Adrenal medulla EPINEPHRINE SECRETION

PLASMA GLUCOSE

PLASMA EPINEPHRINE

ACTIVITY OF SYMPATHETIC NERVES TO ADIPOSE TISSUE AND LIVER

Skeletal muscle GLYCOGENOLYSIS

Liver GLYCOGENOLYSIS GLUCONEOGENESIS

Adipose Tissue LIPOLYSIS

PLASMA GLUCOSE, FATTY ACIDS, GLYCEROL

Hypoglycemia Risk Factors

1.
2. 3. 4. 5.

Missed or delayed meal Eating less food at a meal than planned Vigorous exercise without carbohydrate compensation Taking too much diabetes medicine,(e.g., insulin, insulin secretagogues, and meglitinides) Drinking alcohol

Causes
1.

Fasting hypoglycemia

Result of a serious medical condition

Insulinomas (most are benign)*

Pancreatic tumors-secrete insulin

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

Idiopathic alimentary

Other Causes
1.

Alcoholic hypoglycemia Ingestion of alcohol after a long fast Factitious hypoglycemia Insulin & sulfonylureas Primarily in health care worker and relatives of diabetics Distribution of incorrect drugs to patients*
*Robinson, Irving, et. Al.
Practice, 38, 1. (1994) Closet Hypoglycemia. Journal of Family

2.

Requirements for Diagnosis

Whipples

Triad Symptoms of hypoglycemia Blood glucose levels <50 mg/dL in men or <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 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 Eat foods/beverages containing CHO IV glucose may be required

Immediate:

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, 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 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, retreat 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 rareshould not automatically suspect it on basis of reported symptoms Due to past over-diagnosis, Whipples Triad most important determinant of hypoglycemia In 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 5. Sensitivity to insulin 6. Insulin clearance

Sulfonylureas : hypoglycemic risk

RR
Tolbutamide
Gliclazide Repaglinide

1
1 - 2(2) 1-2

Glipizide
Glimepiride Glibenclamide

2(1)
3 - 4(3) 5(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 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. - a loss of the warning symptoms - the first manifestation of hypoglycemia

Somogyi Effect
Rebound

hyperglycemia Counterregulatory hormones activate gluconeogenesis and glycogenolysis Hormones supress insulin 12-48 hours Also influenced by excessive carb intake

Somogyi Effect

Myxedema Coma

Myxedema
Myxedema is a rare life threatening decompensation of hypothyroidism
Usually in individuals with long-standing hypothyroidism Most often seen in the winter months More common in elderly women with underdiagnosed or undertreated hypothyroidism

Myxedema Coma
End stage of untreated or insufficiently treated hypothyroidism Typical clinical picture:
Elderly obese female Becoming increasingly withdrawn, lethargic, sleepy and confused Slips into a coma

History:
Previous thyroid surgery Radioiodine Default thyroid hormone therapy

Precipitating Events
CVI Myocardial infarction Infection
UTI Pneumonia

Gastrointestinal hemorrhage Acute trauma Administration of sedative, narcotic or potent diuretics

Pathogenesis of Myxedema

Symptoms & signs

Sign of hypothyroidism Hypothermia Bradycardia

Hypoventilation
Hyponatremia Coma

Physical Findings
Comatose or semi comatose Dry coarse skin Hoarse voice Thin dry hair Delayed reflex relaxation time Hypothermia Pericardial, pleural effusions, ascites

Myxedema
Diagnosis
Must have high clinical suspicion Commonly has Hx. Of hypothyroidism Delcine in function is usually insidious in onset

Myxedema
Diagnosis cont
Laboratory evaluation may reveal
Anemia Hyponatremia Hypoglycemia Transaminases CPK LDH Po2 and PCo2 on ABGs

Myxedema
Diagnosis cont.
EKG may reveal
Sinus Bradycardia Prolonged QT interval Low voltage Flattened or inverted T waves

Lab Tests
Free T4 low and TSH high If the T4 is low and TSH low normal consider pituitary hypothyroidism Blood gasses Electrolytes and creatinine Distinguish from euthyroid sick syndrome
Low T3, Normal or low TSH, normal free T4

Management of Myxedema (1)

ICU admission may be required for ventilatory support and IV medications Parenteral thyroxine (not readily available in SA)
Loading dose of 300 400 g Then 50 g daily

Management of Myxedema (2)

Electrolytes
Water restriction for hyponatremia Avoid fluid overload

Avoid sedation Glucocorticoids

Controversial but necessary in hypopituitarism or multiple endocrine failure Dose: Hydrocortisone 40 100 mg 6 hly for 1 week, then taper

Prognosis of Myxedema
Mortality is 20%, and is mostly due to underlying and precipitating diseases

Thyroid Storm
Acute life threatening exacerbation of thyrotoxicosis

Thyroid Storm
A life threatening hypremetabolic state due to hyperthyroidism Mortality rate is high (10-75%) despite treatment Usually occurs as a result of previously unrecognized or poorly treated hyperthyroidism Thyroid hormone levels do not help to differentiate between uncomplicated hyperthyroidism and thyroid storm

Clinical Setting
Patient with Graves disease who has discontinued antithyroid medication OR is previously undiagnosed Hyperpyrexia ( >40 0C ) Sweating Tachycardia with or without AF Nausea, vomiting and diarrhea Tremulousness and delirium, occasionally apathetic

Thyroid Storm: Physical Exam

Temperature Hyperpyrexia Gastrointestinal nausea, vomiting, diarrhea, jaundice Central Nervous System agitation, delirium, psychosis, stupor, coma

Cardiovascular accelerated tachycardia, atrial dysrhythmia, congestive heart failure

Precipitating factors
Withdraw of antithyroid drugs Severe infection DKA CVI Cardiac failure Surgery Trauma radioiodine Drug reaction Iodinated contrast medium

Diagnosis
Free T4, free T3 elevated TSH suppressed Note that findings are not different than that of hyperthyroidism, but the difference is in the setting

Treatment of Thyroid Storm

Sympathetic outflow

Triangle of Treatment Production and release of thyroid hormone Peripheral conversion (T4 T3)

Management of Thyroid Storm (1)

Supportive care
Fluids, containing Glucose Oxygen Cooling Phenobarbital Multivitamins If indicated antibiotics or digoxin

Avoid Aspirin

Management of Thyroid Storm (2)

Specific Measures
Propranolol 40 80 mg 6 hly Methimasole 20 mg 6 hly (pr of po) Lugols Iodine 5 drops (250 mg) orally bd Dexamethasone 2 mg 6 hly Cholestyramine 20 30 g/d

Prognosis
Mortality dropped since the 1920s from 100% to 20 30% Mortality most frequently associated with serious underlying medical conditions