CME Sohag | internal medicine | Diabetes mellitus

Internal medicine training session (1)

Dr. Ahmed Othman Assistant lecturer of internal medicine, Sohag university

Case study (1)

Case Study

• 55 year old, obese man, routinely avoid medical care presented to the clinic with a fasting blood sugar of 108 mg/ml and a 2 hours post-prandial of 186 mg/ml.

Diagnosing Diabetes

Diagnosing Diabetes

Casual plasma glucose ≥ 200mg/dl

AND symptoms

– Polyuria, polydispia, unexplained weight

loss

Fasting plasma glucose of ≥ 126mg/dl

AND symptoms

2 RBS or 2 FPG without symptoms

Oral Glucose Tolerance Test

Fasting

• Oral glucose load of 75g anhydrous glucose dissolved in water

• Plasma glucose testing at 2 hours

Oral Glucose Tolerance Test in pregnancy

Fasting more than 95

• Oral glucose load of 100g glucose dissolved in water

• Plasma glucose testing at 3 hours

1 h more than 180

2 h more than 155

3 h more than140

When to screen…• Screening for T1DM involves the measurement of

autoantibody markers (antibodies to islet cells, insulin, glutamic acid decarboxylase, and tyrosine phosphatase).

• Every 3 years for all individuals >45yo T2DM• More frequently or at a younger age if… BMI >25 - Hypertension Inactive - HDL<35

First degree relative with DM -TG >250 h/o glucose intolerance - PCOS

High risk ethnic group - Vascular disease

h/o gestational DM -Have delivered a baby weighing 4kg

Targets for TreatmentHbA1c <6.5% (Check q 3months until stable and <7,

then q 6months)

Premeal Glucose 90-130mg/dl

Peak Postprandial G <180mg/dl

Systolic <130

Diastolic <80

LDL <100

HDL >40

Triglycerides <150

Annual Monitoring Tests

• Dilated eye exam

• Foot exam

– more often if neuropathy present

• Lipid profile

• Microalbumin measurement

Nutritional Recommendation

• Provide individualized meal planning guidelines

• Carbohydrate training

• Caloric balancing

• Exercise

Diet

Multiple Insulin Injection Therapy

I

N

S

U

L

I

N

I

N

J

E

C

T

I

O

N

30

25

20

35

30

25

40

35

30

Physical activity

Bo

dy w

eig

ht

25 years male IBW 60 kgm

Carbohydrate (65%)390Protein (10%)60

Fat (25%)150

Carbohydrate 100 gmProtein (10%) 15 gm

Fat (25%) 17 gm

Diet Carbohy. Protein Fat _Arabian bread 30 gm --- ---

Cheese 5 gm 10 gm 10 gmHoney 50 gm 2 gm 3 gmGlass of milk 10 gm 5 gm 5 gm_Total 95 gm 17 gm 18 gm


Fat (25%)200


Fat (25%) 22 gm

Diet Carbohy. Protein Fat _Rice 80 gm --- 6 gm

chicken 5 gm 15 gm 12 gmSalad 30 gm 4 gm 4 gm

Orange 10 gm --- ---___Total 125 gm 19 gm 22 gm


Fat (25%)100


Fat (25%) 11 gm

Diet Carbohy. Protein Fat _Tuna sandwich 45 gm 12 gm 10 gmApple 15 gm --- ---

Tea --- --- --- _Total 95 gm 17 gm 18 gm

60 Kg X 30 kcal = 1800 kcal

Breakfast 600 kcal Lunch 800 kcal Dinner 400 kcal

The total calories intake depends on patients age and activity but have to related to the desirable body weight.

Total daily calories = IBW X Estimated daily energyAdd 300 kcal/day during pregnancy.

Add 500 kcal/day during lactation.Fibers, sweeteners, vitamins, and minerals.

Meglitinide AnalogsSulphonylureas

Thiazolindinediones

Metformin(Biguanides)

Alpha GlucosidaseInhibitors

Oral Hypoglycemic

drugs

•Metformin (Biguanides)

•Glybenclemide, Glicliazide

Glipizide, Glimepiride

• Acarbose , Miglitol, Voglibose

• Repaglinide, Nateglinide

• Rosiglitazone , Pioglitazone

• Sitagliptin, Vildagliptin,

Saxagliptin

Spectrum of Oral Hypoglycaemic Agents

• Biguanides

•Sulphonylureas

•-Glucosidase

inhibitors

•Meglitinide analogues

•Thiazolidinediones

DPPV-4 Inhibitors

Oral TherapyTypically reduces HbA1c by 2-3 points

maximum Choosing an Oral Therapy

• Glucophage (Metformin)– Increases sensitivity to endogenous insulin

– Decreases hepatic glucose production– First line for obese patients

• Acarbose (Precose)– Delays glucose absorption

• Sulfonylureas– Increases release of endogenous insulin– First line for non-obese patients

• Thiozolindinediones– Increases insulin sensitivity

Glucophage

Advantages– Minimal weight gain

– No added risk of hypoglycemia

Adverse Effects– GI upset common

– Lactic acidosis (uncommon but 50% mortality)

Starting Dose– 500mg PO BID or 850mg PO QD

– Increase by 500mg Q Week

GlucophageContraindications– Renal impairment: Creatinine > 1.5 for men and > 1.4

for women; (caution is warranted in elderly patients)– Cardiac or respiratory insufficiency that is likely to

cause hypoxia or reduced tissue perfusion– CHF– History of lactic acidosis– Surgery– Severe infection that can lead to decreased tissue

perfusion– Alcohol abuse sufficient to cause acute hepatic toxicity– Use of IV radiocontrast agents

GlucophageOthers

Cidophage 500- Retard 850

Glucophage 500- 1000

Sulfonylureas

Includes:– glipizide (Glucotrol/ minidiab 5),– glimepiride (Amaryl /Dolcy),– glyburide (Diabeta/Micronase)- Glibenclamid (Daonil5 - Diaben 5)up to 3- glicazid( Diamicron80 -MR30-60) antiplatles

Adverse Effects– Hypoglycemia–Weight gain

Thiozolindinediones

Includes:

– rosiglitazone (Avandia)

– pioglitazone (Actos / actozon 30- 45) 15:45

- Repaglinide (Diarol 0.5-1-2)

Contraindications

– Class III or IV CHF

– Baseline ALT > 2.5x normal

Adverse Effects

– Edema

– Weight Gain

Alpha Glucosidase inhbitors

Work on the brush border of the intestine cause carbohydrate malabsorption

Advantages: • Selective for postprandial hyperglycaemia• No hypoglycaemic symptoms

Disadvantages:• Abdominal Distension and flatus• Only effective in mild hyperglycaemia

Alpha Glucosidase inhbitors• Acarbose- 25 mg to 50mg thrice a day

• Miglitol- 25mg to 100mg thrice a day

• Voglibose- 0.2 to 0.3 mg thrice a day

Contraindications

• an inflammatory bowel disease, such as ulcerative colitis or Crohn's disease; or any other disease of the stomach or intestines

• ulcers of the colon

• Intestinal Obstruction

• kidney disease.

http://www.healthline.com/galecontent/inflammatory-bowel-disease

http://www.healthline.com/adamcontent/ulcerative-colitis

http://www.healthline.com/adamcontent/kidney-disease

Sulphonylurea + MetforminIncludes:

– Glibenclamid+met500 (glucovance)

– Glyburid (Diavance 1.25-2.5-5)

Incretin concept

• Insulin secretion dynamics is dependent on the method of administration of glucose

• Intravenous glucose gives a marked first and second phase response

• Oral glucose gives less marked first and second phase insulin response, but a

prolonged and higher insulin

concentration

Insulin secretion profilesIn

sulin

concentr

ation

0 10 20 30 40 50 60 70 80 90

minutes

Glucose given orally

Glucose given intravenously

Iso-glycaemic profilesIn

sulin

concentr

ation

0 10 20 30 40 50 60 70 80 90

minutes

Glucose given orally

Glucose given intravenously to

achieve the same profile

Incretin effect

What are the incretins?• GIP: Glucose-dependent insulinotrophic polypeptide

Small effect in Type 2 diabetes.

• GLP-1(glucagon-like peptide 1)

augmented in the presence of hyperglycaemia.

Action less at euglycaemia and in normal subjects.

• Pituitary Adenylate Cyclase Activating Peptide (PACAP)

GLP-1 Modes of Action in Humans

GLP-1 is secreted

from the L-cells

in the intestine

This in turn…

•Stimulates glucose-dependent

insulin secretion

•Suppresses glucagon secretion

•Slows gastric emptying

Long term effectsdemonstrated in animals…

•Increases beta-cell mass and

maintains beta-cell efficiency

•Reduces food intake

Upon ingestion of food…

Now for the bad News…………..

GLP-1 is short-acting

Modified from J Larsen et al: Diabetes Care 2001; 24:1416-1421

After 7 days

Control

Blood glucose profiles

24-h/day GLP-1 s.c. infusion

16-h/day GLP-1 s.c. infusion

100

200

300

400

04 06 08 10 12 14 16 18 20 22 00 02 04 06

Blo

od

Glu

cose

(mg

/dl)

Time

400

100

200

300

04 06 08 10 12 14 16 18 20 22 00 02 04 06

Blo

od

Glu

cose

(mg

/dl)

Time

Dipeptyl- peptidase inhibitors

Sitagliptin

Vildagliptin

Saxagliptin

Septagliptin

Allogliptin

DPP-4 Inhibitors• Sitagliptin (Januvia)

• Saxagliptin (Onglyza)

• Linagliptin ( Tradjenta)

Take once a day at the same time each day

Improves insulin level after a meal and lowers the amount of glucose made by your body

Side effect

Stomach discomfort, diarrhea, sore throat, stuffy nose, upper respiratory infection.

Comparing the GliptinsSitagliptin Vildagliptin Saxagliptin

Dosing OD BD OD

Renal Failure Approved Not Approved Approved

Hepatic Failure No info No info Safe

With Insulin Not Approved Approved Studies Pending

On Bone Improved BMD? Unknown Unknown

Infections Slight increase Neutral NeutralUTI, URI

Cardiac Impact Reduced Neutral ?reduced CV mortality post ischaemic stunning

Which is the appropriate oral hypoglycaemic agent to use and when?

Mechanism of Action of Sitagliptin

Incretin hormones GLP-1 and GIP are released by the intestine

throughout the day, and their levels increase in response to a meal.

Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and

prolonging the actions of these hormones.

Release ofactive incretinsGLP-1 and GIP Blood glucose in

fasting and postprandial states

Ingestion of food

Glucagon(GLP-1)

Hepatic glucose

production

GI tract

DPP-4 enzyme

InactiveGLP-1

XSitagliptin(DPP-4

inhibitor)

Insulin(GLP-1 and

GIP)

Glucose-dependent

Glucose dependent

Pancreas

InactiveGIP

β cells

α cells

Glucose uptake by peripheral

tissues

30

Determinants of OAD usage

1)Body Mass Index : Metformin, Gliptins

BMI> 22kg/m2

2)Presence of GI symptoms: Sulpha, Gliptins, Glitazones

3)Renal Dysfunction: Gliptins,Glitazones(+/-),Sulpha (variable)

4) Aging Meglitinides, Gliptins(?)

5) Hepatic Dysfunction Nateglinide, Saxagliptin(?)

6) Compliance Gliptins, Glitazones,

7) Cost Metformin, Sulphas, Glitazones

Back to our patient

• During the next five years he was not compliant to his medications despite

• having laser treatment for his left eye twice. And in the last few months

• he noticed edema of his lower limbs.

QUESTIONS

Internal medicine training session (2)

Dr. Ahmed Othman Assistant lecturer of internal medicine, Sohag university

Case study (2)

Case study (2)

• A 32-year-old male with type 1 diabetes since the age of 14 years was taken to the emergency room because of drowsiness, fever, cough, diffuse abdominal pain, and vomiting.

• Fever and cough started 2 days ago and the patient could not eat or drink water.

• He has been treated with an intensive insulin regimen (insulin glargine 24 IU at bedtime and a rapid-acting insulin analog before each meal )

Case study (2)

• On examination he was tachypneic.

• His temperature was 39° C.

• pulse rate 104 beats per minute,

• respiratory rate 24 breaths per minute,

• supine blood pressure 100/70 mmHg;

• he also had dry mucous membranes, poor skin turgor, and rales in the right lower chest. He was slightly confused

Case study (2)

• Investigations:• hemoglobin 14.3 g/dl ,

• white blood cell count 18,000/ μ l,

• glucose 450 mg/dl,

• creatinine 1.2 mg/dl ,

Na+ 152 mEq/L, PO 2 95 mmHg

K+ 5.3 mEq/L PCO 2 28 mmHg,

Cl- 110 mmol/L. HCO3 9 mEq/L

Arterial pH

6.9 O2 sat 98%..

DKA DefinitionDKA = 3 letters= triad of D K A

Diabetic glucose >250 mg/dL (usually 500-800)

Keto

ketones producedketones – both in urine and in serumacetoacetate, acetone, betahydroxybutyratefruity smell, not often encountered in real life)consider that if these criteria aren’t met, it may not be DKA

AcidosisIncreased anion gap, metabolic acidosis; HCO3- <15, pH<7.30

Pathophysiology

InsulinCounterregulatory hormones

Glucagon, Epinephrine, Cortisol, Growth hormone

Normal

Pathophysiology

Excess counterregulatory

hormones

Insulin deficiency

DKA

Etiology

• Insulin deficiencyInsulin missed dose

Pancreatitis

Heavy meal

• Excess Counterregulatoryhormones

• Infection i.e. Pneumonia

• MI

• Stroke

• Trauma

• Emotional

• Pregnancy

• Iatrogenic

Insulin Deficiency

Glucose uptakeProteolysis

Lipolysis

Amino Acids

Glycerol Free Fatty Acids

Gluconeogenesis

GlycogenolysisHyperglycemia Ketogenesis

Acidosis

Osmotic diuresis

PolyuriaPolydipsia

Fruity breath (acetone smell)Kussmaul breathing (acidotic)Mental status changes

DehydrationDry tongue Tachycardia Hypotension Abd pain

Electrolyte imbalance

Clinical manifestations

Clinical manifestations

• Special notes

• Abdominal pain

It is more common in children than in adults

It is multifactorial

dehydration of muscle tissue

Delayed gastric emptying

Ileus from electrolyte disturbances

Metabolic acidosis;

It sometimes mimicks acute abdomen

It is classically periumbilical

Differential Diagnosis• DD of acidotic breathing

– Renal failure

– Amonia increase in HCF

– Hysterical

• DD of diabetic coma

– Lactic acidosis

– Hyperosmolar non-ketotic coma

– Hypoglycemia

• DD of coma in general

• DD of acute abdomen

DKA vs. HHS

HHSDKAMore in elderlyMore in childrenAge

More in type IIMore in type IDM type

> 600> 250Glucose

+ or -+++++Ketonuria/emia

>7.3<7.3pH

>15<15HCO3

HyperosmolarityVariable S osmolarity

Sensitive to small dose

Variable Sensitivity to insulin

DKA vs. HYPOGLYCEMIA

HypoglycemiaDKA

Insulin overdose or hyperinsulinemia

Insulin deficiency or increased counter-reg hormones

Etiology

Acute Gradual Onset

-S of Brain glucopenia- S of sympathetic overactivity

S of hyperglycemiaS of dehydration S of acidosis

Symptoms and signs

hypoglycemiahyperglycemia RBS

No Yes Ketonuria

No YesKetonemia

Rapidly recover if earlyNo effectIV glucose

Golden ruleAny diabetic patient with DKA versus hypoglycemia, give glucose

even before glucose measuring

InvestigationsFor diagnosis

Triad for diagnosis

1. RBS Hyperglycemia > 250 mg/dl

2. Ketonemia and ketonuria

3. Blood gasmetabolic acidosis

– pH < 7.35, anion gap (Na + K) – (Cl + Bicarb) > 10, and Bicarbonate <15

mEq/L

InvestigationsFor diagnosis

• Other findings

– Electrolyte serum level• Hyperkalemia (rarely Hypokalemia), Hyponatremia (rarely

Hypernatremia )

– Investigation for the cause such as• Urine Analysis, AMI panel and ECG, Chest x-ray

– Hyperosmolarity• Normal = 285-295 milli-osmoles per kilogram (mOsmol/kg)

• [Glucose] and [BUN] are measured in mg/dL

InvestigationsFor Monitoring

• RBS

– Every 1 hour till RBS reaches 200 mg/dL or less, then every 6 hours

• Urine ketones

– Every 8h

• Blood gas after fluid replacement

• Electrolyte serum level every 4 hours till correction

Treatment of DKA

• Treatment of predisposing factors

• Initial hospital management

– Care of comatosed patients

– Fluid and electrolytes replacement

– Insulin replacement and glucose administration when needed

– Treatment of complications

• Once resolved

– Convert to home insulin regimen

– Prevent recurrence

Fluids and Electrolytes• Fluid replacement

– Restores perfusion of the tissues

– Average fluid deficit 3-6 liters

• Initial resuscitation with saline

– 1 L of normal saline over the first ½ hour then

– 1 L of normal saline over ½ hour then

– ½ L of normal saline over 1 hour then

– ½ L of normal saline over 2 hours

– Then the rate will depend on clinical judge (BP, CVP, basal lung crepitation)

Fluids and Electrolytes

• K+ level (check at 0,2,6,10,24 hr).

– If Hyperkalemia (> 5.5 meqlL)

• initially present

• No treatment as it resolves quickly with insulin drip

– If normal level (3.5-5.5 meqlL)

• Add 20-30 meql for each Liter of infused fluid

– If Hypokalemia (<3.5 meqlL)

• Add 40 meq for each Liter of infused fluid


• Phosphate deficit

– May want to use potassium phosphate

• Bicarbonate

– Not given unless pH <7 or bicarbonate <5 mmol/L or unresolved acidosis

after fluid replacement

– Dose (mmol of NaHco3) = -------------------------------------------

– Dose (No of ampoules of NaHco3) = ----------------------------------------

BW x Becar deficit

6

BW x Becar deficit

150


• Na level:

– Calculate the corrected Sodium (for each 100

mg/dL glucose above 100, add 1.6 meq/l to Na

level)

• If corrected Na is High or Normal use Half NS

(250-1000 ml/hr)

• If corrected Na is Low use NS, rate depends on

severity of volume depletion

Insulin Therapy

• Initial dose

– IV bolus of 0.1-0.2 units/kg (~ 10 units) regular insulin

– Infusion insulin at 0.1 units/kg/hr (max 8 units/hr).

• Maintenance dose (Check BG Q1hour, goal is 50-80

mg/dl/hr)

– If falling too rapidly, decrease the rate

– If falling too slowly increase the rate by 50-100%

• Continue IV insulin until urine is free of

ketones and RBS reaches 250-300 mg/dl

Insulin Therapy

• When RBS reaches 250-300 mg/dl

– Decrease the rate of insulin infusion to 0.05-0.1

IU/kg/hr (goal is to keep RBS in this range until the

gap closes (normal gap 7-8 mEq/l)

– then start home maintenance SC insulin

under umbrella of infused insulin for 2

hours, then continue on SC insulin only .

Glucose Administration

• Supplemental glucose

– Hypoglycemia occurs

• Insulin has restored glucose uptake

• Suppressed glucagon

– Prevents rapid decline in plasma osmolality

• Rapid decrease in insulin could lead to cerebral edema

• Glucose decreases before ketone levels decrease

• Start glucose when plasma glucose < 300

mg/dl

Insulin-Glucose Infusion for DKA

Blood glucose Insulin Infusion D5W Infusion

<70 0.5 units/hr 150 ml/hr

70-100 1.0 125

101-150 2.0 100

151-200 3.0 100

201-250 4.0 75

251-300 6.0 50

301-350 8.0 0

351-400 10.0 0

401-450 12.0 0

451-500 15.0 0

>500 20.0 0

Complications of DKA

• Infection

– Precipitates DKA

– Leukocytosis can be secondary to

acidosis

• Shock

– If not improving with fluids r/o MI

• Vascular thrombosis

– Severe dehydration

– Cerebral vessels

– Occurs hours to days after DKA

• Pulmonary Edema

– Result of aggressive fluid

resuscitation

• Cerebral Edema

– First 24 hours due to aggressive

correction of hypoglycemia or

administration of hypotonic

solution

– c/p: Mental status changes

– Tx: Mannitol

– May require intubation with

hyperventilation

Causes of Cerebral Edema

Mechanism:

• The brain adapts by producing intracellular osmoles (idiogenic

osmoles) which stabilize the brain cells from shrinking while the

DKA was developing.

• When the hyperosmolarity is rapidly corrected, the extracellular

fluids is corrected faster than brain cells

– The brain becomes more hypertonic than the extracellular fluids

water flows into the cells cerebral edema


The many factors have been implicated:

Rapid and/or sharp decline in serum osmolality with treatment.

High initial corrected serum Na concentration.

High initial serum glucose concentration.

Failure of serum Na to raise as serum glucose falls during

treatment.

Glucose

Presentations of Cerebral Edema

Cerebral Edema Presentations include:

Deterioration of level of consciousness.

Headache and blurring of vision

Vomiting

Convulsion.

Treatment of Cerebral Edema

• Reduce IV fluids

• Raise foot of Bed

• IV Mannitol

• Elective Ventilation

• Dialysis if associated with fluid overload or renal failure.

• Use of IV dexamethasone is not recommended.

Prevention of DKA

• Never omit insulin

– Cut long acting in half

• Prevent dehydration and hypoglycemia

• Monitor blood sugars frequently

• Monitor for ketosis

• Provide supplemental fast acting insulin

• Treat underlying triggers

• Maintain contact with medical team

Pitfalls in DKA

• Plasma glucose is usually high but not always

– DKA can be present with RBS < 300 due to

• Impaired gluconeogenesis– Liver disease

– Acute alcohol ingestion

– Prolonged fasting

– Insulin-independent glucose is high (pregnancy)

• Chronic poor control but taking insulin

• Ketone in urine may be –ve in DKA, but always +ve in blood

– Due to measurement of acetoacetic acid in urine not, betahydroxybuteric acid

– Acetone in blood should be done in this case

Pitfalls in DKA

• High WBC may be present without infection

• Infection may be present without fever

• High Creatinine may be present without true renal

function: it may cross react with ketone bodies.

• Blood urea may be elevated with prerenal azotemia

secondary to dehydration.

• Serum amylase is often raised even in the

absence of pancreatitis

Case study (3)

Case study (3)

A 82-year-old male patient was taken to the

emergency room in the afternoon for loss of

consciousness in the previous hour.

The patient had hypertension, chronic

ischemic heart disease, and mild diabetes

treated with glibenclamide daily.

On examination the patient had coma

(Glasgow scale 5) and right hemiplegia.

RBS of this patient is 30 mg/dl

Hypoglycemia or low blood glucose is a clinical state associated with <55mg/dl or low plasma glucose with typical symptoms.

Whipples triad

1) Symptoms consistent with hypoglycemia

2) Low plasma glucose concentration

3) Relief of those symptoms after the plasma glucose level is raised

Risk factors

insulin doses are excessive, ill-timed, or of the wrong type

influx of exogenous glucose

insulin-independent glucose utilization

sensitivity to insulin

endogenous glucose production

insulin clearance

The Journal of Clinical Endocrinology & Metabolism

March 1, 2009 vol. 94 no. 3 709-728

Clinical features

MILD HYPOGLYCEMIA

- mainly adrenergic or cholinergic symptoms

Pallor

Diaphoresis

Tachycardia

Palpitations

Hunger

Paresthesias

Clinical features

MODERATE HYPOGLYCEMIA (<40 mg/dL)

- mainly neuroglycopenic symptoms

Inability to concentrate Confusion

Slurred speech Irrational behaviour

Slower reaction time Blurred vision

Somnolence Extreme fatigue

Clinical features

SEVERE HYPOGLYCEMIA (<20 mg/dL ) Associated with severe impairment of

neurologic function

Completely disoriented behavior

LOC

Coma

Seizures

Treatment

MILD HYPOGLYCEMIA Oral carbohydrates (at least 15gm)

Sources include

• Three glucose tablets (5g each)

• 2 ½ cups of fruit juice

• ½ to ¾ cup regular soda

• 1 cup of milk

If patient is unable to take orally give IV dextrose

Treatment

MODERATE TO SEVERE HYPOGLYCEMIA Dextrose - 50mL of 50% dextrose IV bolus followed by

10% dextrose

Glucagon – 1mg IM or SC can be given

Effective in treating hypoglycemia only if sufficient liver glycogen present

These measures raise blood glucose only transiently

Patient is urged to eat as soon as possible

Prevention

Patient education

Knowing signs and symptoms of hypoglycemia

Take meals on a regular schedule

Carry a source of carbohydrate

Self monitoring of blood glucose

Take regular insulin at least 30 min before eating

Complications of DKA

• Infection

– Precipitates DKA

– Leukocytosis can be secondary to

acidosis

• Shock

– If not improving with fluids r/o MI

• Vascular thrombosis

– Severe dehydration

– Cerebral vessels

– Occurs hours to days after DKA

• Pulmonary Edema

– Result of aggressive fluid

resuscitation

• Cerebral Edema

– First 24 hours due to aggressive

correction of hypoglycemia or

administration of hypotonic

solution

– c/p: Mental status changes

– Tx: Mannitol

– May require intubation with

hyperventilation


Mechanism:

• The brain adapts by producing intracellular osmoles (idiogenic

osmoles) which stabilize the brain cells from shrinking while the

DKA was developing.

• When the hyperosmolarity is rapidly corrected, the extracellular

fluids is corrected faster than brain cells

– The brain becomes more hypertonic than the extracellular fluids

water flows into the cells cerebral edema


The many factors have been implicated:

Rapid and/or sharp decline in serum osmolality with treatment.

High initial corrected serum Na concentration.

High initial serum glucose concentration.

Failure of serum Na to raise as serum glucose falls during

treatment.

Glucose

Presentations of Cerebral Edema

Cerebral Edema Presentations include:

Deterioration of level of consciousness.

Headache and blurring of vision

Vomiting

Convulsion.

Treatment of Cerebral Edema

• Reduce IV fluids

• Raise foot of Bed

• IV Mannitol

• Elective Ventilation

• Dialysis if associated with fluid overload or renal failure.

• Use of IV dexamethasone is not recommended.

Prevention of DKA

• Never omit insulin

– Cut long acting in half

• Prevent dehydration and hypoglycemia

• Monitor blood sugars frequently

• Monitor for ketosis

• Provide supplemental fast acting insulin

• Treat underlying triggers

• Maintain contact with medical team

Pitfalls in DKA

• Plasma glucose is usually high but not always

– DKA can be present with RBS < 300 due to

• Impaired gluconeogenesis– Liver disease

– Acute alcohol ingestion

– Prolonged fasting

– Insulin-independent glucose is high (pregnancy)

• Chronic poor control but taking insulin

• Ketone in urine may be –ve in DKA, but always +ve in blood

– Due to measurement of acetoacetic acid in urine not, betahydroxybuteric acid

– Acetone in blood should be done in this case

Pitfalls in DKA

• High WBC may be present without infection

• Infection may be present without fever

• High Creatinine may be present without true renal

function: it may cross react with ketone bodies.

• Blood urea may be elevated with prerenal azotemia

secondary to dehydration.

• Serum amylase is often raised even in the

absence of pancreatitis

First step into insulin

therapy

(How to start insulin in a patient not controlled on OADs)

Basal insulins

NPH

• Humulin N (Eli Lilly)• Insulatard (Novo)

(also available as insulatard Novolet pen)• Dongsulin N (Highnoon)• Insuget N (Getz)===========================================

AnalogsGlargine (Lantus)Lantus Solostar Pen (Sanofi Aventis)

Detemir (Levimir) by Novo

Basal Insulins

Insulin Type Onset of

action

Peak of

action

Duration

of action

NPH Intermediate

acting1-2 hours 5-7 hours 13-18

hours

Glargine

(Lantus)

Aventis

Long

acting

1-2 hours Relatively

flat

Upto 24

hours

Detemir(Levimir)Novo

Long

acting

2-4 hours 8-12 hours 16-20

hours

The time course of action of any insulin may vary in different individuals, or at different times in

the same individual. Because of this variation, time periods indicated here should be considered

general guidelines only.

Bolous insulins (Mealtime or prandial)

Human Regular• Humulin R (Eli Lilly)• Actrapid (Novo) (Also available as Actrapid novolet pen)• Dongsulin R (Highnoon)• Insuget R (Getz)==========================================

Analogs• Lispro (Humolog) by Eli Lilly• Novorapid by Novo• Aspart• Glulisine (Apidra) by Sanofi Aventis

Bolous insulins (Mealtime or prandial)

Insulin Type Onset of

action

Peak of

action

Duration of

action

Human

regular

Short acting 30-60 minutes 2-4 hours 8-10 hours

Insulin

analogs

(Lispro,Aspart,

Glulisine)

Rapid acting 5-15 minutes 1-2 hours 4-5 hours

The time course of action of any insulin may vary in different individuals, or at

different times in the same individual. Because of this variation, time periods

indicated here should be considered general guidelines only.

Pre mixed

70/30 (70% N,30% R)

• Humulin 70/30 (Eli Lilly)• Mixtard 30 (Novo)

(Also available as Mixtard 30 Novolet Pen)• Dongsulin 70/30 (Highnoon)• Insuget 70/30 (Getz)===================================

Analogs

• Novomix 30 (Novo)• Humolog Mix 25(Lilly)• Humolog Mix 50(Lilly)

Types of Insulin

1. Rapid-acting

2. Short-acting

3. Intermediate-acting

4. Premixed

5. Long-acting

6. Extended long-acting

(Analogs)

(Regular)

(NPH)

(70/30)

(Lantus)

Indications for Insulin Use in Type 2 DiabetesPregnancy (preferably prior to pregnancy)

Acute illness requiring hospitalization

Perioperative/intensive care unit setting

Postmyocardial infarction

High-dose glucocorticoid therapy

Inability to tolerate or contraindication to oral antiglycemic agents

Newly diagnosed type 2 diabetes with significantly elevated blood

glucose levels (pts with severe symptoms or DKA)

Patient no longer achieving therapeutic goals on combination

antiglycemic therapy

Inadequate

Non pharmacological

therapy

1oral agent2 oral

agents

3 oral

agents

Add Insulin Earlier in the Algorithm

•Severe symptoms

•Severe

hyperglycaemia

•Ketosis

•pregnancy

Proposed Algorithm of therapy for Type 2

Diabetes

First step intoInsulin therapy

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Advantages of Insulin Therapy

• Oldest of the currently available medications, has the most clinical experience

• Most effective of the diabetes medications in lowering glycemia

– Can decrease any level of elevated HbA1c

– No maximum dose of insulin beyond which a therapeutic effect will not occur

• Beneficial effects on triglyceride and HDL cholesterol levels

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Disadvantages of Insulin Therapy

• Weight gain ~ 2-4 kg

– May adversely affect cardiovascular health

• Hypoglycemia

– However, rates of severe hypoglycemia in patients with type 2 diabetes are low…

Type 1 DM: 61 events per 100 patient-years

Type 2 DM: 1-3 events per 100 patient-years


The ADA Treatment Algorithm for the Initiation and Adjustment of Insulin

Initiating and Adjusting Insulin

Continue regimen; check

HbA1c every 3 months

If fasting BG in target range, check BG before lunch, dinner, and bed.

Depending on BG results, add second injection (can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)

Recheck pre-meal BG levels and if out of range, may need to add another

injection; if HbA1c continues to be out of range, check 2-hr postprandial levels

and adjust preprandial rapid-acting insulin

If HbA1c ≤7%...

Bedtime intermediate-acting insulin, or

bedtime or morning long-acting insulin (initiate with 10 units or 0.2 units per kg)

Check FG and increase dose until in target range.

If HbA1c 7%...

Hypoglycemia

or FG >3.89 mmol/l (70 mg/dl):Reduce bedtime dose by ≥4 units

(or 10% if dose >60 units)

Pre-lunch BG out of range: add

rapid-acting insulin at breakfast

Pre-dinner BG out of range: add NPH insulin at

breakfast or rapid-acting insulin at lunch

Pre-bed BG out of range: add

rapid-acting insulin at dinner



Target range:3.89-7.22 mmol/L

(70-130 mg/dL)

Nathan DM et al. Diabetes Care. 2006;29(8):1963-72.

If HbA1c ≤7%... If HbA1c 7%...

Step One…








If HbA1c ≤7%...




If HbA1c 7%...

Hypoglycemia












(70-130 mg/dL)



Step One: Initiating Insulin

• Start with either…

– Bedtime intermediate-acting insulin or

– Bedtime or morning long-acting insulin

Insulin regimens should be designed taking

lifestyle and meal schedules into account


Step One: Initiating Insulin, cont’d

• Check fasting glucose and increase dose until in target range

– Target range: 3.89-7.22 mmol/l (70-130 mg/dl)

– Typical dose increase is 2 units every 3 days, but if fasting glucose >10 mmol/l (>180 mg/dl), can increase by large increments (e.g., 4 units every 3 days)


• If hypoglycemia occurs or if fasting glucose < 3.89 mmol/l (70 mg/dl)…– Reduce bedtime dose by ≥4 units or 10%

if dose >60 units

Step One: Initiating Insulin, cont’d


Reduction in overnight and fasting glucose levels achieved by adding basal insulin may be sufficient to reduce

postprandial elevations in glucose during the day and facilitate the achievement of target A1C concentrations.

While using basal insulin alone,never stop or reduce ongoing oral therapy

• If HbA1c is <7%...

– Continue regimen and check HbA1c every 3

months

• If HbA1c is ≥7%...

– Move to Step Two…

After 2-3 Months…


With the addition of basal insulin and titration

to target FBG levels, only about 60% of

patients with type 2 diabetes are able to achieve

A1C goals < 7%.[36] In the remaining patients

with A1C levels above goal regardless of

adequate fasting glucose levels, postprandial

blood glucose levels are likely elevated.








If HbA1c ≤7%...




If HbA1c 7%...

Hypoglycemia












(70-130 mg/dL)


Step Two…


Step Two: Intensifying InsulinIf fasting blood glucose levels are in target range but HbA1c ≥7%, check blood glucose before lunch, dinner, and bed and add a second injection:

• If pre-lunch blood glucose is out of range,

add rapid-acting insulin at breakfast

• If pre-dinner blood glucose is out of range,

add NPH insulin at breakfast or rapid-acting insulin at lunch

• If pre-bed blood glucose is out of range,

add rapid-acting insulin at dinner


Making Adjustments

• Can usually begin with ~4 units and adjust by 2 units every 3 days until blood glucose is in range


When number of insulin Injections increase from 1-2………..Stop or taper of insulin secretagogues

(sulfonylureas).

• If HbA1c is <7%...

– Continue regimen and check HbA1c every 3 months

• If HbA1c is ≥7%...

– Move to Step Three…

After 2-3 Months…










If HbA1c ≤7%...




If HbA1c 7%...

Hypoglycemia












(70-130 mg/dL)


Step Three…

Step Three: Further Intensifying Insulin

• Recheck pre-meal blood glucose and if out of range, may need to add a third injection

• If HbA1c is still ≥ 7%

– Check 2-hr postprandial levels

– Adjust preprandial rapid-acting insulin


Premixed Insulin

• Not recommended during dose adjustment

• Can be used before breakfast and/or dinner if the

proportion of rapid- and intermediate-acting

insulin is similar to the fixed proportions

available


Key Take-Home Messages• Insulin is the oldest, most studied, and most effective

antihyperglycemic agent, but can cause weight gain (2-4 kg) and hypoglycemia

• Insulin analogues with longer, non-peaking profiles may decrease the risk of hypoglycemia compared with NPH insulin

• Premixed insulin is not recommended during dose adjustment

Key Take-Home Messages, cont’d

• When initiating insulin, start with bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin

• After 2-3 months, if FBG levels are in target range but HbA1c

≥7%, check BG before lunch, dinner, and bed,and, depending on the results, add 2nd injection (stop sulfonylureas here)

• After 2-3 months, if pre-meal BG out of range, may need to add a 3rd injection; if HbA1c is still ≥7% check 2-hr postprandial levels and adjust preprandial rapid-acting insulin.

Regimen # 2

First calculate total

daily dose of insulin

Body weight in kgs / 2

•e.g; an 80 kg person will require roughly about

40 units / day.

Dose calculation……..contd

Split the total calculated dose into 4 (four) equal s/c

injections.

–¼ of total dose as regular insulin s/c half-hour

( ½ hr ) before the three main meals with 6 hrs

gap in between.

–¼ total calculated dose as NPH insulin s/c at

11:00 p.m. with no food to follow.

Dose calculation: example

For example in an 80-kg diabetic requiring 40 units per day, start with:

•08:00 a.m. --- 10 units regular insulin s/c ½ hr before breakfast.

•02:00 p.m. --- 10 units regular insulin s/c ½ hr before lunch.

•08:00 p.m. --- 10 units regular insulin s/c ½ hr before dinner.

•11:00 p.m. --- 10 units NPH/ lantus insulin s/c

Dose adjustment

•For adjustment of dosage, check fasting

blood sugar the next day and adjust the

dose of night time NPH Insulin

accordingly i.e. keep on increasing the

dose of NPH by approximately 2 units

daily until you achieve a normal fasting

blood glucose level of 80-110 mg/dl.

Control BSF by adjusting

the prior the dose of NPH

Dose adjustment…contd.• Once the fasting blood glucose has been

controlled, check 6-Point blood sugar as follows:

– Fasting. – 2 hours after breakfast. – Before lunch (and noon insulin) – 2 hours after lunch. – Before dinner (AND EVENING INSULIN)

– 2 hours after dinner

Dose adjustment…contd.

• Now control any raised random reading by adjusting the dose of previouslyadministered regular insulin.

• For example: a high post lunch reading will NOT be controlled by increasing the dose of next insulin (as in sliding scale), rather adjustment of the pre-lunch regular insulin on the next day will bring down raised reading to the required levels.

Examples

•For the following profile:

–Blood sugar fasting = 180 mg/dl

–Blood sugar after breakfast = 250 mg/dl.

–Blood sugar pre lunch = 190 mg/dl

–Blood sugar post lunch 270 = mg/dl

–Blood sugar pre dinner = 200 mg/dl

–Blood sugar post dinner 260 = mg/dl

•We need to increase the dose of NPH at night to bring down baseline sugar level

(BSF) to around 100 mg/dl after which the profile should

automatically adjust as follows:

–Blood sugar fasting = 100 mg/dl

–Blood sugar 02 hrs after breakfast = 170 mg/dl

–Blood sugar pre-lunch = 110

mg/dl –Blood sugar 2 hrs. after

lunch = 190 mg/dl–Blood sugar pre-dinner =

120 mg/dl –Blood sugar 2 hrs. post

dinner = 180 mg/dl

Examples……contd.•Blood sugar fasting = 130 mg/dl •Blood sugar after breakfast = 160 mg/dl•Blood sugar pre-lunch = 130 mg/dl •Blood sugar post lunch = 240 mg/dl•Blood sugar pre-dinner = 180 mg/dl •Blood sugar 2 hrs. post dinner = 200 mg/dl

•This patient needs adjustment of pre-lunch regular Insulin which will bring down post lunch and pre dinner

readings within normal limits.

•2 hrs post dinner blood sugar(200 mg/dl) will be brought down by adjusting pre dinner regular insulin.

Combinations

•In types 2 subjects, once the blood sugar profile is normalized and the patient is not under any stress, the

total daily dose (morning + noon + night + NPH at 11 p.m) may be

divided into two 12 hourly injections of premixed Insulin

Examples….contd.•e.g-1; If a patient is

stabilized on •10U R + 12U R +

10U R + 12U NPH;•then he may be

shifted to•44/2 = 22 units of

70/30 Insulin 12hourly s/c ½ hr before

meal.

•e.g-2; If the adjusted Insulin is

•14U R+16U R+12U R+8U NPH,

•then split the total dose:

30 U 70/30 before breakfast and 20U

70/30 before dinnerto compensate for the high morning and lunch

Insulin.

Combinations………contd.

•Problem: Remember that BD dosing usually fails to cover lunch, especially if it is heavy. So:

•Always check for post lunch hyperglycemia when using this regimen.

•Solution:.1Patients can be advised to take their lunch (heavier

meal) at breakfast; and breakfast (lighter meal) at lunch.

.2Adding Glucobay with lunch some times provides a reasonable control.

.3An alternate combination to overcome the problem is regular insulin for morning and noon, with premixed

insulin at night.

Example •10U R before breakfast + 12U R

before lunch + 22U 70/30 before dinner.

•Insulin will be injected exactly 6 hrsapart as in the QID regimen.

Choice of regimens

.1R+ R+ R+ L****

.2R+ R+ R+ N ***

.3R+ R+ premixed insulin**

.4BD premixed insulins*

Regimen # 3

(Pre mixed)

How to start pre mixed (70/30) Insulin

For pre mixed insulins(70/30 preparations)

Step1:First calculate the total daily starting requirement

of insulin;

body weight(kg)/2

eg, For a 60kg patient,total daily dose =30 units

Step 2:Then devide this dose into 3 equal parts;

10+10+10

Step 3:Give 2 parts in the morning and 1 part in the

evening;

Morning=20U Evening=10 U

Dose titration of Pre-mixed(70/30)

preparations

You can increase or decrease the dose of

pre-mixed insulin by 10 % i.eIf the patients is using,

1-10 units…………….+/- 1 unit

11-20 units……………+/- 2 units

21-30 units……………+/- 3 units

31-40 units……………+/- 4 units…………………..

Advantages and disadvantages of premixed insulins

Advantages:Easy to administer for the physician.

Easy to fill and inject by the patient.

Provides both basal and bolus coverage with fewer number of injections.

Disadvantage:

No dose flexability

If u increase/decrease the dose of one component ,the dose of other component is also changed un desirably

How to solve the problem of nocturnal hypoglycemia

Somogyi phenomenon• Due to

– excess dose of night time insulin, or– Night insulin taken early

• Peaks at 3:00 a.m: hypoglycemia• Counter regulatory hormones released in excess:• Resulting in over correction of hypoglycemia:• Fasting hyperglycemia

• Solution:– Check BSL AT 3 :00 a.m– Give long acting at 11:00 p.m so peak comes

later– Reduce dose of night time insulin

Dawn phenomenon• Growth hormone surge at dawn raises insulin

requirement. • Night time insulin taken early, fades out before

dawn. • Fasting hyperglycemia

Solution• Give long acting insulin not before 11 :00 p.m

• May need to increase dose of night time insulin

Injection Techniques

Sites of injection•Arms

•Legs

•Buttocks

•Abdomen

Sites of injection…….contd.• Preferred site of injection is the

abdominal wall due to

• Easy access – Ample subcutaneous tissue

• Absorption is not affected by exercise.

Injection technique

Technique • Tight skin fold

• Spirit…. X

• Appropriate needle size

• 90 degree angle

• Change site to avoid lipodystrophy

Injection technique…….contd.

INSTRUCTIONS:Keep the needle perpendicular to skin in order to avoid variability in absorption (fig-A) Insert needle upto the hilt (fig-A)Distribute daily injections over a wide area to avoid lipodystrophy and other local complications (fig-B)

Storage

• Injections: refrigerate

• Pens: do not refrigerate

Shelf life•One month

once opened

Thank you allFor

Sparing your valuable time

&

Patient listening

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Health & Medicine

CME Sohag | internal medicine | Diabetes mellitus