DIABETES MELLITUS DIABETES MELLITUS TYPE 1 & TYPE 1 &

MANAGEMENT OF MANAGEMENT OF DIABETIC DIABETIC

KETOACIDOSIS KETOACIDOSIS PRESENTED BY

DR ASHISH SHARMA GUIDED BY

DR MEENA PATEL

DEFINITION

Metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects of insulin secretion, insulin action or both.

OLD CLASSIFICATION (1985)

Type 1, Insulin-dependent (IDDM) Type 2, Non Insulin-dependent (NIDDM)

– obese– non-obese– MODY

IGT Gestational Diabetes

WHO CLASSIFICATION 2000

Is based on etiology not on type of treatment or age of the patient.

Type 1 Diabetes (idiopathic or autoimmune β-cell destruction) Type 2 Diabetes

(defects in insulin secretion or action) Other specific types

Both type 1 & type 2 can be further subdivided into:Not insulin requiringInsulin requiring for controlInsulin requiring for survival

Type 1 Diabetes Mell i tus

Formerly called insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes

T1DM is characterized by low or absent levels of endogenously produced insulin

EPIDEMIOLOGY • The onset occurs predominantly in

childhood, with median age of 7-15 yr, but it may present at any age.

• Indian data suggest an incidence of 10.5/100,000/yr .

• India would have 79 million diabetes by 2030, the highest for any country in the world.

Pathogenesis & Natural history

The natural history includes distinct stages1) Initiation of autoimmunity 2)Preclinical autoimmunity with progressive loss of β-cell function3)Onset of clinical disease4)Transient remission( “Honeymoon period”)5)Established disease6)Development of complications

Both genetic ,environmental and autoimmune factors contribute to the pathogenesis.

Genetic factors- Genetic susceptibility to T1DM is determined by several genes .HLA complex accounts for almost 50 % of genetic risk for type 1 diabetes.Some of the known associations include the HLA DR3/4-DQ2/8 genotype

Association with DR3 has been reported in Indians.

Risk of diabetes is also increased when a parent has diabetes and this risk differs between the 2 parents; the risk is 2% if the mother has diabetes, but 7% when the father has diabetes.

In monozygotic twins, the concordance rate ranges from 30-65%, whereas dizygotic twins have a concordance rate of 6-10%.

Envoirmental factors Many envoirmental agents are thought to

trigger the development of type 1 diabetes including,

Viral infections- Enterovirus , mumps , rubella

Diet- Breast-feeding may lower the risk of T1DM.

Early introduction of cow's milk protein and early exposure to gluten have both been implicated in the development of autoimmunity

Autoimmune factorsWhatever the triggering factor, it seems that in most cases of T1DM that are diagnosed in childhood.

The 1st signs of autoimmunity appear before age 2 yr.

Insulin associated antibodies (IAA)

↓

Glutamic acid decarboxylase 65 kd (GAD65)

&

tyrosine phosphatase insulinoma-associated

. The earliest antibodies are predominantly of the IgG1 subclass

The appearance of autoimmunity is followed by progressive destruction of β cells.

Antibodies are a marker for the presence of autoimmunity, but the actual damage to the β cells is primarily T-cell mediated

PathophysiologyInsulin performs a critical role in the storage and retrieval of cellular fuel.

In normal metabolism, there are regular swings between the postprandial, high-insulin anabolic state and the fasted, low-insulin catabolic state that affect liver, muscle, and adipose tissue

Pathophysiology….T1DM is a progressive low-insulin catabolic state in which feeding does not reverse but rather exaggerates these catabolic processes.

At even lower insulin levels, the liver produces excessive glucose via glycogenolysis and gluconeogenesis, and fasting hyperglycemia begins.

Pathophysiology….Hyperglycemia produces an osmotic diuresis (glycosuria) when the renal threshold is exceeded (180 mg/dL; 10 mmol/L). The resulting loss of calories and electrolytes, as well as the persistent dehydration, produce a physiologic stress with hypersecretion of stress hormones (epinephrine, cortisol, growth hormone, and glucagon)

Pathophysiology….These hormones, in turn, contribute to the metabolic decompensation by promoting glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis (glucagon, epinephrine, growth hormone, and cortisol) while decreasing glucose utilization and glucose clearance.

CLINICAL PRESENTATIONS

Classical symptom triad: polyuria, polydipsia and weight loss

DKAAccidental diagnosisAnorexia nervosa like illness

DIAGNOSTIC CRITERIA Fasting blood glucose

level Diabetic

Plasma >7.0 mmol/ 126mg/dl

Capillary >6.0 mmol IGT Plasma 6.0-6.9 mmol Capillary 5.6-6.0 mmol

2 hours after glucose load

(Plasma or capillary BS) IGT

7.8-11.0 Diabetic level

> 11.1 (200 mg)

DIAGNOSIS In symptomatic children a random

plasma glucose >11.1 mmol (200 mg) is diagnostic.

A modified OGTT (fasting & 2h) may be needed in asymptomatic children with hyperglycemia if the cause is not obvious.

Remember: acute infections in young non-diabetic children can cause hyperglycemia without ketoacidosis.

COMPLICATIONS OF DIABETES

Acute:DKAHypoglycemia

Late-onset:Retinopathy NeuropathyNephropathyIschemic heart disease & stroke

TREATMENT GOALS Prevent death & alleviate symptoms

Achieve biochemical control

Maintain growth & development

Prevent acute complications

Prevent or delay late-onset complications

TREATMENT ELEMENTS

Education Insulin therapy Diet and meal planning Monitoring

HbA1c every 2-monthsHome regular BG monitoring Home urine ketones tests when indicated

EDUCATION

Educate child & care givers about: Diabetes Insulin Life-saving skills Recognition of Hypo & DKA Meal plan Sick-day management

INSULIN A polypeptide made of 2 β-chains. Discovered by Bants & Best in 1921. Animal types (porcine & bovine) were used

before the introduction of human-like insulin (DNA-recombinant types).

Recently more potent insulin analogs are produced by changing aminoacid sequence.

FUNCTION OF INSULIN

Insulin being an anabolic hormone stimulates protein & fatty acids synthesis.

Insulin decreases blood sugar 1. By inhibiting hepatic glycogenolysis and

gluconeogenesis.2. By stimulating glucose uptake, utilization

& storage by the liver, muscles & adipose tissue.

Characteristics of Insulin

There are three characteristics of insulin:

Onset- Is the length of time before insulin reaches the bloodstream and begins lowering blood glucose.Peaktime- Is the time during which insulin is at maximum strength in terms of lowering blood glucose.Duration- Is how insulin continues to lower blood glucose.

The Basics of Insulin: 4 Types

Rapid-acting insulin

Regular or short-acting insulin

Intermediate-acting insulin

Long-acting insulin

Rapid-acting InsulinExamples: insulin lispro or insulin aspart

Onset: Begins to work at about 5 minutes

Peaktime: Peak is about 1 hour

Duration: Continues to work for about 2-4 hours

Regular or Short-acting Insulin

Examples: insulin lispro, Aspart

Onset: Reaches the bloodstream within 30 minutes after injection.

Peaktime: Peaks anywhere from 2-3 hours after injection.

Duration: Effective for approximately 3-6 hours.

Intermediate-acting Insulin

Examples:NPH, Lente

Onset: Reaches the blood stream about 2 to 4 hours after injection.

Peaktime: Peaks 4-12 hours later.

Duration: Effective for about 12 to 18 hours

Long-acting Insulin

Examples: insulin glargine

Onset: Reaches the bloodstream 6-10 hours after injection

Duration: Usually effective for 20-24 hours

INSULIN CONCENTRATIONS

Insulin is available in different concentrations

40, 80 & 100 Unit/ml.

WHO now recommends U 100 to be the only

used insulin to prevent confusion.

Special preparation for infusion pumps is

soluble insulin 500 U/ml.

Insulin Pump Therapy Continuous subcutaneous insulin infusion

(CSII) via battery-powered pumps provides a

closer approximation of normal plasma

insulin profiles.

It accurately deliver a small baseline

continuous infusion of insulin, coupled with

parameters for bolus therapy.

The bolus insulin determined by amount of

carbohydrate intake and blood sugar level

INSULIN REGIMENS Twice daily: either NPH alone or

NPH+SI. Thrice daily: SI before each meal and

NPH only before dinner. Intensive 4 times/day: SI before meals

+ NPH or Glargine at bed time. Continuous s/c infusion using pumps

loaded with SI.

NEW INSULIN PREPARATIONS

Inhaled insulin proved to be effective & will be available within 2 years.

Nasal insulin was not successful because of variable nasal absorption.

Oral insulin preparations are under trials.

ADVERSE EFFECTS OF INSULIN

Hypoglycemia Lipoatrophy Lipohypertrophy Obesity Insulin allergy Insulin antibodies Insulin induced edema

PRACTICAL PROBLEMS

Non-availability of insulin in poor countries injection sites & technique Insulin storage & transfer Mixing insulin preparations Insulin & school hours Adjusting insulin dose at home Sick-day management Recognition & Rx of hypo at home

DIET REGULATION Regular meal plans with calorie exchange

options are encouraged. 50-60% of required energy to be obtained

from complex carbohydrates. Distribute carbohydrate load evenly during

the day preferably 3 meals & 2 snacks with avoidance of simple sugars.

Encouraged low salt, low saturated fats and high fiber diet.

EXERCISE Decreases insulin requirement in

diabetic subjects by increasing both sensitivity of muscle cells to insulin & glucose utilization.

It can precipitate hypoglycemia in the unprepared diabetic patient.

It may worsen pre-existing diabetic retinopathy.

MONITORING

Compliance (check records) HBG tests HbA1 every 2 months Insulin & meal plan Growth & development Well being & life style School & hobbies

ADVANCES IN MONITORING

Smaller & accurate meters for intermittent BG monitoring

Glucowatch continuous monitoring using reverse iontophoresis to measure interstitial fluid glucose every 20 minutes

Glucosensor that measures s/c capillary BG every 5 minutes

Implantable sensor with high & low BG alarm

ADVANCES IN MANAGEMENT

Better understanding of diabetes allows more rational approach to therapy.

Primary prevention could be possible if the triggering factors are identified.

The DCCT studies proves beyond doubt that chronic diabetic complication can be controlled or prevented by strict glycemic control.

TREATMENT MADE EASY

Insulin pens & new delivery products Handy insulin pumps Fine micro needles Simple accurate glucometers Free educational material Computer programs for comprehensive

management & monitoring

TELECARE SYSTEMS

IT has improved diabetes care Internet sites for education & support Web-based systems for telecare are

now available. The patient feeds his HBGM data and get the physician, nurse & dietician advice on the required modification to diet & insulin treatment.

PITFALLS OF MANAGEMENT

Delayed diagnosis of IDDM The honey-moon period Detection & treatment of NIDDY Problems with diagnosis & treatment of

DKA & hypoglycemia Somogyi’s effect & dawn phenomenon

may go unrecognized.

FUTURE PROMISES The cure for IDDM is successful islet cell

transplantation, which will be available in the near future.

Primary prevention by a vaccine or drug will be offered to at risk subjects identified by genetic studies.

Gene modulation therapy for susceptible subjects is a promising preventive measure.

Pancreas & Islet Cell Transplantation

Pancreas transplants are usually given to diabetics with end stage renal disease.

Islet cell transplants, the ultimate treatment of type 1 diabetes is under trial in many centers in the US & Europe with encouraging results but graft rejection & recurrence of autoimmunity are serious limitations.

IMMUNE MODULATION Immunosuppressive therapy for

Newly diagnosedProlonged the honey moonFor high risk children

Immune modulating drugsNicotinamidemycophenolate

GENE THERAPY

Blocks the immunologic attack against islet-cells by DNA-plasmids encoding self antigen.

Gene encode cytokine inhibitors. Modifying gene expressed islet-cell

antigens like GAD.

PREDICTION OF DIABETES

Sensitive & specific immunologic markersGAD AntibodiesGLIMA antibodiesIA-2 antibodies

Sensitive genetic markers• HLA haplotypes• DQ molecular markers

PREVENTION OF DIABETES

Primary prevention• Identification of diabetes gene• Tampering with the immune system• Elimination of environmental factor

Secondary prevention• Immunosuppressive therapy

Tertiary prevention• Tight metabolic control & good monitoring

.

MANAGEMENT OF

DIABETIC KETOACIDOSIS

. INTRODUCTION DKA,a life threatning complication of

diabetes mellitus,occurs more commonly in children with type 1 DM than type 2 DM.

Hyperglycemia,metabolic acidosis, ketonemia,dehydration and vaious electolyte abnormalities result from a relative and absolute deficiency of insulin with or without excess of counter regulatory hormones

. Definition DKA in children is defined as

hypgerglycemia(serum glucose conc. >200-300mg/dl) in the presence of metabolic acidosis (blood pH<7.3 with serum bicarbonate level<15 mEq/L) and ketonemia(presence of ketones in blood).

When measured sr ketones (b hydroxy butyrate plus acetoacetate)exceed 31 mg/dl with or without ketonuria >80mg/dl

. CLINICAL HISTORY Polyuria Polydipsia Weight loss Nausea,vomiting,abdominal pain Headache Restlessness,irritability Lethargy,altered sensorium,loss of

conciousness Fever

.EXAMINATIONFruity odour in breathTachycardiaLow volume pulsesHypotensionImpaired skin turgorDelayed capillary refill timeDehydrationRapid,Deep sighing respiration Kussumaul respiration(met. Acidosis)Bradycardia,hypertension,pappiloedemaAbnormal pupillary reflex,cranial n. palsyposturing

.Biochemical signs• Ketones in urine• Elevated blood glucose(>200 mg%)• Acidemia(pH<7.3)• Collect blood for RFT , CBC, SGOT, SGPT,

BloodC/S (if evidence of infection)

.

Confirm diagnosis of Diabetic Ketoacidosis

.

Mild:pH<7.3, bicarbonate<15mmol/litModerate :pH<7.2, bicarbonate<10 mmol/litSevere:pH<7.1,bicarbonate<5 mmol/lit

.

ShockReduced

peripheral Pulse volume

Reduced concious

Dehdration>5%Not in shock

Clinically acidotic

Vomitiing

Dehydration <5%clinically

.

Resuscitation

Airway+NG tubeCirculation(10-20ml/kg of 0.9%

NS over 30-60 mins)Repeat if necessary- initial

expansion should not exceed total 30 ml/kg

Intravenous therapyCalculate fluid requirments

(maintainence + deficit)Correct over 24 hrs with 0.9NS for first 8-12 hrs followed by 0.45%NS(Add KCl 40 mEq/L)

Start insulin infusion 0.1 u/kg/hrECG for hypo/hyperkalemic

changes

Start with subcutaneous insulin

0.25U/kg 3-4hrly

No improvement

.

Monitoring•Hourly blood glucose•Neurological status

atleast hourly•Hourly fluid input

output•Electrolytes and then

4hrly•Blood gas at

admission and then as indicated

•Monitor ECG for hypo and hyperkalemic

changes

No improvement

Reevaluate

•Uncorrected hypovolemia

•Review dose and rate of insulin

infusion

•Neurological deterioration warning signs

•Headache•Irritability

•Slowing heart rate•Reduced

conciousness level•Hypertension•Bradycardia

•Pupillary inequality

Consider Cerebral

Edema(Exclude Hypoglycemia)

.Intravenous therapy

•Consider fluid to 0.45 NS +dextrose 5%•Continue monitoring as above•Consider reducing Insulin 0.05 U/kg/hr when >pH.7.3,blood glucose <250 mg% and dextrose containing fluid has been started,

Improvement•No emesis•Normal electrolytes•CO2 >16mEq/L•pH>7.3

InsulinStart subcutaneius insulin and then stop iv insulin infusion 1 hr later

DIABETIC KETOACIDOSIS TREATMENT PROTOCOL.

1ST hr 10-20 ml/kg IV bolus 0.9% NaCl or LRInsulin drip at 0.05 to 0.10 u/kg/hr

Quick volume expansion;may be repeated.NPO.Monitor I/O,neurological status.Usefloe sheet. Have Mannitol at bedside;1 g/kg IV push for cerebral edema

2nd hr until DKA resolution

0.45%NaCl:plus continue Insulin drip20 mEq/l Kphos and 20 mEq/l Kac.5% glucose if blood sugar <250 mg/dl

IV rate= 85 ml/kg+maintainence-bolus/23hr

If K<3mEq/L,give 0.5 to 1 mEq/kg as oral K solution OR increase IV K to 80 mEq/L

Variable Oral intake with subcutaneous insulin

No emesis;CO2> 16 mEq/L;normal electrolytes

TIME THERAPY COMMENTS

.• Note that initial IV bolus is considered as

part of the total fluid allowed in the 1st 24 hr and is sutracted before calculating the IV rate.

• Sample calculation for a 30 kg child:• 1st hr=300ml IV bolus 0.9%NaCl or LR• 2nd and subsequent hrs=(85x30)+1750-

300/23=175 ml/hr• (0.45%NaCl with 20 mEq/L Kphos and 20

mEq/L Kac)

.

• The Milwaukee protocol can be used for children of all ages and with all degree of DKA.

• Children with milder DKA recover in 10-20 hr(and need less total IV fluid before switching to oral intake.)

• Those with more severe DKA require 30-36 hrs with this protocol.

• Blood testing should occur every 1-2 hr for children with severe DKA and 3-4 hr for those with mild to moderate DKA.

INSULIN THERAPYTiming-1-2 hr after starting fluid replacement.

Type-Only IV Regular insulin used for m/m of DKA.

Dose-low dose iv insulin 0.1 u/kg/hr is standard.high dose has risk of hypoglycemia,hypokalemia and rapid decline in osmolality.

Prepration-50 units diluted in 50 ml NS to arrive conc. Of 1 u/ml

Duration-administered at same rate(0.1u/kg/hr) until resolution of DKA

Dose adjustment-If hypoglycemia occurs despite increase in strength of dextrose sol. the dose of insulin reduced in decrement of 0.02u/kg/hr upto 0.05 u/kg /hr

Transition to subcutaneous insulin therapy

• As oral feeds advanced iv fluids reduced and change to subcutaneous insulin planned.

• Timing-ideal time to begin is just before a meal.• Rapid acting insulin(lispro,aspart) are

administered sc 15-30 mins prior and regular insulin 1-2 hr prior to stopping infusion to avois rebound hyperglycemia.

• Dose-For pt with DKA at ds onset,recommended TDD is 0.75-1 u/kg(pre pubertal) and 1-1.2 u/kg(pubertal).

• Before Breakfast-2/3 tdd(1/3 r.a. and 2/3 i.a. insulin)

• Before dinner-1/3 tdd(1/3 r.a. and 2/3 i.a. insulin)

Cerebral Edema.Management•Head end elevation•Give Mannitol 0.5-1 gm/kg and repeat if there is no response in 30 mins-2hrs•3% Hypertonic saline (5 ml/kg over 30 mins) can be given•Restrict iv fluids to 2/3•Replace deficit in 72 hr rather than 48 hr•Intubation and ventilation if required