DIABETES MELLITUS

Definition-- DM is a syndrome characterised by chronic hyperglycemia resulting in disturbance of carbohydrate, protein and fat metabolism due to absolute or relative deficiency in insulin secretion and/or relative insulin resistance. Incidence It is estimated that more than 171 million people have diabetes worldwide and this figure will double by the year2030. The top five countries in number of diabetes patients are India,China, United States, Indonesia and Japan.The reasons for increase in diabetes mellitus are ageing of the population,the growing population,sedentary lifestyle,changes in diet and diabetes diagnosed at lower blood glucose levels. Classification TYPE I Immune mediated Idiopathic TYPE II Insulin resistance with relative insulin deficiency TYPE III: specific types Genetic defects of B cell function or insulin function. Pancreatic disease Endocrinal: Acromegaly, Cushing, Glucaganoma, Phaeochromocytoma, Thyrotoxicosis. Drugs: corticosteroids, thiazides, phenytoin, Viral infections Genetic syndromes: Downs, Turners, Kleinfelters, TYPE IV Gestational diabetes

Salient Features of Type 1 amd Type 2 DM

FEATURES GENETIC LOCUS FAMILY HISTORY AGE OF ONSET DURATION BODY WEIGHT INSULIN TYPE I Chromosome 6 Uncommon < 30 yrs Weeks Lean Low or absent TYPE II Multifactorial Common > 40 yrs Months to years Obese Normal or high

GLUCOSE PRESENTATION ACUTE COMPLIT AUTOANTIBODIES INSULIN THERAPY

High , suppressible No complications DKA Present Essential Unresponsive Yes

High, resistant 25% NKHC Absent May be required late Responsive No Metabolic Syndrome

ORAL HYPOGLYCEMICS

EARLY DEATH WITHOUT RX ASSOCIATED WITH

Autoimmune diseases

Diagnosis The current criteria for diagnosis of diabetes mellitus emphasize that
the fasting plasma glucose is the most reliable and convenient test for identifying DM in asymptomatic individuals Venous Whole blood + 15% = Venous Plasma glucose glucose 1 mmol = 18 mg glucose 1 mmol/l = 18 mg/dl A random plasma glucose of more than 200mg/dl or FPG more than 126mg/dl or 2hr post load plasma glucose level more than 200 mg/dl during oral GTT accompanied by classic symptoms of DM (polyuria, polydipsia, weight loss ) is sufficient for diagnoses of DM. Screening (Risk factors) in asymtomatic adults Age > 45 yrs(30 Indian) BMI > 25 (22 Indian) Family history Habitual inactivity Race/ethnicity Previously diagnosed IFG/IGT H/o GDM/ large baby > 9 lbs (4 kgs) Hypertension HDL< 35 mg/dl or TG > 250 mg/dl PCOS or Acanthosis Nigricans H/o vascular disease Investigations Hb, TC, DC, PCV, PC Fasting sugar/RBS RFTs Urine analysis(sugars, ketones,albumin, output) 2

Serum electrolytes ABG - if acidosis is suspected ECG - to rule out asymtomatic IHD HbA1c - long term control ECHO - r/o silent MI CXR Fundal examination

Complications of DM Acute complications 1. Diabetic Ketoacidosis 2. Hyperglycaemic Hyperosmomolar State 3. Hyperglycemia 4. Hypoglycemia Chronic Complications Macrovascular Coronary artery disease Peripheral arterial disease Cerebrovascular disease Microvasclar Retinopathy Maculopathy Neuropathy Nephropathy Others

Gastrointesitinal Glaucoma Genitourinary Periodontal disease Dermatologic Infections Cataracts

Mechanisms of complication 1.Formations of advanced glycosylation end products. 2. Reduction of glucose to sorbitol which functions as a tissue toxin 3. Free radical production and reactive oxygen species formation.

Treatment Goals for adults with diabetes Therapy

1. To eliminate symptoms related to hypergycemia 2. To eliminate long term microvascular and macrovascular complications of DM 3. To allow the patient to achieve as normal a lifestyle as possible . Parameter HbAIC FBS PPBS BP LDL TG HDL Goal < 7% 90 130mg/dl <180mg/dl <130/80mm Hg <10mg/dl <150mg/dl >40mg/dl

NUTRITION Individualised diet No longer calorie restriction Well balanced diet Small frequent meals Calories consumed divided as: Breakfast: 25% Lunch: 30% Dinner: 30 % Filler & snack: 15% Calorie req: (Cal/kg/day) Near ideal wt 30 Obese or overwt 20 Underwt 40 Proteins: 12 18 % ( 0.8 gm/kg ) Fats: 20 25 %, equal amount of PUFA, saturated, monounsaturated FA; EFA ( w6:w3 = 4:1)

Metabolic Actions of Insulin

Increase anabolic carbohydrate metabolism glucose transport(muscle, adipose) glucose phosphorylation glycogenesis glycolysis pyruvate dehydrogenase activity pentose phosphate shunt lipid metabolism tg synthesis fa synthesis (liver) lipoprotein lipase activity(adipose) protein metabolism aa transport protein synthesis Decrease Anticatabolic carbohydrate metabolism gluconeogenesis glycogenolysis lipid metabolism lipolysis

 lipoprotein lipase (muscle) ketogenesis fa oxidation protein metabolism protein degradation

Indications of Insulin RX All Type I DM Gestational DM Initial stabilization of newly maintaining remission Brittle diabetes ketoacidosis Surgery Prevention/Reversal of long term complications Type II Oral Hypoglycemic drug failure

Adverse Effects
Hypoglycemia Weight gain Peripheral edema Insulin antibiotics (animal insulin) Local allergy Lipoatrophy Lipodystrophy

Insulin preparations & guidelines

Rapid acting Insulin Lispro (Humalog ) Insulin( Aspart Novolog) The altered aminoacid sequence of these analogs favour rapid subcutaneous absorptions and rapid onset Usually administered immediately prior to a meal . May be used subcutaneous or via an insulin pump but not recommended for continuous infusion. Administered around 30-60 mins before meals . Main insulin used in continuous IV infusions. Onset 5-15 min Peak Effects 60-120 mins Duration 4-5 hrs

Short acting

Regular insulin

Onset 30-60 mins Peak effects-24-hrs Duration -6-85

Intermediate acting

NPH (Neutral Protamine Hagedorn)

Made by adding protamine to insulin

hrs. Onset 1-3 hrs Peak effects 46-hrs Duration-12-14 hrs Onset 1-3hrs Peak effects 4-8 hrs Duration12-20 hrs Onset 2-4hrs Peak effects 1418hrs Duration-1824hrs Onset:1-2hrs Peakless Duration:2024hrs

Lente

Made by adding Zinc to an actate buffer solution insulin.

Long acting

Ultralente

Zinc suspension of insulin .Its peaks are less prominent than those of NPH. Another insulin analog.It most closely provides a constant basal level of insulin .It is administered at 10 pm. It cannot be mixed with other type of insulin n the same syringe .It is less likely to cause hypoglycaemia Although long acting insulins are often held or halved in dose before surgery.Glargine may be administered as usual to provide basal insulin level during surgery.Ultralente and glargin are used as basal insulin regimens. 70/30 : 70 % NPH/ 30%Regular 50/50 50% NPH / 50 %Regular 75/25 75% Insulin Neutral Protamine Lispro (NPL similar to NPH) & 25% Insulin Lispro The mixture is ntermediate in action and is usually administered twice a day and is also known as Humalog mix

Glargin

Premixed/Combination Premixed insulin formulas help to reduce the likelihood of mixing errors

70/30 Usually given before breakfast 50/50 usually given before dinner.

Oral Hypoglycaemic agents

Sulphonylureas
Mechanism of action Insulin secretagogues stimulate insulin secreation by interacting with ATP sensitive potassium channel on beta cell 6

First generation: Chlorpropramide (60 hrs) Tolbutamide (6-12) Second generation: Glibeclamide (12-24) Glipizide Third generation: Glimepride (18-24) Glipizide XL Metabolised in liver and cleared by the kidneys. Adverse effects:hypoglycaemia,weight gain,rash. Contraindications:DKA,sulfa allergy. Inhibits ishaemic preconditioning thereby increasing the risk of cardiac complications. Initial agent of choice. Sulphonylureas become less effective with progression of disease

Biguanides
Mechanism of action:Biguanides reduce hepatic glucose production and promote peripheral glucose utilization . Metformin (6-8 hrs) Metabolised by kidneys S/E: GI disturbances, lactic acidosis, vit B12 deficiency. Contraindications: hepatic/renal disease, CHF, metabolic acidosis It is commonly administered in type 2 diabetes. Preferred in hyperglycemias & obesity. Alpha glucosidase inhibitors Mechanism of action: Alpha glucosidase inhibitors delay glucose absorbtion -Acarbose -Miglitol Side effects:GI disturbances. Contraindications: cirrhosis, DKA, renal impairment, inflammatory bowel disease. Delays postprandial hyperglycemia.

Thiazolidinediones
Mechanism of action: Thiazolidinediones reduce insulin resistance by binding to receptors in the nucleus of the adipocytes -Rosiglitazone -Piaglitazone . 7 Side effect -Weight gain, raised liver enzymes,induces ovulation. Contraindications:CHF,DKA

Meglitinides
Ripaglinide Nateglinide Side effects Hypoglycemia Contraindications: DKA They have a short duration of action,hence they can be safely continued until cessation of regular meals and restarted on return to oral feeding.

Pramlintide Amylin analogue

Amylin is a pancreatic beta cell hormone co secreted with insulin. Mechanism: Regulation of gastric emptying, limiting the rate of delivery of nutrients to absorptive surfaces Supression of post prandial glucagon secretion Replinishment of hepatic glycogen stores

Future Therapies
Implanted glucose analyzer (with electric transmission to surface watch) A Glucagon like peptide receptor antagonist such as GIP 1Decreased appetite,decreased glucose output and regeneration of Bcells.Will revolutionise the treatment of diabetes Islet cell transplants medications INGAP peptide- regrowth of normally functioning islet cells without the need of transplants.

Glycemic management of type 1 diabetes:

Require insulin all the times.and benefit from tight control of blood glucose levels to retard glucotoxicities..

Glycemic management of type 2 diabetes

Patient with type 2 diabetes

Medical nutrition therapy increased physically activity weight loss + metformin

Reassess A1C

Combination therapy Metformin + second agent Reassess A1C Combination therapy metformin + two other agents Reassess A1C Insulin + metformin

Anaesthetic considerations: 1CVS Considerations Increase chances of CAD ( males- double risk, females tripple risk ) Increase chances of silent MI Decrease threshold of arrythmias Cardiac dysautonomia Sudden hypotension on induction Absence or exaggerated intubation response Diabetic cardiomyopathy 2CNS:Increase chances of CVA

3Peripheral Nervous System:

_-

Peripheral neuropathy Nerve injury & nerve ischaemia Care at positioning & transport

Use of nerve blocks Avoid epinephrine containing LA solutions

4Autonomic Nervous System:

Gastroparesis: aspiration increased, hence need of increased preoperative fasting, rapid sequence induction & aspiration prophylaxis. Asymptomatic hypoglycemia: stringent monitoring Pressor response to intubation may be exaggerated Sudden death syndrome, Cardiac denervation: persistent intraoperative hypotension require vasopressors, increased risk of perioperative cardiac arrest. Blunted HR response to atropine requiring adrenaline Shortened QT: arrhythmias Postural hypotension: profound hypotension under regional anaesthesia. More susceptible to depressant effect of anesthetic drugs Others: gustatory sweating, diarrhoea, atonic bladder (infection), impotence

5Respiratory
Decrease ventilatory response to PaCO2 and PaO2 More chances of respiratory tract infection Increase susceptability to ventilatory depressant drugs Decrease FVC & FRC due to glycosylation of connective tissue proteins Decrease2,3-DPG decrease release of O2 to tissues Affects O2 transport by causing glucose to bind to Hb molecules and alter the allosteric binding between beta chains.

6AIRWAY Stiff joints syndrome

Restricted neck movements Restricted jaw opening Difficult intubations Exaggerated response to intubations

7RENAL SYSTEM
More chances of ARF in perioperative period Intrinsic disease Hemodynamic impairment Urosepsis UTI- most common post operative complication RF- incidence 7%,

8OTHERS
Proliferative retinopathy vitreous hemorrhages on laryngoscopy & intubaton Infection: poor wound healing, trophic ulcers, more chances of sepsis. Associated acute complications: DKA, hypoglycemia Increased risk of hypothermia.

9Problems during surgery and anaesthesia

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The perioperative problems posed by surgery in the diabetic patients are 1. Surgical induction of the stress response a. The secretion of catecholamines ,cortisol and growth hormone oppose glucose homeostasis as these hormones have anti insulin and hyperglycaemic effects Glycogenolysis and gluconeogenesis are stimulated and peripheral glucose uptake is decreased causing hyperglycemia and ketosis b. Excessive release of inflammatory cytokines such as tumor necrosis factor interleukin -1 and interleukin-6 and immobility itself is associated with reduced skeletal muscle insulin sensitivity leading to a hyperglycaemic c. In fasting patients undergoing elective intraperitoneal procedures , blood glucose levels typically increases to between 126-180 mg/dl During cardiac surgery the disturbance of glucose homeostatisis is greater with blood glucose values rising above 270 mg/dl in subjects without diabetis. Stress may precipitate diabetic crisis . (Ketoacidosis or hyperglycemic hyperosmolar coma 2. Interruption of oral intake which may be further prolonged after gastrointesitinal surgery . Starvation can lead to ketoacidosis.Preoperative insulin administration is required to control blood sugar . The patient can be reverted to his pre surgery diabetes management only after he resumes his oral intake . 3. Altered consciousness may mask the symptoms and signs of hypoglycemia

4. Circulatory disturbance associated with anaesthesia and surgery may alter the absorption of subcutaneous insulin . So intravenous administration is preferred perioperatively . 5. Hyperglycaemic is associated with increased risk of complications such as wound infection and poor neurological outcomes in susceptible patients.

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Perioperative Glycemic Control Type 1Diabetes: Require insulin and might be considered for tight control of blood glucose levels. Minor surgery: Glucos/regular insulin/potassium infusion with the start of preoperative fast. This is continued until regular diet and insulin intake is resumed. Major surgery: GIK Regimen or Albertis regime Tight control regimen Type2 Diabetes Diet controlled- treat as normal patient.Fasting blood sugar should be measured on the morning of surgery and intraoperatively On OHA:(if controlled) Long acting Suphonylureas are best discontinued 48-72 hrs before surgery. Short acting Sulphonylureas may be held the night before or morning of surgery to minimise the risk of perioperative hypoglycaemia. Metformin should be discontinued at least 1-2days prior to surgery. The drug should be withhold 72 hours following surgery or iodinated radiocontrast procedures.Can be restarted after documentation of normal renal function. -- No OHA on day of surgery On OHA if uncontrolled : Insulin (GIK) Minor surgery: GIK infusions or variable rerimen or stop insulin and direct therpy accoding to frequent glucose monitoring Major surgery: Shift to insulin GIK regimen Tight control if required Regular insulin post operativelyonce oral feeds start Glucose insulin potassium (GIK) Regimen Aim :To prevent hypoglycaemia, ketoacidosis and hypokalemia Protocol Patients with normal renal function and normal potassium levels may receive dextrose containg fluids with additional potassium (10-20 eq/l) and insulin . Accidentally if infusion rate is increased extra dextrose will also go. Therefore there are less chances of patients going in hypoglycemia . However if insulin requirements changes one will have to discard this solution and will have to prepare another one. Start GIK (10,10,10) @ 100-125 ml/hr after checking BS & K levels 2-3 hrly BS charting

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Blood sugar (mg/dl) 90 90-180 180-360 >360

Infusion D10 + 5 U insulin + 10 K mEq/l 10 + 10 + 10 10 + 15 + 10 10 + 20 + 10

Postoperatively GIK @ 100-125 ml/hr BS 4 hrly till orals Stop GIK after starting oral feeds, start regular insulin s.c. Dose 20% extra if infection/obese/steroids No Lactate containing fluids

Tight control regimen 1 Aim: To keep plasma glucose levels at 79 to 120 mg/dl .Mantainence of such levels may improve wound healing and prevent wound infection , improve neurologic outcome after global or focal CNS ischemic insults or improve weaning from cardiopulmonary bypass. Protocol 1. On the evening before surgery determine the preprandial blood glucose level 2. Through a plastic cannulas begin an intravenous infusion of 5% dextrose in water at a rate of 50ml/hr 70kg body weight 3. Piggyback an infusion of regular insulin (50 U in 250ml of 0.9 % sodium chloride ) to dextrose infusion with an infusion pump . Before attaching this piggyback line to the dextrose infusions flush the line with 60 ml of infusion mixture and discard the flushing solution . This approach saturates insulin binding sites on the tubing 4. Set the infusion rate by using the following equation : Insulin =plasma glucose (mg/dl) 150 (Note The denominator should be 100 if the patient is taking corticosteroids eg 10 mg of prednisolone a day or its equivalent, not to include inhaled steroids . 5. Repeat blood glucose measurements every 4 hrs as needed and adjust insulin appropriately to obtain blood glucose levels of 100 to 200 mg/dl

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6. On the day of surgery intraoperative fluids and electrolytes are managed by continued administration of non dextrose containing solutions 7. Determine the plasma glucose level at the start of surgery and every 1-2 hrs for the rest of 24 hr period . Adjust the insulin dosage appropriately Tight control regimen 2 Aim: Same as for tight control regimen 1 Protocol 1. Obtain a feedback mechanical pancreas and set the controls for the desired plasma glucose regimen . 2. Institute 2 appropriate intravenous line The last regimen may well supersede above all others if the cost of a mechanical pancreas can be reduced and if control of hyperglycemia is shown to make a meaningful difference perioperatively.It it has superseded all others in many ICUs and for good reason. At the conclusion of the procedure the patients usual insulin regimen is resumed when the normal eating schedule is achieved . If oral nutritional intake continues to be in doubt ,smaller doses of usual long lasting insulin (NPH) can be used supplemented with more frequent injections of short acting(lispro) insulin trying to maintain the blood glucose in th 100-200mg/dl range . If the patient was managed with an insulin drip and continues to be hospitalized the infusion should be maintained until normal nutritional intake is secured . When transferring the patient from an insulin infusion to subcutaneous injections the infusion shouls be continued for 30-45 minutes after the first injection to provide overlap in insulin supply as the subcutaneous depot is mobilized. Increasing numbers of patients with type 1 diabetes are managing this diseae with insulin pumps . When undergoing surgical procedures it is best to maintain the patients usual basal rate ( typically 0.5-1 units/hr ) during the procedure. Each hospital should designate certain personnel who are capable of assessing and maintaining such devices . If this is not possible such patients should be maintained on intravenous insulin infusions or have specific other instructions given by the supervising endocrinologists.

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VARIABLE RATE REGIMEN To maintain BS 120-180 mg/dl Mix 5 U insulin in 500 ml NS ( 100 ml = 1 U) Infuse @ 0.5-1.0 U/hr Check BS regularly Provide sufficient glucose (5-10 gm/hr) & K (2-4 mEq/l)

<80 80-120 120-180 180-240 >240

Turn off insulin. Give 25 ml D50%. Recheck in 30 min. Decrease insulin by 0.3 U/hr No change Increase insulin by 0.3 U/hr Increase insulin by 0.5 U/hr

Anaesthetic agents affecting blood sugar Isoflurane Sevoflurane, Halothane :Inhibits glucose stimulated insulin release in dose dependent manner Glucose tolerance impaired Propofol :Lipid load leading to metabolic impairment ( ICU sedation ).Uunlikelt to be relevant in short sedation or induction doses Etomidate Derease steroids Decrease glycemic response to surgery Ketamine :causes significant hyperglycemia Midazolam Decrease ACTH & Cortisol secretion. Decrease sympathoadrenal activity Decrease glycemic response to surgery

Regional Anaesthesia
Advantages Awake patient, hence intraoperative hypoglycemia can be noticed Decreased chance of Aspiration ,PONV, and Thromboembolism Rapid return to diet & insulin/OHA Metabolic effects of anaesthetic drugs avoided Epidural anaesthesia blocks catecholamine release Avoids tracheal intubation ( and difficult airway!) Excellent analgesia Disdvantages 15

LA requirement is decrease due to increased sensitivity Higher risk of nerve injuries Adrenaline can lead to ischaemic neuronal damage Infection risk is increased Epidural abscess Contraindicated in presence of peripheral neuropathy PVD keep in mind Medicolegal significance Autonomic neuropathy-severe hypotension may occur.

Out Patient Surgery

Can evaluate history in advance Endorgan disease does not require monitoring Prehydration is available or is unnecessary No CNS ischaemia or plant cardiopulmonary bypass Not pregnant Patient or vested home mate can determine blood glucose level Has vested home mate Can take temperature or look for red wound Plan higher admit rate

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Bibliography
Millers Textbook Of Anaesthesiology Stoelting Anaesthesia & Coexisting Diseases Artusio & Yao Objective Anaesthesia Review 2009(Tata Memorial Hospital) Davidson Principles Of Medicine American Diabetes Association Tayside Joint Formulary Section 21 Guidelines for the Perioperative Management of Patients with Diabetes Anaesthesiology Clinics ;September 2006 Harrisons Textbook of Medicine World Anaesthesia Day 2007 British journal of Anaesthesia-2000

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