DIABETES MELLITUS AND ANAESTHETIC IMPLICATIONS

Dr.R.Selvakumar. M.D.D.A.DNB

Professor & H.O.D,Dept of Anaesthesiology,K.A.P.Viswanatham Govt Medical College,Trichy-Tamilnadu.India.

DEFINITION

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. 

WHY ARE WE WORRIED?

Chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

An estimated 25% of diabetic patients will require surgery. Mortality rates in diabetic patients have been estimated to be up to 5 times greater than in nondiabetic patients, often related to the end-organ damage caused by the disease.

Infections account for 66% of postoperative complications and nearly one quarter of perioperative deaths in patients with DM. Data suggest impaired leukocyte function, including altered chemotaxis and phagocytic activity.

The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues.

Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action.

Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient

BASIC PROBLEM

In one category, type 1 diabetes, the cause is an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes can often be identified by serological evidence of an autoimmune pathologic process occurring in the pancreatic islets and by genetic markers.

In the other, much more prevalent category, type 2 diabetes, the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. 

CLASSIFICATION

Symptoms of marked hyperglycemia include polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also accompany chronic hyperglycemia.

Acute, life-threatening consequences of uncontrolled diabetes are hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.

SYMPTOMS

Acute consequences of untreated, or inadequately treated, diabetes mellitus include dehydration (resulting from the osmotic diuretic effect of glycosuria), acidaemia (because of accumulation of lactic and/or ketoacids), fatigue, weight loss and muscle wasting (because of lipolysis and proteolysis in absolute insulin deficiency)

Long-term complications of diabetes include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Patients with diabetes have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes.

Chronic effects of diabetes microvascular (including proliferative retinopathy and diabetic nephropathy), neuropathic (autonomic and peripheral neuropathies) and macrovascular complications (atherosclerotic disease). 

DIABETES MELLITUS- DIAGNOSTIC CRETERIA1. Symptoms of diabetes plus casual plasma glucose concentration ≥200 mg/dl (11.1 mmol/l). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.

or2. FPG ≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.

or3. 2-h postload glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

The use of the hemoglobin A1c (A1C) for the diagnosis of diabetes is not recommended.

categories of FPG values are as follows:FPG <100 mg/dl (5.6 mmol/l) = normal fasting glucose;FPG 100–125 mg/dl (5.6–6.9 mmol/l) = IFG (impaired fasting glucose);FPG ≥126 mg/dl (7.0 mmol/l) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described below).

OGTT :2-h postload glucose <140 mg/dl (7.8 mmol/l) = normal glucose tolerance;2-h postload glucose 140–199 mg/dl (7.8–11.1 mmol/l) = IGT (impaired glucose tolerance);2-h postload glucose ≥200 mg/dl (11.1 mmol/l) = provisional diagnosis of diabetes 

Ketoacidosis is an extension of normal physiological mechanisms that compensate for starvation. Normally, in the fasting state, the body changes from metabolism based on carbohydrate, to fat oxidation. Free fatty acids are produced in adipocytes, and transported to the liver bound to albumin. There they are broken down into acetate, and then turned into ketoacids (acetoacetate and beta-hydroxybutyrate).

The ketoacids are then exported from the liver to peripheral tissues (notably brain and muscle) where they can be oxidised.

PATHO-PHYSIOLOGY OF KETO-ACIDOSIS

 The rate-limiting step in the manufacture of ketones in the liver is the transfer of fatty acids (acyl groups) from Coenzyme A to carnitine. Carnitine acyl transferase I is the relevant enzyme, often referred to as CAT-I. To a certain degree, increased levels of carnitine will drive this transfer, but the main factor that inhibits CAT-I is the level of malonyl CoA in the liver. High levels of malonyl CoA effectively turn off the enzyme.

Malonyl CoA is manufactured by another enzyme called Acetyl CoA carboxylase. Acetyl CoA carboxylase activity is in turn regulated by the amount of citric acid in the cell. The more the Krebs' cycle is whirling around (and citrate is being produced), the greater the activity of Acetyl CoA carboxylase, which in turn results in inhibition of ketoacid production.

Turn off the supply of substrate into Krebs' cycle, and ketoacids are formed.

Diagnostic criteria for DKA:

Blood glucose level >250 mg/dl, a moderate degree of ketonemia, serum bicarbonate <15 mEq/l, arterial pH <7.3, and an increased anion gap metabolic acidosis.

DIAGNOSIS OF KETO-ACIDOSIS

The assessment of ketonemia, the key diagnostic feature of ketoacidosis, is usually performed by the nitroprusside reaction.

The nitroprusside reaction provides a semiquantitative estimation of acetoacetate and acetone levels but does not recognize the presence of β-hydroxybutyrate, which is the main ketoacid in DKA.

Therefore, this test may underestimate the level of ketosis. 

A word of caution...!

DIABETIC AUTONOMIC NEUROPATHY

CardiovascularResting tachycardiaExercise intoleranceOrthostatic hypotensionSilent myocardial ischemiaGIEsophageal dysmotilityGastroparesis diabeticorumConstipationDiarrheaFecal incontinence

MetabolicHypoglycemia unawarenessHypoglycemia-associated autonomic failureSudomotorAnhidrosisHeat intoleranceGustatory sweatingDry skin

CLINICAL FEATURES OF DAN

Clinical manifestations of DAN Exercise intolerance.decreased cardiac output in response

to exercise in individuals with DAN.  Intraoperative cardiovascular lability.Orthostatic hypotension.Orthostatic hypotension is defined as a fall in blood pressure (i.e., >20 mmHg for systolic or >10 mmHg for diastolic blood pressure) in response to postural change, from supine to standing .In patients with diabetes, orthostatic hypotension is usually due to damage to the efferent sympathetic vasomotor fibers, particularly in the splanchnic vasculature.

Silent myocardial ischemia/cardiac denervation syndrome.

HOW TO INVESTIGATE DAN..?

Heart rate response to deep breathing (i.e., beat-to-beat heart rate variation, R-R variation).Beat-to-beat variation in heart rate with respiration depends on parasympathetic innervation. 

Heart rate response to standing.This test evaluates the cardiovascular response elicited by a change from a horizontal to a vertical position. In healthy subjects, there is a characteristic and rapid increase in heart rate in response to standing that is maximal at approximately the 15th beat after standing. This is followed by a relative bradycardia that is maximal at approximately the 30th beat after standing. In patients with diabetes and autonomic neuropathy, there is only a gradual increase in heart rate. The patient is connected to an electrocardiogram (ECG) monitor while lying down and then stands to a full upright position.ECG tracings are used to determine the 30:15 ratio, calculated as the ratio of the longest R-R interval (found at about beat 30) to the shortest R-R interval (found at about beat 15). 

TESTS OF AUTONOMIC NEUROPATHY

VALSALVA MANEUVER

Phase I: Transient rise in blood pressure and a fall in heart rate due to compression of the aorta and propulsion of blood into the peripheral circulation. Hemodynamic changes are mostly secondary to mechanical factors.Phase II: Early fall in blood pressure with a subsequent recovery of blood pressure later in the phase. The blood pressure changes are accompanied by an increase in heart rate. There is a fall in cardiac output due to impaired venous return causing compensatory cardiac acceleration, increased muscle sympathetic activity, and peripheral resistance.Phase III: Blood pressure falls and heart rate increases with cessation of expiration.Phase IV: Blood pressure increases above the baseline value (overshoot) because of residual vasoconstriction and restored normal venous return and cardiac output.

VALSALVA MANEUVER IN A NORMAL PERSON

50

100

150

1

2

3

B.P

Heart Rate

•Small increase in B.P•Sustained expiration causing a fall in B.P•Overshoot of B.P on release

VALSALVA MANEUVER IN A PATIENT WITH DAN

50

100

150

1

2

3

B.P

HR

•Small increase in B.P•Fall of B.P with slow regaining•No overshoot on release

Technique: The subject sits quietly and blows into a mouthpiece at a pressure of 40mmof Hg for 15 seconds. The heart rate, measured from an ECG, normally increase during the manoeuvre, followed by a rebound bradycardia after the pressure has been released.Result: The ratio of the longest R-R interval after the manoeuvre to the shortest while blowing is measured and the result expressed as the ‘Valsalva ratio’. The result is usually expressed as the mean ratio of three successive tests.

VALSALVA RATIO

The high frequency variation of heart rate which coincides with breathing is called ‘ Respiratory Sinus Arrhythmia- RSA’. During RSA, heart rate increases during inspiration and decreases during expiration.

2. Heart rate response to deep breathing:

Technique: The subject sits quietly and breathes deeply and evenly at six breaths per minute, a rate which produces maximum variation in heart rate.

Result: Maximum and minimum heart rates during each breathing cycle are measured and the mean of the differences during three successive cycles taken to give the maximum-minimum heart rate.

696 ms 709 ms 724 ms 733 ms 735 ms 748 ms 751 ms

Inspiration Expiration

Increased heart rate

Decreased parasympathetic

tone

Nucleus solitaries (brainstem)

Activation of stretch receptors in the lung, chest wall, and heart

Inspiration

Decreased heart rate

Increased parasympathetic

tone

Nucleus solitaries (brainstem)

Relaxation of stretch receptors in the lung, chest wall, and heart

Expiration

RESPIRATORY SINUS ARRHYTHMIA

Technique: The patient lies quietly on a couch and then stands unaided with an ECG continuously recording. On changing from horizontal to vertical, there is a reflex vagally mediated response whereby a rapid increase in heart rate occurs, maximal at about the 15th beat after standing and followed by slowing , maximal after the 30th beat.

3. Immediate heart rate response to standing:

Result: This is expressed as the 30:15 ratio, the ratio of the longest R-R interval around the 30th beat to the shortest around the 15th beat.

4. Blood pressure response to standing:

Technique: Blood pressure is measured with an ordinary sphygmomanometer while lying and again after standing for at least one minute. On standing there is immediate pooling of blood in the lower limbs and splanchnic bed with a fall in blood pressure but, If baroreflex function is normal, this is rapidly corrected by peripheral vasoconstriction.

Result: The difference in systolic BP is taken as the measure of postural blood pressure change.

5. Blood Pressure response to sustained handgrip:

Technique: Sustained (isometric) muscle exercise causes a heart rate-dependent increase in cardiac output and systemic BP. A simple test based on this reflex uses a handgrip dynamometer with handgrip maintained at 30% of the maximum voluntary contraction up to a maximum of five minutes with BP measured every minute.

Result: The difference between diastolic BP just before release of the handgrip and that after starting is a measure of the response.

Normal Borderline Abnormal

Tests reflecting parasympatheticFunction

Heart rate response to ValsalvaManoeuvre(Valsalva ratio) 1.21 1.11-1.20 1.10

Heart rate (R-R interval) variationduring deep breathing (maximumHeart rate) 15 beats/min 11-14 beats/min 10 beats/min

Immediate heart rate response tostanding (30:15 ratio) 1.04 1.01-1.03 1.00

Tests reflecting sympathetic functionBlood pressure response to standing(fall in systolic blood pressure) 10mmHg 11-29 mmHg 30 mmHg

Blood pressure response to sustainedhandgrip (increase in diastolic bloodpressure) 16 mmHg 11-15 mmHg 10mmHg

If all five are used, patients can be categorized as:1.Normal: all five tests normal or one borderline.

2.Definite involvement: two or more of the heart rate tests abnormal.

3. Severe involvement: two or more of the heart rate tests abnormal plus one or both blood pressure tests abnormal, or both borderline.

REVIEW OF DRUGS AND TREATMENT

Rapid acting insulins:Regular insulin (Humulin R, Novolin R)Insulin lispro (Humalog)Insulin aspart (Novolog)Insulin glulisine (Apidra)Prompt insulin zinc (Semilente, Slightly slower acting)

Intermediate acting insulins :Isophane insulin, neutral protamine Hagedorn (NPH) (Humulin N, Novolin N)Insulin zinc (Lente)

Long acting insulins:Extended insulin zinc insulin (Ultralente)Insulin glargine (Lantus)Insulin detemir (Levemir)

Biguanides

Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Among common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.Typical reduction in glycated hemoglobin (A1C) values for metformin is 1.5–2.0%

Metformin (Glucophage) may be the best choice for patients who also have heart failure, but it should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast, as patients are at an increased risk of lactic acidosis.

Phenformin (DBI) was used from 1960s through 1980s, but was withdrawn due to lactic acidosis risk.

Thiazolidinediones

Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism.. The final result is better use of glucose by the cells.Rosiglitazone pioglitazone (Actos)troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk[8]

Thiazolidinediones (pioglitazone, rosiglitazone) mechanism of action is similar to that of metformin and however is not associated with lactic acidosis. Nevertheless, these drugs are generally discontinued as they are not insulin secretagogues and may also cause fluid retention in the postoperative phase

First-generation agentstolbutamideacetohexamidetolazamidechlorpropamide

Second-generation agentsglipizideglyburide or glibenclamideglimepiridegliclazideglycopyramidegliquidone

Sulphonyl urea

Interest in the potassium channel‐blocking effect of sulphonylureas and, hence, interference with myocardial ischaemic preconditioning, has increased recently. 

Glimepiride may not block potassium channels,but angioplasty patients receiving sulphonylureas have greater mortality and morbidity than those given insulin. The general implications of this observation are not clear but, until data from well‐conducted studies are available, it would seem prudent to convert patients taking sulphonylureas to insulin several days before cardiac or other major surgery or procedures where myocardial perfusion may be compromised.

Sulphonyl ureas and myocardial conditioning...

Nonsulfonylurea secretagoguesrepaglinidenateglinide

Alpha-glucosidase inhibitors

miglitolacarbosevoglibose

Alpha glucosidase inhibitors (acarbose, miglitol) weaken the effect of oligosaccharidases and disaccharidases in the intestinal brush border, effectively lowering the absorption of glucose after meals. However, in preoperative fasting states, this drug has no effect and thus should be discontinued until the patient resumes eating

Peptide analogs

Incretins are insulin secretagogues. The two main candidate molecules that fullfill criteria for being an incretin are glucagon-like peptide-1(GLP-1) and gastric inhibitory peptide (glucose-dependent insulinotropic peptide, GIP).

Injectable Glucagon-like peptide analogs and agonists

ExenatideLiraglutide

Lixisenatide

Glucagon-like peptide-1 (GLP-1) agonists (exenatide, liraglutide) are held the day of surgery as they slow gastric motility and may delay restoration of proper gastrointestinal function during recovery.

Gastric inhibitory peptide analogs

Dipeptidyl Peptidase-4 Inhibitors

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 by inhibiting its degradation by dipeptidyl peptidase-4.Examples are:

vildagliptin (Galvus)sitagliptin (Januvia)saxagliptin (Onglyza)linagliptin (Tradjenta)alogliptinseptagliptinTeneligliptin

dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, linagliptin) work by a glucose dependent mechanism (reducing the risk of hypoglycemia even in fasting patients) they may be continued if necessary

Injectable Amylin analogues

Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. As of 2007, pramlintide is the only clinically available amylin analogue.

Like insulin, it is administered by subcutaneous injection. The most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces.

Drug class: Mechanism of action Half-life (h) Adverse effects Biguanides Decrease hepatic gluconeogenesis,

increase insulin sensitivity 6 –18 Diarrhoea, nausea, vomiting, lactic acidosis

Gl Sulphonylureas Stimulate insulin secretion, decrease insulin resistance 2 –10

Hypoglycaemia,

lactic acidosis Meglitinides Stimulate pancreatic insulin

secretion 1 Hypoglycaemia

Thiazolidindiones Regulate carbohydrate and lipid metabolism, reduce

insulin resistance and hepatic glucose production 3 –8 Fluid

retention, increased

cardiac risk including congestive heart failure,

hepatotoxicity

Glucosidase inhibitors Reduce the intestinal absorption of ingested glucose 2 –4 Gastrointestinal

irritation, flatus

(DDP-4) inhibitors Reduces breakdown of hormone-incretins (glucagon-like peptide type-1),

enhance insulin secretion, decrease glucagon

INVESTIGATIONS TO BE PERFORMED IN A DIABETIC PATIENT:

INVESTIGATIONS:

BASELINE VALUE FOR FUTURE REFERENCES

TO RULE OUT END ORGAN DAMAGECARDIAC WORKUP –ECG,ECHO,STRESS ECHO,ANGIOGRAM,ISOTOPE STUDIES

RENAL FUNCTION STUDIES

LFT

EYE-FUNDUS

TESTS FOR DAN

CONTD….

Prayer Sign:

Patient is unable to approximate the palmar surface of phalangeal joints despite of maximal effort.

Palm Print Test:Degree of inter-phalyngeal joint involvement can also be assessedby scoring the ink impression made by the palm of dominanthand.

PER-OPERATIVE GLYCAEMIC MANAGEMENT:

The immediate perioperative problems facing the diabetic patient are: (i) surgical induction of the stress response with catabolic hormone secretion; (ii) interruption of food intake, which may be prolonged following gastrointestinal procedures; (iii) altered consciousness, which masks the symptoms of hypoglycaemia and necessitates frequent blood glucose estimations; and(iv) circulatory disturbances associated with anaesthesia and surgery, which may alter the absorption of subcutaneous insulin.

Although no strict standard for surgical cancellation has been determined, the Yale New-Haven Hospital recommends postponing surgery if glucose is greater than 400 mg/dL.

Etomidate blocks adrenal steroidogenesis and hence cortisol synthesis, by its action on 11β‐hydroxylase and cholesterol cleavage enzymes, and consequently decreases the hyperglycaemic response to surgery

High‐dose opiate anaesthetic techniques produce not only haemodynamic, but also hormonal and metabolic stability.

Impact of Anaesthetic drugs

Ketamine has a dual effect on blood Glucose level

The aim of intraoperative management is to provide adequate anesthesia, proper positioning and to avoid hypoglycemia, hyperglycemia, ketoacidosis and electrolyte disturbances.

It is important to time diabetic patients as first in the operating list, thus shortening the starvation period.

Positioning of the patient is also very important to avoid pressure sores and it should be done gradually to avoid sudden drop in blood pressure.

There are no contraindications to standard anesthetic induction or inhalational agents

Careful titration of inducing agents should be done with adequate preloading to avoid hypotension due to autonomic neuropathy

Rapid sequence induction with cricoid pressure should be done if gastroparesis is suspected.

A nasogastric tube can be positioned and aspiration should be done if required.

Anticipate difficulty in intubation and back up of laryngeal mask airway, proper blades and endotracheal tubes, tracheostomy facility and expert help should be ensured

literature suggests keeping glucose levels between 150 and 200 mg/dL (8 to 11 mmol/L) during surgery 

Establish separate intravenous access for a "piggyback" infusion of regular insulin(100 U per 100 mL 0.9% saline). The infusion rate can be determined by using the following formula: insulin (U/hr) = serum glucose (mg/dL)/150

Separate I.V line for haemodynamicalterations with normal saline. RL should be considered as glucose containing solution.

INTRAOPERATIVE GLYCAEMIC MANAGEMENT

PATIENTS WITH DIABETIC KETOACIDOSIS

No elective surgeryDelay the emergency to treat it as far as possibleCorrect DehydrationSupply intravenous insulinIf needed dextroseTreat acidosisCorrect electrolyte imbalancesIntense monitoring

Bicarbonate administration in patients with DKA remains controversial. Severe metabolic acidosis can lead to impaired myocardial contractility, cerebral vasodilatation and coma, and several gastrointestinal complications. However, rapid alkalinization may result in hypokalemia, paradoxical central nervous system acidosis, and worsened intracellular acidosis (as a result of increased carbon dioxide production) with resultant alkalosis. Controlled studies have failed to show any benefit from bicarbonate therapy in patients 

However, most experts in the field recommend bicarbonate replacement in patients with a pH <7.0. In patients with DKA with arterial pH ≥7.0, or in patients with HHS, bicarbonate therapy is not recommended

POST-OPERATIVE MANAGEMENT

POST-OPERATIVE PERIOD

Insulin-glucose infusion should be continued till at least 2 hours after the first meal.

Blood sugar should be monitored every 2 hourly and normal insulin regime or oral hypoglycemic agents can be started with the first meal.

Postoperative hyponatremia is a common electrolyte abnormality and hypokalemia if not answered at the right time may lead to cardiac arrhythmias.

Good analgesia decreases catabolic hormone secretion. Nonsteroidal anti-inflammatory drugs should be used with caution in patients with renal dysfunction.

Judicious use of antibiotics and better wound care and postoperative glycemic control can prevent postoperative infection

Nausea and vomiting should be prevented, and if present, should be treated vigorously.

dr.r.selvakumarprofessor of anaesthesiologyk.a.p.viswanatham govt medical college,trichirapalli

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