ANAESTHESIA FOR DIABETES
Diabetes is a chronic systemic disease due to a relative or absolute insulin lack. Both acute hyper- or hypo- glycaemia and long-term complications are of anaesthetic relevance. Diabetics have higher morbidity and mortality as surgical patients.
Diagnosis is made on classical presentation of thirst, polyuria and random plasma level >11, or fasting plasma >7mM/l (BSL >6.1mM/l). "Impaired Fasting Glycaemia" exists if fasting plasma glucose is 6.1 – 7.0 mM/l (BSL 5.6 – 6.0). Note that results of blood glucose estimations are different from plasma glucose.
The diagnosis of "Gestational Diabetes Mellitus" now includes impaired glucose tolerance tests.
Prevalence of diabetes is 7.2% in persons aged 25 and older (85% type 2). 1 in 300 people have Type 1 diabetes. For every diagnosed case of Type 2 diabetes there is another undiagnosed person. A further 16% of the adult population have either impaired glucose tolerance or impaired fasting glucose (makes one wonder what is 'normal'!)
The oral glucose tolerance test (OGTT) involves an overnight fast then a 50g glucose meal followed by hourly blood sugars for 3 hours. At 2 hours, plasma glucose 7.1 to 11.0 is borderline; >11.1 indicates diabetes.
The glycaemic index is the ratio of the area under the blood glucose vs time curve for an amount of food containing 50g of carbohydrate compared to the curve generated by 50g of glucose. High glycaemic index foods result in high, brief peak blood glucose levels similar to ingestion of pure glucose. After eating high GI food, blood glucose falls rapidly, causing hunger and sometimes hypoglycaemia. Low glycaemic index foods (GI's of 20-30) result in much less BSL elevation because the peak lower and the total area under the curve is less - unfortunately they are slower to satiate hunger.
It's not easy to predict the GI of a food. High fibre, intact capsules around grains, high amylose content, high sugar to starch ratio, low gelatinisation of starch, acidity and high fat/protein content all reduce GI. Starch is easier to absorb than many sugars. Not all breads are equal (wholemeal and white are near 100, but most high-grain Burgen breads are near 25-35, and others are in between), but potato, pasta, refined flour crackers and rice are near 100; unrefined cereals, legumes, vegetables and temperate fruits are low while tropical fruits, processed cereals like corn flakes and rice bubbles are high. Protein and fat are obviously low. Good books are available that list the GI of common carbohydrate foods A detailed serarchable database is available on the glycemicindex.com website..
If you have impaired glucose tolerance, find it hard to diet without hunger, or suffer hypoglycaemic episodes when fasting, eating low-GI foods is beneficial. One consequence of diets high in high GI foods is that hyperinsulinaemia occurs. Some dietary experts suggest an 'insulin index' for foods. High insulin levels induce insulin resistance, cause fat accumulation and inhibit lipolysis. Several studies have shown a 2 to 5 times greater incidence of Type 2 diabetes and obesity when diets are dominated by high GI foods.
See also Foster-Powell, Kaye, Susanna HA Holt, and Janette C Brand-Miller. "International table of glycemic index and glycemic load values: 2002." The American Journal of Clinical Nutrition, Vol. 76, 2002, pp. 5-56. This extensive table lists 750 foods and is the definitive journal article.
Classification is by causation (beta cell destruction; insulin resistance/hyposecretion; pregnancy; others), andis staged (impaired glucose tolerance, inpaired fasting glycaemia, insulin dependence).
Type 1: Juvenile or Ketotic
Autoimmune and non-immune forms. Beta-cell destruction. Usually insulin dependent. Aetiology involves nongenetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. Genetic susceptibility indicated by HLA association, esp HLA DR3, DR4, Dw3, Dw4, B8, and B15, and 50% twin concordance. Viral infection is implicated, during pregnancy or in childhood. Cocksackie B4, enterovirus, measles viruses are implicated. Enterovirus infection during pregnancy doubles likelihood of diabetes in siblings, particularly when onset is at age <3 years. A long prodrome before presentation is likely, which may be serologically identifiable in the absence of symptoms. Treatment with Cyclosporin A within 6 weeks of onset may prevent ongoing diabetes in up to 50% of patients.
Type 2: "Maturity-onset"
Varying degrees of insulin hyposecretion and insulin resistance. Long (and damaging) asymptomatic phase. Factors increasing the risk of developing Type 2 diabetes include childhood and abdominal obesity, reduced exercise levels, gestational diabetes and eating energy-rich, low-fibre and high glycaemic index foods.
Ketosis is rare, and lipolysis inhibited. High (100%) identical twin concordance. No HLA associations. May require insulin but usually not insulin dependent. Usually have markedly impaired 'rapid response' after an IV glucose tolerance test, with post-prandial hyperglycaemia. These peak levels associate with development of secondary microvascular complications.
Aim for HbA1C < 7%. A 1% fall in HbA1C with Rx gives approx 21% reduction in diabetes-related complications or death. 50% of type II patients will exceed 7% after three years and many will require insulin.
ie other diabetic states where the cause is known. Should increase as more causes of Type 2 diabetes are identified. Include:
2. FACTORS INFLUENCING BLOOD GLUCOSE
3. GLUCOSE STORES
Typical daily energy requirement at rest is 40 Cal/Kg or 2800 Cal per day. 50% is usually provided by COH (requiring about 350g of glucose at 4 Cal/g). Hepatic glycogenolysis can provide up to 200g/day in the fasting state and under these circumstances fat utilisation for energy requirements increases.
70g is stored in the liver as glycogen (5-6% maximum of hepatic weight), and this alone is adequate for about 8-10 hours at rest. The liver can mobilise glucose from circulating triglyceride and glycerol after this.
Peptide hormone from β cells of pancreas. 51 AA's, α and β chains with disulphide links (C peptide released when Proinsulin cleaved). Serum T½ 5 min (Hepatic clearance) but biological T½ 30 min.
Serum insulin levels usually peak at around 60-100 mU/l after a meal, in response to increases in blood sugar, arginine, leucine, and glucagon. Infusion of insulin at 2 U/hr results in similar plasma levels systemically. Total daily excretion about 25 - 40 U/day, increased by sepsis, stress, pregnancy, presence of insulin antibodies, etc.
Acts by ↑ c-AMP and other intracellular peptides, resulting in
↑ glucose entry to fat, muscle, heart ? via enhancement of facilitated diffusion
↑ Glycogen stores (hexokinase (G6P → G1P), glycogen synthetase)
↑ Amino Acid uptake, protein anabolism
↑ K+ entry to cells causing hypokalaemia
↑ Fat store (decreased lipase activity, increased triglyceride synth from glucose)
All commercial insulins are sold in 100U/ml vials. 1 μg = 25 Units.
Bovine (α8, α10, β30) insulin is little different from human insulin and is purified so that contaminants are less then 10 parts per million. Porcine insulins are no longer available.
Purified insulins with reduced levels of pro-insulin are available (MC, "single peak or SP", or "highly purified"), but there is no strong evidence that these reduce the development of insulin antibodies, prevent diabetic complications, or have different durations of action. They are useful in the management of local skin reactions and fat atrophy. Dose of highly-purified insulins may need a slight reduction.
Human insulins are obtained by either replacing the β30 alanine in porcine insulin with the threonine which should be in human insulin or by recombinant DNA methods in bacteria such as E. Coli.
Insoluble insulins, which are modified to delay absorbtion (Isophane, protamine zinc, or zinc suspension) should not be given IV; only use soluble or neutral.
Insulin Glargine (Lantus) is a modified long-duration peakless recombinant human insulin; at α21, apsparagine is replaced with glycine, and 2 asparagines are added to the C-terminus of the α-chain. The supplied solution has a pH of 4.0, in which the drug is soluble, when injected subcutaneously, physiological pH causes spontaneous formation of slowly dissolving hexamers.
Recently inhaled insulin is available on a trial basis; this has a rapid onset of peak effect and can be titrated to effect, even during food consumption. Usually added to a daily basal slow-release insulin injection.
5. INSULINS AVAILABLE ON THE AUSTRALIAN MARKET
Not all may be available.
6. ORAL HYPOGLYCAEMIC AGENTS
Initiated when diet/exercise fail after 3 months or if hyperglycaemia is severe. Metformin is the drug of first choice, reducing subsequent incidence of complications more than any other therapy. Suphonylureas should be used if Metformin is contraindicated or added to improve control, even though the impact of a combination is not huge. Suplhonylureas are more likely to cause hypoglycaemia and weight gain.
Mixed actions which potentiate the effects of insulin. Risk of lactic acidosis is not as great as was thought; more likely in the elderly, after dehydration and with higher doses. C/I in the elderly, hepatic, cardiac and renal disease, alcohol users. Dose must be reduced with renal impairment. Tend to cause weight loss but can cause dose-related diarrhoea, nausea, abdominal bloating, eased by administration with food. Metformin (Diabex, Diaformin, Glucophage, Novomet, Glucohexal) is the only one available in Australia.
First used in 1940's. Act by increasing Insulin release. Bind to a ATP-binding component in the ATP-sensitive K+ channel. In general these drugs have long biological half-lives, are highly protein-bound (problems with warfarin, MAOI's, Sulphonamides, Salicylates, beta-blockers, etc.), and are hepatically cleared. Side-effects include weight gain, hypoglycaemia, flushing with alcohol, cholestasis, and possible acceleration of vascular disease. May improve control in brittle Type 1 diabetics, and may increase HDL's. Examples:
C) METFORMIN / GLIBENCLAMIDE COMBINATION
500/2.5 or 500/5 (metformin/glibenclamide Glucovance®) fixed-dose presentations. Max 3-4 tablets/day. Useful if either drug alone is inadequate. CI as for metformin (elderly, hepatic, renal) because severe hypos are more common.
These are thiazolidinedione peroxisome proliferator-activated receptor-gamma activators. Rosiglitazone (Avandia) and pioglitazone (Actos) are available in Australia. Third-line treatment when others contraindicated or poorly tolerated. Weight gain and fluid retention are common; idiosyncratic and potentially severe hepatic injury is the major drawback. Can take 8 weeks for maximal benefit; dose must be increased very slowly.
Rapidly absorbed, 50% bioavailability (increased by food), linear kinetics, elimination half-life 8-24 hours. Enhances effects of insulin on peripheral target sites. Major drawback is 2% incidence of hepatic injury, requiring monitoring of liver enzymes; risk of death even if monitored is 1:100,000. Lowers BP. Adding troglitazone 200-600mg qid to glyburide improves control over either drug alone and lowers fasting serum insulin levels, or results in similar control to suphonylureas or or biguanides.
E) GLYCOSIDASE INHIBITORS
F) MEGLITINIDE ANALOGUES
Stimulate insulin release by inhibiting beta-cell membrane ATP-sensitive potassium channels via a different receptor from the suphonylureas. Nateglinide (short-acting D-phenylalanine derivative for Type 2 treatment. Rapid oral absorbtion and stimulation of insulin secretion. Adding 120mg tds before meals, to a suphonylurea lowers post-prandial peak BSL's and improves overall control of difficult patients.
Only Repaglinide (Novonorm) is available in Australia.
7. COMPLICATIONS OF DIABETES
Onset typically rapid; initially the patient becomes agitated, sweaty, and may complain of circumoral paraesthesia or palpitations, progressing to confusion, coma, and convulsions. Symptoms are non-specific and mediated by sympathetic nerves, hence reduced in beta blocked patientsand those with significant autonomic neuropathy, and largely absent under anaesthesia. Prolonged severe hypoglycaemia results in cerebral damage, and its prevention is essential. Rx:
B) HYPERGLYCAEMIA / KETOSIS
Usually gradual in onset, hyperglycaemia causes osmotic polyuria and thirst, but if the Insulin lack is sufficient to significantly reduce glucose entry to the cells, then Acetyl Co-A accumulates and is shunted into acetone and beta-hydroxy-butyrate, causing ketoacidosis, with nausea and vomiting, abdominal pain, confusion, and eventually coma. Rx:
Acidosis is due to accumulation of acetyl Co-A being shunted into Acetone and beta-hydroxy-butyrate, and improves when intracellular glucose allows activation of the Krebs cycle to burn up the acetyl-Co-A. Bicarbonate is rarely required and has potential for hypokalaemia.
C) VASCULAR DISEASE
Cardiac, cerebral, peripheral. Microangiopathy - especially retinal and renal. Leads to heart disease, stroke, diabetic ulcers, gangrene, amputation, renal failure, blindness. Commonest cause of blindness in people under the age of 60 years, second commonest reason for needing dialysis, commonest reason for non-traumatic amputation.
D) RENAL IMPAIRMENT
Hypertension, oedema, proteinuria.
E) AUTONOMIC AND PERIPHERAL NEUROPATHY
Abnormalities of autonomic innervation of the cardivascular system have been associated with sudden death, arrythmias, postural hypotension, and poor ability top compensate for bloodloss, cardiac depression, etc. A history of postural hypotension, silent infarction, impotence, abnormal sweating, bladder disturbances, paroxsmal diarrhoea, and other peripheral neuropathy should alert you to this potential problem. A reduction of the normal tachycardic response to standing up can be used as a simple test. The heart rate should increase by more than 10% from the 15th to 30th beat on standing.
G) DECREASED RESISTANCE TO INFECTION
8. ANAESTHESIA FOR DIABETIC PATIENTS
Aim is to avoid hypoglycaemia (especially intra-operatively), provide glucose delivery to the tissues, and avoid hyperglycaemia (and ketosis). Blood glucose usually falls during the preoperative fast and rises during and after surgery.
A fasting patient still has an obligatory requirement for about 200g of glusose per day, which is reduced by about 50% with ketoadaptation of prolonged fasting. Hepatic Glycogen stores are usually adequate for 12-24 hours, and glucose should be given for prolonged fasts, especially in children.
In general diabetic patients should be put early on the list to avoid long fasting times, and should have dextrostix performed during surgery. Admission several days preop for stabilisation and contacting the endocrine or diabetic team may be useful with brittle diabetics.
HbA1C is a stable glycosylated form of haemoglobin which is present in the blood in proportion to the average glucose level over time. As an index of control 5-8% is normal, and >8% represents poor control.
Management of diabetes depends on
9. TREATMENT REGIMES
a) Type II diabetes, oral Rx
Omit hypoglycaemic agents for one or two (chlorpropamide) days preop. Start 5% dextrose infusion in a.m. May require sliding scale after major surgery.
b) Type II diabetes, Insulin Rx
These patients are not usually insulin dependent. Simple half a.m. dose regimes are suitable for most procedures.
c) Insulin dependent diabetics
Must have some insulin perioperatively - many different regimes to choose from. Some techniques of insulin administration include:
1) Half usual a.m. dose of insulin
More modern interpretations are to give say 2/3 of the long-acting component and only give the short-acting component if surgery will start in the morning.
2) Sliding scale subcut insulin
Note that the peak effect of any subcut insulin is at 3-4 hours, so this is a safe but slow way to manage BSL. No sliding scale results in a perfect BSL in any one patient, the actual values need to be adjusted if the outcome tends to be too high or too low. It usually takes at least 24 hours before the effectiveness of a given scale is known.
3) IV Dextrose and Insulin together, ie
500ml 10% dextrose + 10 U insulin + 10 mM K+ at 100 ml/hr (2U/hr)(St Vin)
1000ml 5% dextrose + 10 U insulin + 10 mM K+ at 125 ml/hr (1.25U/hr)
Advantage of this method is that insulin will always be administered with dextrose - very useful preoperatively. Discarding the first 100-200 ml or adding 100 ml of haemaccel may minimise loss of insulin through adsorbtion to tubing.
4) Separate Dextrose and Insulin infusions
Requires operator intelligence and close observation, but very useful in brittle diabetics, infected cases,etc. Usually best to keep dextrose running at a constant rate. Daily glucose requirements met with 150g glucose (600Cal) which is 3 litres of 5% or three 500ml bottles of 10% dextrose - add daily K+. Insulin requirements vary depending on usual dose, and surgical stress - typically 1-3 U/hr, more postop up to 8 U/hr.
Difficulties arise in writing a good algorithm for setting infusion rate. The best way is for regular review by a dedicated physician who sets the rate after considering all relevant things, and reviews responses to any changes in the appropriate timeframe. That's what we should be doing in theatre.
On the ward the nursing staff are often left to follow written orders; the response to these orders is reviewed from time to time and the orders rewritten if needed. Two philosophically different methods exist:
1. BSL - Dependant Rate Methods (IV sliding scales, BSL/N techniques).
A step change in the infusion rate takes about 2 hours to stabilise, so titration is still slow, but faster than with a subcut regime. 12-hourly revies are appropriate for fine-tuning an IV sliding scale. IV sliding scales set the infusion to different rates according to the BSL. An alternative system for adults is to set infusion rate to the BSL/10 or the BSL/5 (or BSL/8 etc, depending on insulin requirements). This apporach causes the insulin infusion rate to be directly proportional to BSL and still requires 12-hourly review. BSL/10 translates to 0.5U/hr if BSL is 5, 1 U/hr if it's 10, etc.
2. Titration methods (step infusion up/down if outside desired range)
In these systems the medical staff simply check the BSL at 2 hourly intervals; if the BSL is higher than desired, the infusion is increased, or if too low it is decreased. Hence the actual infusion is not directly related to the BSL. These systems tend to 'home in' on the actual needs of the patient and are self-stabilising should the patient's insulin requirements change The steps can be logarithmic, ie 0.5, 0.7, 1, 1.4, 2, 2.8, 4, 5.6, 8 units/hr; note how every 2 steps the rate doubles. Start the rate at an educated guess and then:
10% dextrose at 1 ml/k/hr + Insulin 20-40 mU/kg/hr.
No special requirements but state clearly how you want the diabetes managed, and look for complications which may influence your anaestheic management.
2) Choice of Anaesthesia
No special requirements. Regional techniques minimise the stress response and allow the patient to commumicate symptoms of hypoglycaemia; the risk of infection and autonomic neuropathy need to be considered.
3) Special Problems
1) Hyperglycaemia at the time of cerebral ischaemic insults is associated with a poor outcome. It is thought that the extra glucose allows greater intracellular lactate accumulation and a more severe acidosis. Blood sugars should be very carefully kept within the normal range, therefore, in neurosurgery, carotid endarterectomy, and cardiac surgery.
2) In cardiopulmonary bypass both morbidity and mortality are higher in diabetics than non-diabetic patients. A dextrose-free pump prime is recommended; very high insulin requirements occur in the rewarming period.
3) Surgical removal of infected tissue (ie amputation of gangrenous limb, incision of abscess, etc) results in dramatic reductions in Insulin requirement (and the danger of hypoglycaemia) postoperatively.
4) The pregnant diabetic requires very close monitoring and is normally induced early. Separate insulin and dextrose infusions are commonly used, with reduced Insulin requirements after birth.
5) Monitoring. Be aware of increased cardiovascular risk - monitor accordingly. Check urine output. Check BSL regularly - 5% dextrose is about 200 mM/l so don't use the drip arm or arterial lines flushed with 5% dextrose!
6) Positioning. Care with heels and other pressure areas.
Rare; present with hypoglycaemia provoked by exercise or fasting. Tumour location difficult (usually <1cm) but usually palpable at operation.
Rx includes high carbohydrate diet, Diazoxide 100-600 mg daily, and for metastases Coeliac intra-arterial streptozotocin.
1. Alberti KGMM, Thomas DJB. The Management of Diabetes During Surgery. Br. J. Anaesth. 1979; 51 : 693.
2. Clarke BF, Ewing DJ, Campbell IW. Diabetic Autonomic Neuropathy. Diabetologica 1979; 17 : 195-212.
3. Walts et al. Perioperative Management of Diabetes Mellitus. Anaesthesiology 1981; 55 : 104-109.
4. American Family Physician Journal www.aafp.com/
5. Diabetes Australia web site http://www.diabetesaustralia.com.au/ - full of information!
Last updated Tuesday, April 13, 2010