Diabetes Mellitus in Anaesthesia

Anaesthesiologists frequently encounter patients with diseases of the endocrine system, in particular diabetes mellitus. The major risk factors for people with diabetes undergoing surgery are the associated end-organ diseases: cardiovascular autonomic neuropathy, joint collagen tissue, and immune deficiency. Due to the fact that endocrine diseases can be associated with significant peri-operative morbidity and mortality, it is critical that anaesthesiologists understand these disorders and when indicated request the appropriate investigations.

Introduction
Diabetes mellitus affects patients of all ages and due to its increasing prevalence, [14] virtually all physicians will inevitably be confronted with diabetic patients requiring anaesthesia and surgery. Patients with diabetes have a significantly increased risk of premature mortality and an increased risk of microvascular and cardiovascular complications[5,6] and are often sicker than most non-diabetic patients and therefore place a proportionally larger burden on anaesthetic services. Some reports have suggested that diabetic patients undergoing elective surgery are at a greater risk of morbidity from myocardial ischaemia, wound infection, renal ischaemia and cerebrovascular infarction. [7] A 50% increase in early mortality following coronary artery bypass grafting has been described in diabetic patients. This increased mortality is consequent to impaired myocardial function, a higher incidence of sternal wound infections and an increased likelihood of delayed stroke, all of which result in a longer hospital stay.[8,9] End-organ damage from diabetes may be a more important indicator of peri-operative outcome than the presence of diabetes itself. The major risk factors affecting diabetic patients undergoing surgery include cardiovascular dysfunction, renal insufficiency, joint collagen tissue abnormalities (e.g. cervical joint stiffness) and neuropathies (cardiovascular and GI effects), all of which may influence the effects of anaesthetics.[6] Therefore, a major focus for anaesthesiologists should be the pre-operative and pre-procedural evaluation and treatment of the potentially complicating factors of diabetes.

Diabetes-related Complications
Cardiovascular Disease
Cardiovascular pathology is a major cause of death in 80% of diabetic patients and diabetes is a major risk factor for cardiovascular disease, along with smoking, hypertension and hyperlipidaemia. [10] In the USA, heart disease was noted on 68% of diabetes-related death certificates among people aged 65 years or older. Adults with diabetes have heart disease death rates about two to four times higher than adults without diabetes. [11] Compared with the general population, diabetic men have more than a four fold greater probability of having CAD, while women have a five fold greater likelihood. Making a diagnosis is difficult as some diabetic patients may suffer from CAD but not experience its typical symptoms. This reduced appreciation of ischaemic pain may impair timely recognition of myocardial ischaemia, delaying therapy. One study demonstrated that the rate of unrecognised myocardial infarction was 39% in diabetic patients and 22% in non-diabetic patients.[12] The mechanism of painless myocardial ischaemia is not fully understood but may be related to autonomic neuropathy or CAD itself.[13,14] The presence of orthostatic symptoms (e.g. >15 beats/min increase in heart rate or >20 mmHg decrease in systolic arterial pressure 510 min after changing from a supine to upright position) is a sign of autonomic neuropathy and indicates potential operative haemodynamic instability. In the DIAD study, cardiac autonomic dysfunction was a strong predictor of ischaemia.[15] Peri-operative management of diabetic patients with other risk factors, such as advanced age, smoking, hypertension and hyperlipidaemia, should be modified if there is a likelihood of myocardial ischaemia. Asymptomatic type I diabetic patients with severe nephropathy who are scheduled for renal transplantation have been shown to benefit from preoperative screening and appropriate coronary revascularisation. [16] Questions regarding exercise tolerance and shortness of breath with exertion may provide important information regarding any underlying heart disease or the degree of compensation. Diabetic patients may also be prone to specific cardiomyopathies that are due to secondary microvascular changes. These heart defects can progress from impaired ventricular relaxation to diastolic dysfunction with high left-ventricular filling pressures and heart failure. This type of dysfunction may respond well to -blockers and calcium channel blockers, which act by decreasing heart rate and increasing diastolic relaxation. [17]

Diabetic Autonomic Neuropathy

Autonomic neuropathy develops in approximately one third of people with diabetes and affects many organ systems. Only a small proportion of these patients display symptoms such as orthostatic hypotension, syncopal episodes, reduced HRV, baseline tachycardia and a prolonged QT interval. Patients with these symptoms may be at an increased risk of ventricular arrhythmias and sudden perioperative death.[18] The diagnosis of diabetic autonomic neuropathy is based on a battery of autonomic function tests; RR variation, Valsalva manoeuvre and postural blood pressure tests may be useful in determining the presence of cardiovascular autonomic dysfunction. [13,14] The most common diabetic neuropathy is a distal symmetrical sensory or sensory-motor polyneuropathy. Diabetic neuropathy can also affect the thermoregulatory response to hypothermia; the pathogenesis of this effect may be related to inappropriate regulation of peripheral vasoconstriction, a process that normally conserves body heat. One study reported that the core temperature of diabetic patients with autonomic dysfunction was lower 2 hours into surgery compared with non-diabetic participants and diabetic patients without autonomic dysfunction. [19] The cardiovascular effect of insulin is paradoxical in autonomic neuropathy patients. Observations have suggested that insulin has a dual effect in patients without autonomic neuropathy: a vasoconstricting effect mediated by the sympathetic nervous system at therapeutic dose of insulin and a vasodilator effect mediated by nitric oxide at supratherapeutic dose; in patients with autonomic neuropathy, insulin causes a decrease in supine blood pressure and exacerbates postural hypotension, primarily by decreasing arterial vascular resistance and plasma volume. [20]

Diabetic Nephropathy
Diabetic nephropathy is the leading cause of end-stage renal failure in developed countries. According to the US Centers for Disease Control and Prevention > 35% of people aged 20 years with diabetes have chronic kidney disease. Long-term, uncontrolled hyperglycaemia is an important risk factor in the development of end-stage renal disease.[21] ACE inhibitors may slow the decline of renal function; however, because of an increased risk of deteriorating renal function, the use of ACE inhibitors should be avoided in patients with a creatinine concentration of 3.0 mg/dL or a creatinine clearance of 30 ml/min.[22] Due to the risk of accumulation of the biguanide metformin in patients with compromised renal function (serum creatinine > 130 mmol/L or creatinine clearance < 60 ml/min or eGFR < 45ml/min/1.73m 2) or patients who undergo large or extensive surgical procedures[23] this medication should be discontinued in these situations to avoid a predisposition to lactic acidosis. In major surgeries it is generally recommended to withhold metformin 48 hours before the operation and to resume therapy at least 48 hours after surgery or on resumption of oral nutrition, providing renal function has been evaluated and is normal. In spite of many candidates, no agent has been demonstrated to be renal protective in the peri-operative setting, although adequate renal perfusion with appropriate haemodynamic monitoring may reduce the risk of postoperative renal dysfunction.[24]

Gastroparesis
Diabetes may affect numerous parts of the GI system. Diabetic gastroparesis is characterised by a delay in gastric emptying and reflects diabetic GI autonomic neuropathy. [14] Oesophageal dysfunction is indicated by symptoms such as heartburn and dysphagia and results in part from vagal neuropathy. Diabetic patients are at risk for pulmonary aspiration during the induction of anaesthesia secondary to delayed gastric emptying. While metoclopramide is not a first-line drug for post-operative nausea and vomiting as it crosses the blood brain barrier and may cause extrapyramidal side-effects, but it may be effective in normalising delayed solid emptying rates. Cisapride administration prior to anaesthesia failed to demonstrate any effect on gastric contents or postoperative GI motility.[25]

Stiff-joint Syndrome
Stiff-joint syndrome may occur as a result of collagen glycosylation in the cervical joints, leading to intubation difficulties in 30% of diabetic patients. Stiffness of the fourth and fifth interphalangeal joints and the resulting alterations in a patient's palm prints may be a good predictor of a difficult intubation.[26] In contrast, other studies have reported no relationship between the 'prayer sign' (inability to approximate the palmar surface of the phalangeal joints despite maximum effort) and difficult laryngoscopy.[27]

Warner et al.[28] examined 725 patients, including 209 with diabetes, who underwent renal or pancreatic transplantation under general anaesthaesia with endotracheal intubation. Patients with diabetes were found to have a significantly higher frequency of difficult laryngoscopy when compared to patients without diabetes (p=0.002).

Anaesthetic Agents and Diabetes Mellitus

Surgery produces a stress response that can be modified by anaesthetic agents. Furthermore, anaesthetics can affect glucose homeostasis peri-operatively in diabetic patients by decreasing catabolic hormone secretion. [29] Some neuromuscular blocking agents may present problems for the diabetic patient. Succinylcholine can transiently increase serum potassium concentrations by 0.51 mEq/l. The use of succinylcholine should be avoided if patients have elevated baseline serum potassium concentrations. Diabetic patients with end-stage renal disease, or any patient on dialysis, ideally should be dialysed within the 24 h before elective surgery. Close monitoring of train-of-four should be implemented in diabetic patients with hepatic/renal dysfunction, and appropriate agents should be selected according to the drugs' pharmacokinetic parameters.[30] Midazolam is a benzodiazepine that is metabolised in the liver. The typical pre-operative dosing of midazolam (15 mg) as an anxiolytic does not usually present a problem in the diabetic patient, but infusions of midazolam have been shown to decrease ACTH and cortisol secretion.[31] Benzodiazepines reduce sympathetic stimulation but increase growth hormone secretion, resulting in a decrease in the hyperglycaemic response to surgery. This effect is significant if midazolam is given by continuous infusion at (0.125 mg/kg/h).[31] Etomidate inhibits adrenal steroid production and can decrease the hyperglycaemic response to surgery by 1 mmol/L in non-diabetic patients.[32] The effect of this drug on diabetic patients has not been established. The use of opiates, such as morphine, is of considerable importance in diabetics with renal insufficiency. The active metabolite morphine-6-glucoronide is cleared by the kidney. If utilised, the initial dose of morphine needs to be reduced to 75% of the standard dose in patients with a GFR of 1050 ml/min, and 50% in patients with a GFR < 10 ml/min. Meperidine also produces an active metabolite, normeperidine, with an excitatory effect on the CNS. Fentanyl is primarily metabolised in the liver by CYP3A4, making it an attractive choice for patients with renal dysfunction. A sufficiently high dose of opiates creates haemodynamic, hormonal and metabolic stability by blocking both the entire sympathetic nervous system and the hypothalamic-pituitary axis;[33] abolition of the catabolic hormonal response to surgery should be beneficial in diabetic patients. The titration of opiates and related sedative agents should be based on the patient's clinical response that may be exaggerated in diabetes. Alpha-2 agonists reduce both sympathetic tone and the release of norepinephrine from nerve terminals. Clonidine decreases the release of ACTH and cortisol,[34,35] improves peri-operative haemodynamics and decreases the requirement for anaesthetics. The effect on the glycaemic response to surgery in non-diabetic patients is inconsistent,[34 36] but one study reported that premedication with clonidine in type 2 diabetic patients 90 minutes before surgery improved blood glucose control. This treatment also decreased insulin requirements by decreasing circulating catecholamines but had no effect on cortisol concentration or growth hormone secretion. Dexmedetomidine decreased insulin secretion following major surgery without exacerbating the glycaemic response, an effect attributed to a reduction of sympathetic activity. Volatile agents, such as halothane, enflurane and isoflurane inhibit the insulin response to glucose in vitro in a reversible and dose-dependent manner.[3739] Halogenated agents, such as halothane and sevoflurane, produce greater negative inotropic effects in diabetic patients than in non-diabetic patients.[40] The effect of propofol on insulin secretion is not known. Diabetic patients have a reduced ability to clear lipids from the circulation,[41] a fact that is relevant when propofol is used for prolonged sedation in the intensive care unit. One study also demonstrated that propofol produces negative inotropic effects in diabetic cardiomyocytes. [42]

Anaesthetic Technique
No evidence suggests that one anaesthetic technique or another affects mortality or morbidity in diabetic patients. Spinal, epidural or other regional blockade modulate the secretion of catabolic hormones and insulin secretion. In 1980 Halter and Pflug[43]demonstrated that spinal anaesthesia (dermatome level T2T6) induced a reduction in the acute insulin response to glucose, whereas low spinal anaesthesia (dermatome level T9T12) induced no such reduction. Furthermore, regional techniques provide the advantage of allowing the patient to remain conscious and to decrease the surgical stress response. Regional anaesthesia also decreases blood loss and leads to a decreased risk of

thromboembolism. There are, however, some disadvantages of performing a neuroaxial block in diabetic patients, such as cardiovascular instability and the possible exacerbation of peripheral neuropathy due to the fact that nerve fibres in diabetic patients may be more susceptible to anaesthetic toxicity. This increased susceptibility may be the result of the nerves in diabetic patients being exposed to a higher local concentration of anaesthetics due to impaired blood flow and worsened by the fact that the nerves are already stressed by chronic ischaemic hypoxia. [44]

Perioperative Management
Different regimens permit almost any degree of peri-operative glucose control, but the tighter the control desired, the more frequently blood glucose levels must be monitored. It is generally recommended to aim for normoglycaemia in hospitalised patients. However, the degree of glucose control required for improving outcomes is debatable, especially in the immediate pre-and intra-operative period, for patients undergoing non-cardiac surgery. The main concern of the anaesthesiologist in the peri-operative management of diabetic patients has always been the avoidance of harmful hypoglycaemia; made more difficult by the reduced level of consciousness masking its signs and symptoms. Type I diabetic patients need some level of insulin at all times and might be considered candidates for tight control of blood glucose (80110 mg/dL). Type 2 diabetic patients have endogenous insulin and current data support the concept that they do not benefit from similarly tight control unless they are in an intensive care setting. [4550] According to the most recent ACC/AHA guidelines, it is prudent to control glucose levels (< 150 mg/dL) in patients who develop acute hyperglycaemia, or have diabetes and are at risk for acute myocardial infarction and are undergoing vascular or major non-cardiac surgery with a planned intensive care unit admission. [51] Generally speaking, glucose levels > 200 mg/dL are considered detrimental and require treatment. It is important to exclude diabetic ketoacidosis and non-ketotic hyperglycaemic hyperosmolar states in patients presenting with very high glucose levels; surgery in the presence of such conditions carries a high mortality. Glucose levels can deviate significantly in the peri-operative period due to variations in the endogenous production of glucose and insulin, exogenous administration of insulin and insulin sensitivity. Tight glycaemic control (< 110 mg/dL) in the peri-operative period is not universally accepted. Furthermore, one can expect frequent (524%) episodes of hypoglycaemia, potential increases in mortality and the need to monitor glucose levels closely.[52]Maintaining glucose levels to < 180 mg/dL appears to be an appropriate goal.[53,54] The DIGAMI study was the first to show a large reduction in mortality at 1 year among diabetic patients who were treated with an intensive insulin regimen on admission for myocardial infarction with insulin treatment extending to 1 year.[55] However treating diabetic patients in such an aggressive manner using insulin requires consideration of other needs and the increased risk of hypoglycaemia. In implementing this protocol, a patient should be willing to commit to both an acute and a long-term intervention programme to fully improve their prospects.

Summary
Endocrine disorders should be identified and evaluated before surgery. Diabetes affects multiple organ systems, and the peri-operative effects of diabetes can be profound. Peri-operative management should be based on the type of diabetes, end organ dysfunction and the desired degree of glucose control in the peri-operative periods.