Secondary Logo

Journal Logo


Perioperative care of diabetic patients

Scherpereel, P. A.; Tavernier, B.

Author Information
European Journal of Anaesthesiology: May 2001 - Volume 18 - Issue 5 - p 277-294



Diabetes mellitus (DM) is the most common metabolic disease and its incidence is increasing. Many new insights concern classification, mechanisms of glucose transport and insulin resistance, clinical aspects during the perioperative period and recent therapeutic approaches, especially new oral hypoglycaemic agents.

The American Diabetes Association (ADA) and the World Health Organisation (WHO) have recently proposed new classifications [1]. Type 1 (instead of juvenile or insulin-dependent diabetes mellitus – IDDM) is immune mediated, associated with idiopathic forms of beta-cells dysfunction, which lead to absolute insulin deficiency. Its incidence remains stable at 0.4% affecting equally males and females, usually young persons Table 1. Type 2 diabetes is a disease of adult onset. Insulin resistance, a major factor in the pathogenesis of Type 2 diabetes mellitus, is due mostly to decreased stimulation of glycogen synthesis in muscle by insulin, related to an inpaired insulin-stimulated glucose transport [2]. The incidence of Type 2 diabetes (previously non-insulin-dependent diabetes diabetes mellitus – NIDDM) rises to 6.6%, reaching 8.0% in the population aged > 65 years. The WHO estimates the number of Type 2 diabetic patients in the world to be 150 million in 2000 and will rise to 213 million in 2010.

Table 1
Table 1:
Classification, physiopathology and prevalence of diabetic mellitus

This increasing frequency is due partly to a greater number of aged patients, but also to an earlier occurrence in younger people. Other explanations are a modification of the definition of the diabetic status by the WHO characterized by a threshold of glycaemia at 7 mmol L−1 (instead of 7.8 mmol L−1 previously), but also an absolute increase linked to environmental factors (obesity, diet, sedentary habit) acting on polygenic predisposition. Type 3 corresponds to a wide range of specific types of diabetes, including various genetic defects of beta-cell function and in insulin action, or both, and diseases of exocrine pancreas: endocrinopathies, drug or chemical-induced, infections.

Type 4 is gestational diabetes, appearing usually at 24–30 weeks, in 4% of pregnancies, 30–50% of them developing a Type 2 diabetes within 10 years. Recent data have been published concerning genetic defects, insulin resistance, and impairment of glucose transport and cell utilization [3]. Insulin improvements, human insulins and more recently modified insulins (Lispro, Novorapid, Glargine), technical progress with bedside monitoring of glycaemia and constant infusion techniques have pushed the risks linked to the imbalance of blood–glucose regulation during the perioperative period into the background [4]. Conversely, end-organ pathology, due to a long-term poorly controlled diabetes, constitutes the prominent risk, and it is more important in Type 2 than in Type 1 diabetes today when patients are better educated to control their blood–glucose concentrations themselves and to manage their own injections of insulin. Impaired glycosylation of proteins due to chronic hyperglycaemia, could be responsible for systemic disorders concerning blood vessels, heart, lungs, kidneys, eyes, nerves and joints, constituting diabetic end-organ pathology [5,6]. A tight glucose control in patients with Type 2 diabetes reduces the incidence of diabetic end-organ pathology [7,8]. For the diabetic patient who is to be exposed to surgery, an accurate evaluation of well being is vital, seeking pathology associated with the diabetes, often neglected or usually silent clinically. Clinical recommendations from scientific societies emphasize the role of this consultation, the transmission of information from the general practitioner and the diabetologist to the anaesthesiologist and maintenance of a record of events and treatments, kept by the patient [9,10].

Glucose metabolism and pathogenesis of diabetes mellitus

Insulin was discovered more than 75 years ago, but the understanding of the pathogenesis of diabetes mellitus begun only recently, especially the mechanisms by which insulin promotes the uptake of glucose into cells [3].

Glucose homeostasis and glucose transport

Blood glucose concentrations need to be maintained within narrow limits. This target can be reached by the finely tuned hormonal regulation of peripheral glucose uptake and hepatic glucose production. A rise in blood–glucose concentration rapidly stimulates insulin secretion. Insulin increases glucose transport, metabolism and storage by muscle and adipocytes but inhibits glucagon secretion and lowers serum free fatty-acid concentrations, leading to a reduction in hepatic glucose production. The lipid bilayer of cell membranes needs carbohydrate-transport systems to be crossed. Recently, two different molecular families of cellular transporters of glucose have been cloned.

  • • Sodium-linked glucose transporters are mainly restricted to the bowel and kidney, allowing an active glucose transport against a glucose concentration gradient [


  • • Facilitated diffusion transporters down glucose concentration gradients. Five homologous transmembrane proteins, GLUT-1, 2, 3, 4 and 5, are encoded by distinct genes with different substrate specificities, kinetic properties and tissue distribution responsible for their functional roles. Impaired glucose transport appears as a cause of decreased insulin-stimulated muscle glycogen synthesis in Type 2 diabetes [

2] and to a lesser extent, insulin resistance contributes to the morbidity associated with Type 1 diabetes.

GLUT-4 is the main insulin-responsive glucose transporter, mainly located in muscle cells and adipocytes. In normal muscle cells and adipocytes, GLUT-4 is recycled between the plasma membrane and intracellular storage pools, but in the absence of insulin, 90% of GLUT-4 is sequestered intracellularly Figure 1. Insulin allows the translocation of GLUT-4 from intracellular storage vesicles to the plasma membrane, thus increasing the glucose transport into the cell [12].

Figure 1.
Figure 1.:
Mechanisms involved in the translocation of GLUT-4 glucose transporters in muscle cells and adipocytes inspired by Shepherd PR, Kahn BB. New Engl J Med 1999; 341: 248–257. Copyright © 1999 Massachusetts Medical Society. All rights reserved.

Insulin-stimulated intracellular movement of GLUT-4 is initiated by the binding of insulin to the extracellular portion of the transmembrane insulin receptor Figure 2. A sequential pathway allowing glucose transport starts with insulin signalizing, via tyrosine kinase phosphorylation [13]. The main substrates for this tyrosine kinase include insulin receptor substrate molecules (IRS-1, 2, 3 and 4). Activation of phosphoinositide-3-kinase induces translocation of GLUT-4 to the plasma membrane then the signalling cascade is followed by the docking of GLUT-4-containing vesicles at the plasma membrane and by their fusion with it [14]. Several proteins have been identified in GLUT-4-containing vesicles, such as an insulin-responsive aminopeptidase. The fusion forms a specific complex that links the GLUT-4-vesicle with the plasma membrane allowing glucose transport across the membrane by a mechanisms of endocytosis [15].

Figure 2.
Figure 2.:
Levels of insulin action corresponding to the receptors according to Scheen AJ and Lefebvre PJ [28] in Chambrier C, sensibilité à l'insulin du métabolism du glucose chez le patient agressé. Thesis 286-99, Université Lyon, 1999.

Possible causes of resistance to the stimulatory effects of insulin on glucose transport

Various mechanisms have been proposed to explain insulin resistance.

Mutations in glucose transporters (GLUT).

Mutations in GLUT-1 are associated with intractable seizures due to a defect in glucose transport across the blood–brain barrier [16], whereas GLUT-2 mutations cause Fanconi–Bickel syndrome [17]. Mutations in GLUT-4 could be involved in insulin resistance but modifications in the GLUT-4-gene are very rare in Type 2 diabetic patients with a prevalence similar to non-diabetic subjects [18].

Tissue-specific alterations in GLUT-4 production.

This is not the cause of insulin resistance in obesity and diabetes, but an increase in GLUT-4 reduces hyperglycaemia and improves insulin sensitivity in experimental diabetes [19]

Defects in the intracellular translocation of GLUT-4.

Diabetes is associated with impairment in insulin-stimulated movement of GLUT-4 from intracellular vesicles to the plasma membrane [20]. Insulin resistance could be the result of a defect in the insulin-signalling pathways, the translocation of GLUT-4 containing vesicles, their docking and their fusion with the membrane [15]. Nevertheless there are at least two different intracellular pools of recruitable GLUT-4 in muscle, and at least one of the pools can respond to stimuli other than insulin in subjects with insulin resistance.

Defects in signalling pathways.

Activation by insulin of phosphatidylinositol-3-kinase in muscle is reduced in diabetic patients [21], but the main defect in signalling may be proximal due to a decrease of the insulin receptor substrate-1 (IRS1) phosphorylation in diabetes.

Impairment of insulin-stimulated glucose transport by circulating or paracrine factors.
  • • Free fatty acids [

22] which decrease uptake of glucose in peripheral tissue.

  • • Glucose and glucosamine [

23]. Hyperglycaemia inhibits insulin secretion and reduces the action of insulin in peripheral tissues, while a tight control of blood–glucose concentrations in diabetic patients can improve insulin resistance in muscle. The mechanisms of glucose toxicity in muscle may involve the hexosamine pathway. Glucosamine reduces insulin-induced stimulation of glucose transport and GLUT-4 translocation in the muscle.

  • • Tumour necrosis factor α (TNFα) inhibits insulin signalling in isolated muscle and adipose tissue [

24]. Nevertheless, monoclonal antibodies that neutralize TNFα and reverse insulin resistance in rats do not improve insulin resistance in Type 2 diabetic patients [25].

Insulin resistance is a major factor in the pathogenesis of diabetes, probably caused by defects in glucose transport, related to impairments in the translocation, docking, fusion and activation of GLUT-4 glucose transporters upon the dependence of alterations in intracellular signalling. Improvement in the action of glucose transporters – by exercise or drugs (sulfonylureas, biguanides, thiazolidinediones, etc.) – increases insulin sensitivity and may reduce the morbidity associated with Type 2 diabetes.

Surgical stress and glucose metabolism

Hyperglycaemia induced by surgical stress results from endocrine modifications characterized by a defect of the synthesis of the unique hormone decreasing the blood–glucose concentration, insulin, and a simultaneous increase of all the counter regulatory hormones: glucagon, cortisol, growth hormone (GH) and epinephrine Figure 3. Epinephrine stimulates glucagon secretion and inhibits the activity of the beta cells, thus responsible for a decreased synthesis of insulin. Glucagon enhances, but transitorily, the hyperglycaemia induced by hypoinsulinism, amplified and prolonged by cortisol [26]. The permanence of hyperglycaemia during the postoperative period suggests a resistance, insensitivity or a lack of response to insulin. During the postoperative period, hyperglycaemia is a consequence of an increased hepatic glycogenolysis. Hyperglycaemia is more important in IDDM, because of the lack of an efficient reactional hyperinsulinism [27]. Insulin resistance concerns all the tissues and all the metabolic systems and results from defect Figure 2 before, after or at the level of the receptor [28]. Nevertheless, the sensitivity to insulin varies in different tissues. In the liver, insulin sensitivity is only reduced, whereas in the peripheral tissues it is nearly abolished.

Figure 3.
Figure 3.:
Neuroendocrine stress response and blood–glucose regulation [4].

The mechanism of the insensibility to insulin is related to a defect of glucose transport. In the muscle after surgery, insulin-stimulated glucose transport is reduced by half due to a decrease or a suppression of GLUT-4 translocation when stimulated by insulin [29].

Mediators involved in the insulin resistance are not yet fully elucidated, but may be independent of stress-induced endocrine reaction, since an insulin resistance may appear after surgery, without a simultaneous increase of catecholamines, glucagon or cortisol [30]. Inflammatory mediators (TNFα, cytokine) interfere with glucose metabolism after surgery [31] but other factors, such as hypocaloric nutrition and bed rest, contribute to insulin resistance after surgery [32].

After surgery, glucose metabolism, but also the metabolism of lipids and proteins, are modified. Lipolysis of triglycerides increases, inducing a release of non-esterified fatty acids (NEFA) and glycerol in the plasma. Glycerol, after hepatic phosphorylation, enters the neoglucogenesis cycle. NEFA represent the major part of energetic substrates during the postoperative period, corresponding to 75–90% of the available calories. Lipolysis depends upon a hormone-dependent lipase, inhibited by insulin, which conversely stimulates lipogenesis.

The postoperative period is characterized by an increased protein catabolism [33] as well as by an increased hepatic synthesis of acute phase proteins, but catabolism increases more than synthesis. Nitrogen balance remains negative despite energy and protein uptake, in relation with the importance of the surgery and eventual complications, but also preoperative nutritional status, age and gender. Protein catabolism has important consequences on wound healing and immune defences. Increased energy production and protein catabolism are due to a hormonal stress response, but also to the production of TNFα and interleukine IL-1. In diabetic patients, metabolic impairments are amplified and the consequences are more deleterious – these are all responsible for postoperative morbidity. This is the reason why it may be of interest to attempt to decrease the stress response to surgery by various pathways: reduction of the surgical wound size by laparoscopic surgery [34–36]; utilization of epidural and/or analgesic anaesthesia [37,38]; and reduction of the effects of hormones and mediators on the target organs by different drugs.

Preoperative assessment of the diabetic patient: risk evaluation

Classically, the pathogenesis of diabetic complications was related to four types of disturbances:

  • • a non-specific macroangiopathy by atherosclerosis;
  • • more specific microvascular lesions, affecting essentially the kidney, the heart and the retina;
  • • an autonomic neuropathy concerning mainly the heart, the gastro-intestinal and urinary tracts;
  • • collagen anomalies responsible for defects in connective tissues.

Today, an unifying hypothesis suggests that an impaired glycosylation of proteins, due to chronic hyperglycaemia, may lead to systemic diseases related to defects in the vessels, heart, lungs, nerves and joints [39].

The preoperative investigation is the most important step in the management of the diabetic patient before surgery [40]. A systematic search of diabetic complications has moved towards target organs and is all the more necessary because a clinical latency is usual.

Cardiovascular risk assessment

The main cardiovascular disturbances observed in the diabetic patient consist of coronary artery disease, arterial hypertension, ventricular function impairment, cardiac dysautonomy and even some instances of sudden death. A recent meta-regression analysis of data from 100 000 patients has shown a relationship between blood–glucose concentration and the incidence of cardiovascular events, even above the diabetes threshold [41].

Diabetic coronary artery disease (CAD).

During the operative period, the diabetic patient must be considered as a high-risk patient for cardiac ischaemia. Myocardial infarction is twice as frequent and represents the more usual cause of death in the aged diabetic patient. Myocardial ischaemia and infarction may be silent and unrecognized because of the sympathetic denervation of the heart [42], which characterizes the cardiac autonomic neuropathy (CAN). This may abolish the heart's adaptation to stress. The detection of coronary artery disease in diabetic patients is difficult [43]. The standard ECG has a poor predictive value, because anomalies are inconsistent. Studies have shown that 15–60% of adult diabetics, without symptoms of CAD, have abnormal exercise electrocardiography and alterations of myocardial perfusion on scintigraphy consistent with CAD. In these cases, coronary angiography is justified only if it leads to a modification of the management in the patient's care [44].

Arterial hypertension.

Arterial hypertension has been reported among 29–54% of patients, with Type 1 or Type 2 diabetes [45]. Initially, the mechanism is similar to an essential hypertension, involving angiotensin II, even if the plasma renin activity (PRA) is classically low in the diabetic patient. In the second stage, an impairment of the glycosylation of collagen proteins can produce a loss of elasticity of the vessel wall, inducing a systolic hypertension. Finally, hypertension becomes permanent when glomerulosclerosis and diabetic nephropathy develop. Treatment is based upon alpha adrenoceptor blocking drugs, calcium-channel blocking drugs, and angiotensin-converting enzyme inhibitors, rather than diuretics and beta-adrenoceptor blocking agents [46].

Diabetic cardiomyopathy.

A specific cardiomyopathy may occur in the diabetic patient without any hypertensive or ischaemic cardiopathy. Diabetes induces modifications of the synthesis of specific proteins by cardiac myocytes and some of these perturbations are rapidly removed by insulin [47]. Other impairments concern the iso-enzyme content of myosin, specific contractile proteins and calcium exchange. The loss of ventricular performance in the diabetic heart is a consequence of increased total calcium content of the cardiomyocyte and a decreased rate of the calcium uptake by sarcoplasmic reticulum and of the adenosin triphosphate activity. Over a longer term, the weakness of the myocardial wall could develop from the deposit of abnormal glycoproteins and collagen [48]. Several studies using Doppler echocardiography have revealed the existence of silent cardiomyopathy in the diabetic patient [49]. Evaluation of left ventricular function using Doppler echocardiography has shown that the impairment observed in the diabetic patient is due to a failure of left ventricular filling rather than a decreased contractility or an increased afterload [50]. The severity of diastolic abnormalities is correlated with microangiopathy, especially retinopathy and nephropathy [51].

Cardiac autonomic neuropathy (CAN).

Autonomic neuropathy is a major complication of diabetes mellitus. CAN involves 20–40% of diabetics with hypertension. Degeneration of afferent and efferent fibres of both sympathetic and parasympathetic nerves of the heart and peripheral vasculature explains the occurrence of painless myocardial ischaemia and infarction and an impaired cardiovascular response to exercise and stress. CAN is independent of age, duration of diabetes or severity of microvascular complications. CAN is thought to increase intraoperative cardiovascular morbidity [52].

The haemodynamic instability, due to the baroreflex impairment, is not well tolerated by the diabetic patient, especially in case of associated cardiopathy or coronary artery disease. Induction of anaesthesia and tracheal intubation do not induce tachycardia or hypertension in the diabetic patient, but are associated with a reduction in cardiac output [53] and hypotension [54]. Nevertheless, haemodynamic instability is inconstant [55].

Tachycardia at rest, orthostatic hypotension and loss of cardiovascular reflexes are reliable signs of CAN and may be easily demonstrated by the preoperative examination [40]. Screening tests for CAN may be used routinely [56] to assess the cardiovascular autonomic function at the bedside [57]. The parasympathetic innervation of the heart (pneumogastric or vagus nerve) can be assessed by the existence of respiratory sinusal dysrhythmia and the response to a Valsalva manoeuvre. The disappearance of heart rate variations induced by deep breaths is a sensitive, reproductible and specific test, at the early stage of the vagal denervation of the heart. The decrease of R-R variations in the ECG is correlated with the cardiac parasympathetic nerve impairment [58] as well as with the suppression of heart rate slowing and blood pressure changes during a Valsalva manoeuvre. The alteration in sympathetic cardiac function can be shown by orthostatic hypotension. The severity of the hypotension can be assessed by a fall in diastolic pressure induced by ‘head-up tilt’ positioning. The response to the ‘cold-pressor test’ is diminished; also diastolic blood pressure increases after surgery of a handgrip maintained for at least 5 min.

A single abnormal test is not sufficient to identify cardiac autonomic neuropathy and a score Table 2 derived from a panel of tests is necessary [59]. Sometimes, defective cardiovascular regulation due to an abnormal sensitivity of the baroreflex cannot be demonstrated by conventional tests for CAN in insulin-dependent diabetic patients [60].

Table 2
Table 2:
Diabetic dysautonomic neuropathy scoring [40]

Some clinical circumstances may have a direct effect on the incidence of perioperative morbidity and mortality.

  • • Cardiorespiratory arrest in relation to a transient hypoxia is responsible for unexpected sudden deaths [


  • • Dysrhythmias, and especialy ventricular fibrillation, are linked to an imbalance between reduced vagal activity and maintained sympathetic tone [

62]. A direct relationship between prolonged QT intervals and ventricular dysrhythmia or the occurrence of sudden death has been demonstrated in diabetic and non-diabetic patients with renal failure [63]

  • • Perioperative haemodynamic instability induced by anaesthesia is now controversial [


Neurological risk

Diabetic neuropathy concerns peripheral sensory and motor nerves, as well autonomic function with CAN, but also alterations in other visceral functions such as stomach and/or bladder paresis, implying important consequences for anaesthetic management. The pathogenesis of diabetic neuropathy remains partly unknown, but it has been suggested that an inhibition of myoinositol uptake by the nerve could induce a deficiency of sodium–potassium ATPase activity, an impaired cellular sodium permeability and neural dysfunction. Nerve ischaemia could be a result of a chronic compression of the vasa nervorum by endoneurial oedema. The accumulation of sorbitol leading to nerve oedema, then to nerve ischaemia, supports the unified hypothesis of both metabolic and vascular mechanisms in the pathogenesis of diabetic neuropathy. Alterations in endothelin-1 release and action could also be significantly involved [64].

Peripheral neuropathy.

Peripheral neurological alterations with mono- or polyneuritis are frequent. When Type 2 diabetes is diagnosed, 7.5% of patients already have clinical symptoms and 15% show electromyographic impairments. After 25 years of evolution, clinical symptoms are present in 50% of diabetic patients and mortality increases from 10% to 27% at 10 years when a peripheral neuropathy exists [65]. During anaesthesia, the risk of nerve compression linked to positioning of the patient is increased [66]. After anaesthesia, pre-existing asymptomatic nerve alterations may appear. Even if a risk demonstrated with local and regional anaesthesia has never been clear in the diabetic patient, it is probably preferable to avoid plexus and truncal blocks with pre-existing motor or sensory abnormalities in order to avoid the implication of the anaesthetist.

Autonomic neuropathy.

Besides cardiac dysfunction, autonomic neuropathy may cause anaesthetic accidents due to diabetic gastroparesis, often associated with alterations of oesophageal motility, with a decrease in its lower sphincter tone, thus increasing the risk of regurgitation and vomiting during induction and in the postoperative period. Gastroparesis, linked to vagal denervation, consists of late gastric emptying, essentially for solid particles, reduced peristalsis and importantly gastric stasis [67]. Gastroparesis may justify an increase in the duration of preoperative starvation or else to perform induction similarly to a method used for a patient with a full stomach. In the postoperative period, gastric emptying may be improved by erythromycin which acts as a motilin-like factor [68].

Unnecessary bladder catheterization must be avoided because of the increased risk of urinary sepsis due to stasis of urine in the bladder; if a catheter has to be used it should be removed at the earliest opportunity.

Respiratory risk

At an early stage of the disease, impairment of respiratory function appears in both Type 1 and Type 2 diabetics. It is present even in the prediabetic state, and progresses rapidly [69] before stabilization, even when the diabetic state is managed correctly. Conversely, if the diabetes is poorly controlled, with a high glycosylated haemoglobin (HbA1c) plasma level, pulmonary function impairment is significantly more important than in a control group correctly treated, with a glycosylated haemoglobin close to normal values [70]. Clinical symptoms, such as dyspnoea, are usually minor. A decrease in the reactivity to cough as well as in the ventilatory response to hypoxia and hypercapnia is observed. Respiratory function tests have shown reduced tidal volume, decreased forced expired ventilation (FEV) and an impairment of carbon monoxyde diffusion (DLCO), related to a loss of lung elastic properties and alterations of transport capacities [71].

Renal risk

In the diabetic patient, the intrinsic renal disease, including glomerulosclerosis and renal papillary necrosis, enhances the risk of acute renal failure in the perioperative period. Major contributing factors are haemodynamic impairment, decreased kidney perfusion and urosepsis, due to the stasis of urine, which is related to autonomic dysfunction of the bladder and diabetic susceptibility to infection. Urinary infection is the most common postoperative complication in the diabetic patient exposed to surgery [72]. Renal failure, with an incidence of 7%, is the most frequent major complication [73]. Microalbuminuria, in a Type 2 diabetic patient, is an early predictive factor of proteinuria, and a witness of general severity of diabetes rather than a specific risk marker of renal failure [74].

Difficult intubation risk and joint abnormalities

Abnormal cross-linking of collagen by a non-enzymatic glycosylation is thought to release abnormal collagen in skin, small vessels, joints and lungs. In Type 1 diabetes, skin-collagen glycation, glycoxidation and cross-linking are lower in subjects with long-term intensive vs. conventional therapy of Type 1 diabetes. Glycated collagen products are more relevant than HbA1c as markers of complications in diabetics [75]. A specific syndrome was been described in 1986 by Salzarulo and Taylor [76] in juvenile-onset diabetes, called ‘stiff joint syndrome’ (SJS). SJS is characterized by a fixation of the atlanto-occipital joint, with a limitation of head extension, associated with a rapidly progressive microangiopathy, a non-familial short stature, a tight waxy skin and a limited joint mobility. The rigidity of the atlanto-occipital joint and the lack of extension of the occiput on the first cervical vertebra make endotracheal intubation difficult or impossible. SJS affects first the small joints of the fingers and hands. Failure to approximate the palmar surfaces of the interphalangeal joints (‘prayer sign’) and the reduced palm print [77] are highly correlated to SJS and may be sensitive predictive factors of difficult laryngoscopy and intubation in diabetics. A lateral cervical radiograph is essential for an accurate diagnosis. A retrospective search has shown a greater than 10-fold increase in the likelihood of difficult laryngoscopy compared with non-diabetic patients [78]. The incidence of SJS was evaluated by meta-regression analysis on the basis of 1500 cases of Type 1 diabetes, from 10 series published in the literature and it was found to be at 33.2%.

Metabolic risk

For a long time, anaesthetists have focused their attention on glycaemic control during the perioperative period, neglecting the preoperative assessment of end-organ pathology, which appears today as the most important factor of morbidity and mortality in the diabetic patient. The end-organ pathology can be prevented by a long-term, tight control of blood glucose in a range of values close to normal. This goal is best achieved by the Type I diabetic patient's education to self-control the glycaemia and to take charge of his own treatment, managing his diet and the insulin injections. Conversely, Type 2 diabetes, which appears later in life, with less acute complications, was neglected for a long time and the poor control resulted in end-organ pathology. Today earlier diagnosis, better control by several classes of hypoglycaemic agents Table 2 and standardized protocols [79] might lead to a decreased morbidity and mortality in Type 2 diabetes. The selection of oral antihyperglycaemic agents as first-line drugs or combined therapy should be based upon both the pharmacological properties of the compounds and the clinical characteristics of the patients [80].

Perioperatively, there is no evidence that outcome is improved when blood glucose is kept near to normal values by a tight control [81] which is necessary in very few circumstances [9]. Conversely, a tight control of glycaemia may induce hypoglycaemia, which is especially dangerous in the anaesthetized patient due to the lack of warning symptoms (sweating, restlessness, stomach pain) and the risk of major cerebral complications in case of prolonged and neglected hypoglycaemia. Hyperglycaemia may cause damage only when significant, leading to hyperosmolarity, polyuria and dehydration. Exceptionally, surgery is responsible for diabetic ketoacidosis. Endocrine response to surgery produces protein catabolism, inducing impairment in wound healing, and an immune depression that explains the increased risk of infection in diabetic patients.

Immune and infectious risk

The susceptibility of diabetic patients to infection is well known [6]. Major hyperglycaemia, even for a short period, facilitates proliferation of germs (bacteria, fungi). They are usually not virulent, but can cause nosocomial infections, fulminating pneumopathy (due to aspergillus) in the diabetic patient. Diabetic imbalance depresses the immune system. The mechanism of postoperative impairment of immune function in the diabetic patient is not yet fully elucidated, but is probably multifactorial implying chemotaxis of polynuclear leucocytes [82] and alterations in leucocyte function [83]. A relationship between the impairment of neutrophil bactericid function and blood–glucose control has been demonstrated [84]. Conversely, insulin infusion improves neutrophil function in diabetic patients scheduled for cardiac surgery [85]. Lymphocytes possess insulin receptors on the surface of the plasma membrane. An increased number of insulin receptors signal the activation of lymphocytes and lymphoblasts under experimental conditions. Antibody synthesis by lymphocyte B and plasmocytes is inhibited in poorly controlled diabetic patients. Nevertheless, neither the type of diabetes, nor HbA1c plasma level, nor the long-term hyperglycaemia explains the alterations in neutrophil chemotaxis [86].

Alterations in other blood cells are observed, especially in platelets, permanently activated in the diabetic patient due to an increased lipid peroxydation [87]. Preoperative assessment of diabetic patients is essential, fully justifying the legally mandatory consultation and data transmission [9].

Anaesthesia for diabetic patients

A rational care of the metabolic state during the perioperative period results in improved management of diabetes and anaesthesia controls the hormonal stress response, as described above.

Locoregional anaesthesia

The possibility of inhibiting the hormonal and metabolic stress response to surgery by epidural analgesia has been widely investigated by Danish anaesthetists [88]. Epidural anaesthesia blocks catecholamine release, irrespective of the segmental level [89], but prevents the increase of blood glucose and ketone bodies only if the block reaches T10 or T8, involving the splanchnic nerves, adrenal medulla and liver [90]. In diabetic patients, often with coronary artery disease, it is interesting to note that epidural anaesthesia reduces oxygen consumption prior to peripheral vascular surgery [91]. During the postoperative period, the maintenance of the epidural analgesia reduces protein catabolism [88].

General anaesthesia

Metabolic and endocrine stress response to surgery might also be inhibited by high doses of potent opioids [92]. Nevertheless, the blockade is limited to the intraoperative period and after surgery segmental levels rapidly become similar to controls [93]. Reduced hyperglycaemia is strictly limited to the operative period, but afterwards the difference compared with the control group disappears. Peroperative increase in lactate and free fatty acids is slight or unmodified. The metabolic benefit of such techniques disappears rapidly in the postoperative period unless analgesia is maintained. Nowadays, there is no convincing argument to prefer locoregional anaesthesia instead of general anaesthesia. Nevertheless, it is important to make anaesthesia as stable as possible, including efficient premedication and adequate analgesia, although pain is not the only factor inducing the stress response. Quality of anaesthesia is especially important when dysautonomia exists. The aim is to obtain haemodynamic stability.

The choice and the type of anaesthesia depends upon existing end-organ pathology more than on the search of an elusive endocrine and metabolic control.

Perioperative blood–glucose control

For a long time, control of blood glucose was considered to be the major problem for diabetic patients requiring anaesthesia. Nowadays, a consensus exists on the basis of the development of new insulins, availability of constant rate infusion by electric syringe pumps, and the possibility of accurate and reliable blood–glucose monitoring at the bedside [9].


Glucose infusion must be perfectly controlled throughout the operative period, unless administration of insulin becomes impossible. If gastric dysautonomia exists the infusion should be started before surgery to allow a longer starvation period. The usual rate of infusion is between 5 and 10 g h−1 or 1.2–2.4 mg kg −1min−1 [94] corresponding approximatively to 125 mL h−1 of 5% glucose i.v. for a normal sized adult.

Short-acting insulins, given i.v., are the only way to adapt delivery of insulin needed immediately during the perioperative period. Human insulin produced by biosynthesis or genetic engineering is used regularly, but a new class of analogues has recently appeared. Among them, insulin Lispro is a newly developed analogue of human insulin, where the positions of the amino acids, lysine and proline, have been switched at the end of the β chain of the insulin molecule [95]. This leads to three major differences in pharmacokinetics: the action of the drug begins faster, it has a higher peak and its duration is shorter than with human insulin. Improvements have been observed in the HbA1c level and in the control of severe resistance to human short-acting insulin [96]. Lispro insulin is effective in the treatment of acutely decompensated Type 1 diabetes and its rapid action may be advantageous [97]. Nevertheless, the absorption profile of Lispro insulin is the same as that of human regular insulin in both syringes and bags. The use of syringes instead of bags, a higher product concentration, faster flow rate and pre-wash of the infusion tubing were shown to substantially decrease the lag time [98].

Other medium and long-acting insulin analogues such as glargine are currently being developed and will provide better metabolic control in time but are not yet used in the perioperative period.

Many therapeutic protocols using various techniques have been proposed. Bolus injections have been abandoned due to the very short plasma half-life of insulin (8 min), producing important glycaemic fluctuations. Infusions of glucose–insulin–potassium (GIK) have the drawback of insulin adsorption on bag and tubing [99]. Insulin i.v. infusions, at constant and modulated flow rates, by an electric syringe pump, in concentrated solutions have become the reference method [100,101]. This technique allows a regular flow rate that is independent of haemodynamic variations, minimizing the doses used, rapid modifications of flow rate and induces an instantaneous effect. It is reliable and safe if simple rules are observed. A simultaneous dextrose infusion at a constant flow rate should be given. The solution should be pre-prepared for a period no longer than 6 h and one i.v. catheter should be devoted exclusively to the insulin infusion.

Bedside monitoring of blood glucose by reagent strips and refractometers, and in the near future by biosensors, is usually adequate. The precision of glucose meters, in the hands of experienced operators, gave a coefficient of variation of 6.7% to 11.1%, with a high correlation with values obtained in the laboratory (0.95–0.98) [102].

Adequate blood–glucose concentrations during the operative period remains subject to controversy. Some authors consider that tight control is useless and potentially dangerous [81] and others think that even for a short period hyperglycaemia is deleterious [103]. Arguments include the possibility of immune depression and an increased risk of infection [104] but the risk of persistent hypoglycaemia in an anaesthetized patient must warn us to be cautious. A blood–glucose concentration maintained between 6.0 and 12.0 mmol L−1 seems to be a reasonable target. A tighter control between 5.5 and 6.7 mmol L−1 (1.0–1.2 g L−1) is only necessary in three special circumstances: aorto-coronary bypass, surgery with interruption of cerebral blood flow and in obstetrics, due to the risk of hypoglycaemia in the newborn by reactional insulin secretion [9].


Old fashion protocols such as ‘no glucose, no insulin’ or reduced doses of insulin have been abandoned because they are inadequate and potentially dangerous. Conversely, the artificial pancreas has an equivocal indication. Insulin and glucose, infused separately at controlled flow rates by electric syringe pumps, are most often used for Type 1 diabetes and/or major surgery [105]. Modalities for the control of the blood–glucose concentration during the perioperative period depend upon the type of diabetes, its control and the type of surgery, whether minor or major, elective or emergency.

General schedule.

Non-insulin-dependent diabetic patients can keep to their usual diet and treatment and can be maintained until the day before surgery if the diabetes is controlled and surgery is minor. Sulphonylureas can be continued without any problems, but traditionally, biguanides must be stopped 48 h before surgery, for fear of a possible lactic acidosis [106]. The preoperative starvation period, surgery and four postoperative hours are covered by a substitutive glucose infusion. If the diabetes is uncontrolled and/or surgery is major, sulphonylureas must be stopped and replaced by i.v. insulin at a constant flow rate, adjusted according to frequent blood–glucose level controls Table 4. Many new oral anti-diabetic agents have appeared during the past years [107], providing a much better control of Type 2 diabetes. New therapeutic schedules involve combinations to cover several mechanisms of action [108] and a whole range of indications Table 5. Sulphonylureas essentially stimulate insulin secretion, biguanides (metformin) act by promoting glucose utilization and reducing hepatic glucose production, alpha-glucosidase inhibitors (acarbose) slow down carbohydrate absorption from the gut and thiazolidinediones (troglitazone) enhance cellular insulin action on glucose and lipid metabolism [109]. Most have been introduced very recently and there is lack of data concerning anaesthesia of the diabetic patients receiving such drugs.

Table 4
Table 4:
Protocols for blood glucose control using 5% dextrose i.v. at a constant flow rate 1.2–2.4 mg kg −1min−1 (125 mL h−1 for an adult)
Table 5
Table 5:
Oral hypoglycaemic agents

Diabetic patients treated with insulin can also be maintained with subcutaneous insulin at the usual dose if the diabetes is well controlled and surgery is short or minor. In that case, oral feeding is substituted by a glucose infusion until return to oral intake. Conversely, if the diabetes is uncontrolled, even for a short operation, and evidently for a major and/or long procedure, it will require a controlled infusion. Insulin doses will be adjusted according to blood–glucose measurements every 30 min initially, then every hour. Potassium is given according to the initial serum potassium concentration and its change in time. In a diabetic patient it is recommended to schedule surgery at the beginning of the morning programme to avoid long-term starvation and additional stress. The return to the previous treatment, for any type of diabetes, is realized when oral feeding is resumed.

Special cases.

Some particular situations require special recommendations [9,110]

  • Ambulatory patients. Diabetes is not a contraindication to day-case surgery for short and minor procedures, for both Type 1 and Type 2 diabetes, when it is correctly controlled. Insulin injection or an oral anti-diabetic drug will be given in the morning on site, the breakfast being replaced by an infusion of glucose. The procedure is scheduled at beginning of the programme to allow a light meal at lunchtime with the aim that the patient will be discharged in the late afternoon, after a final check on the blood–glucose concentration. Vomiting or major hyperglycaemia (> 14 mmol L−1 or 2.5 g L−1) contraindicates return to home.
  • Emergency surgery. In case of emergency, metabolic management will be limited to fast correction of dehydration, major hyperosmolarity or ketoacidosis. Hyperglycaemia alone is not a contraindication to emergency surgery, but severe hyperglycaemia will be treated before induction by injection of one or several i.v. boluses of 5 U insulin to try to decrease the blood–glucose concentration below 11 mmol L−1 (2 g L−1). In case of infection or emergency, aiming for glycaemic control may be elusive as long as the cause is not treated. When gastroparesis exists, due to dysautonomia, the induction technique for anaesthesia must be the same as for a full stomach. Insulin infusion i.v at a constant flow rate is mandatory in emergency cases.
  • Diabetes and pregnancy. Maternal and fetal morbidity and mortality have strongly decreased [

111] but remain a main concern in diabetic mothers. Anaesthetic consultation must be performed early, between the 20th and 24th week of pregnancy, due to the risk of premature delivery and diabetic decompensation.

The anaesthetist's intervention during delivery is often necessary for analgesia or anaesthesia, due to the high frequency of instrumental deliveries and Caesarean sections, but also to take charge of glycaemic control during the peripartum period. Clinical assessment will investigate possible end-organ pathology, dysautonomia and difficult tracheal intubation, linked not only to diabetes but also to the pregnancy. Some obstetric treatments can interfere with diabetes care such as corticosteroids, prescribed to prevent hyalin membrane syndrome, β2 adrenergic drugs used to avoid premature delivery or β-adrenceptor blocking drugs, used in the treatment of hypertension in pregnant patients.

During delivery, tight control of blood–glucose concentration is mandatory, to avoid hypoglycaemia which is likely to stop labour by decreasing the strength of uterine contractions, and the development of hyperglycaemia, causing a risk of fetal hypoglycaemia by reactional insulin secretion. After delivery, the sudden fall of placental lactogen hormone concentration suppresses insulin resistance, implying a reduction of insulin doses by 30–50%, 20 min after delivery. In gestational diabetes, insulin therapy can be stopped after delivery [112]. Conversely in the other types of diabetes, insulin therapy will need to be maintained by i.v. infusion at a constant flow rate, before returning to s.c. injections. Daily doses should usually be reduced by 10–20% compared with the dose used on the day before delivery. Epidural analgesia is specially recommended in pregnant diabetic women; dysautonomia is not a contraindication, if recognized early enough, and previous vascular filling and/or ephedrine infusion can avoid arterial hypotension. Local anaesthetics need to be used in a low concentration, in a reduced volume and without an additional vasoconstrictor agent. Caesarean section will preferably be performed under locoregional anaesthesia to avoid difficulties of intubation and to allow an early oral feeding.

  • Cardiac surgery. Anaesthesia for cardiac surgery in diabetic patients includes some special points:
  • • a high incidence (12%) of diabetes in the history of patients requiring coronary by-pass surgery;
  • • a tight control of blood–glucose concentration during the operative period is justified to avoid brain ischaemia and lowers the risk of wound infection after open heart surgery [


  • • enhanced hyperglycaemia during extracorporeal circulation, requiring increased insulin doses
  • • it is necessary to perfectly assess cardiac function preoperatively, because in addition to coronary artery disease, these patients may have dysautonomia, reduced ventricular compliance and an increased left ventricular diastolic pressure; and
  • • diabetes may increase the risk of anaphylaxis due to treatment with protamine [


  • Neurosurgery. Deleterious effects of hyper- as well as hypoglycaemia on the brain metabolism in ischaemic situations are well known but there is no guideline for anaesthesia in diabetic patients in neurosurgery, except the following recommendations:
  • • blood–glucose concentrations must be carefully monitored during the operative period and should be maintained close to normal values [


  • • sudden glycaemic variations must be avoided and alterations of blood glucose should be gradual;
  • • the use of vasoactive adrenergic drugs, frequently used in neurosurgery, enhances glycaemia.


Control of blood–glucose concentrations during the perioperative period is a problem that can be solved by technology, and the anaesthetist should focus his attention on the end-organ pathology [115]. The latter can be improved by a tighter control of Type 2 [116] as well as Type 1 diabetes [8]. End-organ pathology, investigated before surgery, determines the risk and the choice of monitoring and anaesthetic techniques. Progress in recent years [117] have resulted in better evaluation of the problems and mainly of a stricter application of protocols and guidelines. In the future, improvements may come from a better control in the long term by insulin analogues, new oral anti-diabetic agents, waiting genetic therapy or islets transplantation.


Table 3
Table 3:
Relationship between deterioration of autonomic nervous system and scoring of diabetic dysautonomic neuropathy [40]


1 Committee report. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1999; 22 (Suppl.1):.
2 Cline GW, Petersen KF, Krssak M, et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 1999; 341: 240–246.
3 Sheperd PR, Kahn BB. Mechanisms of disease: glucose transporters and insulin action. Implication for insulin resistance and diabetes mellitus. N Engl J Med 1999; 341: 248–257.
4 Scherpereel P. Le diabétique en période periopératoire. Traité D'endocrinologie – Nutrition. Encycl Méd-Chir. Paris: Elsevier, 10-366-GSO, 2000.
5 Ralley FE. The diabetic patient: a challenge or just a routine? Can J Anaesth 1996; 43: R14–R18.
6 Scherpereel P. Endocrine problems in anaesthetic practice. Curr Opin Anaesthesiol 1990; 3: 439–443.
7 UK Prospective Diabetes Study group (UKPDS Group). Intensive blood-glucose control with sulphonyl ureas or insulin compared with conventional treatment and risks of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853.
8 The Diabetes Control and Complications Trial. Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342: 381–389.
9 Brogard JM, Diemunsch P, Grimaud D, et al. Recommandations de l'ALFEDIAM Diabète et anesthésie: prise en charge du diabétique en période opératoire. Diabète Métab 1995; 21: 197–206.
10 American Diabetes Association (ADA). Clinical practice recommendations. Diabetes Care 1999; 22 (Suppl.1): S1–114.
11 Wright EM, Turk E, Zabel B, Mundlos S, Dyer J. Molecular genetics of intestinal glucose transport. J Clin Invest 1991; 88: 1435–1440.
12 Kandror KF, Pilch PE. Compartmentalization of protein traffic in insulin-sensitive cells. Am J Physiol 1996; 271: E1–E14.
13 Roques M, Pinget M. Les voies de transmission du signal insuline. Med Sci 1996; 12: 1247–1252.
14 Frevert EU, Kahn BB. Differential effects of constitutively active phosphatidylinositol 3 – kinase or glucose transport, glycogen synthase activity and DNA synthesis in 3T3-L1 adipocytes. Mol Cell Biol 1997; 17: 190–198.
15 Rea S, James DE. Moving GLUT-4: the biogenesis and trafficking of GLUT-4 storage vesicles. Diabetes 1997; 46: 1667–1677.
16 Seidner G, Alvarez MG, Yeh JI, et al. GLUT−1 deficiency syndrome caused by haploinsufficiency of the blood–brain barrier hexose carrier. Nat Genet 1998; 18: 188–191.
17 Santer R, Schneppenheim R, Dombrowski A, Gotze H, Steinmann B, Schaub J. Mutations in GLUT-2, the gene for the liver-type glucose transporter, in patients with Fianconi–Bickel syndrome. Nat Genet 1997; 17: 324–326.
18 Bjorbaek C, Echwald SM, Hubricht P, et al. Genetic variants in promoters and coding regions of the muscle glycogen synthase and the insulin responsive GLUT-4 genes in NIDDM. Diabetes 1994; 43: 976–983.
19 Tozzo E, Gnudi L, Kahn BB. Amelioration of insulin resistance in streptozotocin diabetic nice by transgenic overexpression of GLUT-4 driven by an adipose-specific promoter. Endocrinology 1997; 138: 1604–1611.
20 Zierath JR, He L, Guma A, Wahlstrom ED, Klip A, Wallberg-Henriksson H. Insulin action on glucose transport and plasma membrane GLUT-4 content in skeletal muscle from patients with NIDDM. Diabetologia 1996; 39: 1180–1189.
21 Bjornholm M, Kawano Y, Lehtinet M, Zierath JR. Insulin receptor substrate-1 phosphorylation and phosphatidylinositol-3 kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 1997; 46: 524–527.
22 Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46: 3–10.
23 McClain DA, Crook ED. Hexosamines and insulin resistance. Diabetes 1996; 45: 1003–1009.
24 Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA. The expression of TNF alpha by human muscle: relationship to insulin resistance. J Clin Invest 1996; 97: 1111–1116.
25 Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti TNF-alpha antibody (CDP 571) on insulin sensitivity and glycaemic control in patients with NIDDM. Diabetes 1996; 45: 881–885.
26 De Fronzo RA, Sherwin RS, Felig P. Synergistic interactions of counter regulatory hormones: a mechanism for stress hyperglycaemia. Acta Chir Scand 1980; 498 (Suppl.): 33–48.
27 Heise T, Heinemann L, Starke AA. Simulated postaggression metabolism in healthy subjects: metabolic changes and insulin resistance. Metabolism 1998; 47: 1263–1268.
28 Scheen AJ, Lefebvre PJ. Insulin action in man. Diabetes Metabolism 1996; 22: 105–111.
29 Thorell A, Nygren J, Hirshman MF, et al. Surgery-induced insulin resistance in human patients: relation to glucose transport and utilization. Am J Physiol 1999; 276: E754–E761.
30 Thorell A, Nygren J, Ljungqvist O. Insulin resistance: a marker of surgical stress. Curr Opin Clin Nutr Metab Care 1999; 2: 69–78.
31 Blumberg D, Hochwald S, Burt M, Donner D, Brennan MF. Tumor Necrosis Factor alpha stimulates gluconeogenesis from alanine in vivo. J Surg Oncol 1995; 59: 220–224.
32 Nygren J, Thorell A, Efendic S, Nair KS, Ljungqvist O. Site of insulin resistance after surgery: the contribution of hypocaloric nutrition and bed rest. Clin Sci 1997; 93: 137–146.
33 Chambrier C, Aouifi A, Bon C, Saudin F, Paturel B, Bouletreau P. Effects of intraoperative glucose administration on circulating metabolites and nitrogen balance during prolonged surgery. J Clin Anesth 1999; 11: 646–651.
34 Bellon JM, Manzano L, Larrad A, Honduvilla GN, Gujan J, Alvarez-Mon M. Endocrine and immune response to injury after open and laparoscopic cholecystectomy. Int Surg 1998; 83: 24–27.
35 Kristiansson M, Saraste L, Soop M, Sunqvist KG, Thorne A. Diminished interleukin-6 and C- reactive protein responses to laparoscopic versus open cholecystectomy. Acta Anesthesiol Scand 1999; 43: 146–152.
36 Sietses C, Wiezer MJ, Eijbouts QA, et al. A prospective randomized study of the systemic immune response after laparoscopic and conventional Nissen fundoplication. Surgery 1999; 126: 5–9.
37 Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia. Their role in postoperative outcome. Anesthesiology 1995; 82: 1474–1506.
38 Scherpereel P. Reaction endocrinienne et metabolique à la chirurgie: modifications liées aux techniques anesthesiques. In:Conferences D'actualisation 1996 – 38ème Congrès National d'Anesthésie et de Réanimation. Paris: Elsevier, 1996: 317–328.
39 Milaskiewicz RM, Hall GM. Diabetes and anesthesia: the past decade. Br J Anaesth 1992; 68: 198–206.
40 Scherpereel P. Conduite pratique d'une consultation pré-anesthésique chez un diabétique. In: Grimaud D, Ichai C. M., eds. Anesthesie reanimation du patient diabétique. Masson, Paris, 1999: 63–72.
41 Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95,783 individuals followed 12.4 years. Diabetes Care 1999; 22: 233–240. .
42 Milan Study on Atherosclerosis and Diabetes (MISAD) group. Prevalence of unrecognized silent myocardial ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus. Am J Cardiol 1997; 79: 134–139.
43 Paillole C, Ruiz J, Juliard JM, Leblanc H, Gourgon R, Passa P. Detection of coronary artery disease in diabetic patients. Diabetologia 1995; 38: 726–731.
44 Passa P, Drouin P, Issa Sayen M, et al. Coronaires et diabetes, recommandations de l'ALFEDIAM. Diabete Metab 1995; 21: 446–451.
45 Ramos OL. Diabetes mellitus and hypertension. Hypertension 1988; 11: 14–18.
46 Christlieb AR. Treatment selection considerations for the hypertensive diabetic patient. Arch Intern Med 1990; 150: 1167–1174.
47 Gagliero E, Barrieux A, Lehman C, Dillmann WH. Diabetes-induced changes of proteins synthetized by adult cardiac myocytes are partially reversed by insulin. J Moll Cell Cardiol 1988; 20: 427–434.
48 Spector KS. Diabetic cardiomyopathy. Clin Cardiol 1998; 21: 885–887.
49 Thuessen L, Christiansen JS, Mogensen CE, Henningsen P. Echocardiographic determined left ventricular wall characteristics in insulin-dependent diabetic patients. Acta Med Scand 1988; 224: 343–348.
50 Paillole C, Dahan M, Cayaha F, Cohen-Solal A, Passa P, Gourgon R. Prevalence and significance of left ventricular filling abnormalities determined by Doppler echocardiography in young type 1 (insulin dependent) diabetic patient. Am J Cardiol 1989; 64: 1010–1016.
51 Zoneraich S. Small-vessel disease, coronary artery vasodilator reserve and diabetic cardiomyopathy. Chest 1988; 94: 5–8.
52 Burgos LG, Ebert TJ, Asiddao C, et al. Increased intraoperative cardiovascular morbidity in diabetics with autonomic neuropathy. Anesthesiology 1989; 70: 591–597.
53 Vohra A, Kumar S, Charlton AJ, Olukoga AO, Boulton AJM, McLeod D. Effect of diabetes mellitus anaesthesia and tracheal intubation. Br J Anaesth 1993; 71: 258–261.
54 Latson TW, Ashmore TN, Reinhart DJ, Klein KW, Giesecke AH. Autonomic reflex dysfunction in patients presenting for elective surgery is associated with hypotension after anesthesia induction. Anesthesiology 1994; 80: 326–337.
55 Keyl C, Lemberger P, Palitzsch KD, Kochmuth K, Liebold A, Hobbhann H. Cardiovascular autonomic dysfunction and hemodynamic response to anesthetic induction in patient with coronary artery disease and diabetes mellitus. Anesth Analg 1999; 88: 989–991.
56 Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985; 5: 491–498.
57 Raucoules-Aime M, Grimaud D. Prise en charge perioperatoire des sujets à risque. Les diabetiques. Presse Med 1998; 27: 444–451.
58 Tsueda K, Huang KC, Dumont SW, Wieman TJ, Thomas MH, Heine MF. Cardiac sympathetic tone in anesthetized diabetics. Can J Anaesth 1991; 38: 20–23.
59 Piha SJ. Cardiac autonomic reflex tests: normal responses and age related related references values. Clin Physiol 1991; 11: 272–290.
60 Weston PJ, James MA, Panerai RB, McNally PG, Potter JF, Thurston H. Evidence of defective cardiovascular regulation in insulin dependent diabetic patients without clinical autonomic dysfunction. Diabetes Res Clin Prat 1998; 42: 141–148.
61 Page MM, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet 1978; 1: 14–16.
62 Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death. Circulation 1992; 85 (Suppl.): 177–191.
63 Kirvela M, Yli-Han Kal A, Lindgreen L. QT dispersion and autonomic function in diabetic and non diabetic patients with renal failure. Br J Anesth 1994; 73: 801–804.
64 Hopfner RL, Gopalakrisnan V. Endothelin: emerging role in diabetic vascular complications. Diabetologia 1999; 42: 1383–1394.
65 Partanen J, Niskanen L, Lehtinen J, Mervaala E, Shtonen O, Uusitupa M. Natural history of peripheral neuropathy in patients with non insulin dependent diabetes mellitus. N Engl J Med 1995; 333: 89–94.
66 Stoelting RK. Considerations in the anaesthetic management of patients with diabetes mellitus. Curr Opin Anaesthesiol 1996; 9: 245–246.
67 Ishihara H, Singh H, Giesecke AH. Relationship between autonomic neuropathy and gastric contents. Anesth Analg 1994; 79: 943–947.
68 Janssens J, Peeters TL, Vantrappen G, et al. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. Preliminary studies. N Engl J Med 1990; 322: 1028–1031.
69 Lange P, Groth S, Mortensen J et al. Diabetes mellitus and ventilatory capacity: a five year follow-up study. Eur Respir J 1990; 3: 288–292.
70 Ramirez LC, Dal Nogare DA, Hsia C, et al. Relationship between diabetes control and pulmonary in insulin dependent diabetes mellitus. Am J Med 1991; 91: 371–376.
71 Sandler M, Bunn AE, Stewart RI. Cross-section study of pulmonary function in patients with insulin-dependent diabetes mellitus. Am Rev Respir Dis 1987; 135: 223–229.
72 Hjortrup A, Sorensen C, Dyremose E, Jhortso NC, Kehlet H. Influence of diabetes mellitus on operative risk. Br J Surg 1985; 72: 783–785.
73 MacKenzie CR, Charlson MR. Assessment of periperative risk in the patient with diabetes mellitus. Surg Gynecol Obst 1988; 167: 293–299.
74 Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of litterature. Arch Intern Med 1997; 157: 1413–1418.
75 Monnier VM, Bautista O, Kenny D, et al. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial. Diabetes 1999; 48: 870–880.
76 Salzarulo HH, Taylor LA. Diabetic ‘stiff joint syndrome’ as a cause of difficult endotracheal intubation. Anesthesiology 1986; 64: 366–368.
77 Nadal JL, Fernandez BJ, Escobar IC, Black M, Rosenblatt WH. The palm print as sensitive predictor of difficult laryngoscopy in diabetics. Acta Anaesth Scand 1998; 42: 199–203.
78 Hogan K, Rusy D, Springhan SR. Difficult laryngoscopy and diabetes mellitus. Anesth Analg 1988; 67: 1162–1165.
79 Recommandations de l'ANAES. Suivi du patient diabétique de type 2 à l'exclusion du suivi des complications. Diabetes Metab 1999; 25 (Suppl. 2): 1–64.
80 Scheen AJ, Lefebvre PJ. Oral antidiabetic agents. A guide to selection. Drugs 1998; 55: 225–236.
81 Roizen MF. Is tight perioperative control of diabetes warranted ? Anesthesiology 1982; 56: 242.
82 Mowat AG, Baum J. Chemotaxis of polymorphonuclear leucocytes from patients with diabetes mellitus. N Engl J Med 1971; 284: 621–627.
83 Bagdade JD, Rodt RK, Bulger RJ. Impaired leucocyte function in patients with poorly controlled diabetes. Diabetes 1974; 23: 9–15.
84 Gallagher SJ, Thomson C, Frazer WD, et al. Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control. Diabet Med 1995; 12: 916–920.
85 Rassias AJ, Marrin CAS, Arruda J, Whalen PK, Beach M, Yeager MP. Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesth Analg 1999; 88: 1011–1016.
86 Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B. Impaired leucocyte function in diabetics patients. Diabet Med 1997; 14: 29–34.
87 Davi G, Ciabattoni G, Consoli A, et al. In vivo formation of 8-iso-prostaglandin F2alpha and platelet activation in diabetes mellitus. Circulation 1999; 99: 224–229.
88 Kehlet H, Brandt MR, Hanssen AP, Alberti KG. Effect of epidural analgesia on metabolic profiles during and after surgery. Br J Surg 1979; 66: 543–546.
89 Pflug EA, Halter JB. Effects of spinal anesthesia on adrenergic tone and the neurocrine responses. Anesthesiology 1981; 55: 120–126.
90 Engquist A, Brandt MR, Fernandes A, Kehlet H. The blocking effect of epidural analgesia opn the adrenocortical and hyperglycemic responses to surgery. Acta Anaesthesiol Scand 1977; 21: 330–335.
91 Stanley GD, Pierce ET, Moore WS, Lewis KP, Bode RH. Spinal anesthesia reduces oxygen consumption in diabetic patients prior to peripheral vascular surgery. Reg Anesth 1997; 22: 53–58.
92 Hall GM. Fentanyl and the metabolic response to surgery. Br J Anaesth 1980; 52: 561–562.
93 Walsh ES, Paterson JL, O'Riordan JBA, Hall GM. Effects of high-dose fentanyl anaesthesia on the metabolic and endocrine response to cardiac surgery. Br J Anaesth 1981; 53: 1155–1165.
94 Hirsch IB, McGill JB, Cryer PE, White PF. Perioperative management of surgical patients with diabetes mellitus. Anesthesiolgy 1991; 74: 346–359.
95 Koivisto VA. The human insulin analogue insulin lispro. Ann Med 1998; 30: 260–266.
96 Noble SL, Johnston E, Walton B. Insulin lispro: a fast-acting insulin analog. Am Fam Physician 1998; 57: 279–286.
97 Attia N, Jones TW, Holcomb J, Tamborlane WV. Comparison of human regular and lispro insulins after interruption of continuous subcutaneous insulin infusion and in the treatment of acutely decompensated IDDM. Diabetes Care 1998; 21: 817–821.
98 Ling J, Hu M, Hagerup T, Campbell RK. Lispro insulin: adsorption and stability in selected intravenous devices. Diabetes Educ 1999; 25: 237–245.
99 Alberti KG. Diabetes and surgery. Anesthesiology 1991; 74: 209–211.
100 Scherpereel P, Lefebvre J, Fourlinnie JC, Robelet D. Insulinothérapie intraveineuse par faible doses à débit constant dans le traitement du coma diabétique. Anesth Analg 1977; 34: 1263–1275.
101 Taitelman U, Reece EA, Bessman AN. Insulin in the management of the diabetic surgical patient. Continuous intravenous infusion versus subcutaneous administration. JAMA 1977; 237: 658–660.
102 Ting C, Nanjii AA. Evaluation of the quality of beside monitoring of the blood glucose level in a teaching hospital. CMAJ 1988; 138: 23–26.
103 Palumbo PJ. Blood glucose control during surgery. Anesthesiology 1981; 55: 94–95.
104 Assan R, Reach G, Poussier P. Controle de la glycémie et insulinothérapie en milieu chirurgical. Ann Chir 1981; 35: 728–729.
105 Watts NB, Gebhart SSP, Clark RV, Philipps LP. Postoperative management of diabetes mellitus: steady-state glucose control with bedside algorithm for insulin adjustement. Diabetes Care 1987; 10: 722–728.
106 Peters A, Kerner W. Perioperative management of the diabetic patient. Rev Expt Clin Endocrinol 1995; 103: 213–218.
107 Brown DL, Brillon D. New directions in type 2 diabetes mellitus: an update of current oral antidiabetic therapy. J Natl Med Assoc 1999; 91: 389–395.
108 De Fronzo RA. Pharmacology therapy for type 2diabetes mellitus. Ann Inter Med 1999; 131: 281–303.
109 Scheen AJ, Lefebvre PJ. Troglitazone: antihyperglycemic activity and potential role in the treatment of type 2 diabetes. Diabetes Care 1999; 22: 1568–1577.
110 Santelli D, Ortega D, Martin D. Anesthesie du diabétique en situations particulières (ambulatoire, urgences, femme enceinte, chirurgie cardiaque et neurochirurgie). In: Grimaud D, Ichai C, M, eds. Anesthesie réanimation du patient diabétique. Masson, Paris, 1999: 95–112.
111 Rees GA, Hayes TM, Pearson JF. Diabetes, pregnancy and anaesthesia. Clin Obst Gynaecol 1982; 9: 311–312.
112 Jovanovic-Peterson L, Peterson CM. Pregnancy in the diabetic women: guidelines for a successful outcome. Metab Clin North Am 1992; 21: 433–456.
113 Zerr NJ, Furnary AP, Grunkeiermaier GR, Bookin S, Kanhere V, Starr A. Glucose control lowers the risk of wound infection in diabetics after open heart surgery operation. Ann Thor Surg 1997; 63: 356–361.
114 Takenoshita M, Sugiyama M, Okuno Y, Inagaki Y, Yoshiba I, Shimazaki I. Anaphylactoïd reaction to protamine confirmed by plasma tryptase in a diabetic patient during open heart surgery. Anesthesiology 1996; 84: 233–235.
115 Ralley FE. The diabetic patient: a challenge or just a routine ? Can J Anaesth 1996; 43: R14–R18.
116 Laakso M. Benefits of strict glucose and blood pressure control in type 2 diabetes. Lessons from the UK prospective diabetes study. Circulation 1999; 99: 461–462.
117 The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342: 381–389.
118 Elridge AJ, Sear JW. Perioperative management of diabetic patients. Any changes for the better since 1985? Anaesthesia 1996; 51: 45–51.


    © 2001 European Academy of Anaesthesiology