The response to stress is mediated through activation of the hypothalamic paraventricular nucleus and locus ceruleus, which in turn activate the pituitary-adrenal axis and sympatho-adrenal system. The responses of these systems are graded with higher levels of stress (e.g., the APACHE score, Glasgow Coma Scale, type of surgery, etc.), leading to higher levels of cortisol and catecholamines [18, 19]. A high cortisol level increases hepatic glucose production, stimulates protein catabolism and increases circulating amino acid concentrations, providing precursors for gluconeogenesis. Epinephrine stimulates glucagon secretion and inhibits insulin release by pancreatic β-cells.

Activation of the pituitary-adrenal and sympatho-adrenal axes acts synergistically with proinflammatory cytokines (TNF-α, IL-1 and IL-6) to induce SIH via an increase in hepatic glucose production and the promotion of insulin resistance. Insulin resistance contributes to increased hepatic glucose production and decreased peripheral glucose uptake [2]. SIH seems to mainly depend on increased hepatic glucose production through the activation of hepatic gluconeogenesis. The TNF-α-mediated increase in glucagon synthesis is thought to play a main role in the increased hepatic gluconeogenesis.

The increased plasma glucose level that occurs during stress alters the body’s homeostasis through multiple partially known mechanisms. The interpretation of how these changes affect homeostasis, either in a positive or negative manner, is the key to considering SIH either as a physiologic and protective adaptation [19] or as an exaggerated and deleterious response that must be reversed [14].

Some authors consider SIH as a means to improve the glucose gradient between the plasma and the intracellular medium in non-insulin-dependent tissues, especially the brain and the reticuloendothelial system, in situations of maldistributed microvascular flow [19]. In fact, a shift in membrane glucose transporters expression occurs during stress that favours the transport of glucose down a concentration gradient to brain cells and macrophages via up-regulation of GLUT-1 [20]. Conversely, expression of GLUT-4, which favours glucose transport to peripheral tissues, is down-regulated during stress [21].

Furthermore, it has been postulated that acute hyperglycaemia may protect against cell death following ischaemia by promoting antiapoptotic pathways and favouring angiogenesis [19]. Hence, endogenous cardioprotective mechanisms, although they have only been tested in animal models, have been demonstrated to become transiently activated by short-term hyperglycaemia through enhancement of vascular endothelial growth factor and nitric oxide synthase (eNOS) expression, NO formation, activation of cell survival signals, and decreased oxidative stress [22].

Conversely, increases in counterregulatory hormones and insulin resistance can be deleterious by increasing lipolysis and free fatty acid concentrations, which may be toxic to the ischaemic myocardium, leading to cardiac arrhythmias, sympathetic overactivity, increased blood pressure, oxidative stress and endothelial dysfunction [23]. In addition hyperglycaemia can impair immune system function by reducing phagocytic activity of macrophages, impairing chemotaxis of polymorphonuclear neutrophils, and increasing expression of adhesion molecules and free radical production in immune cells, which will ultimately increase the risk of infection [24].

In conclusion, the question of whether SIH is beneficial or detrimental cannot be definitively determined because evidence exists in support of both arguments. From a practical standpoint, it would be wise to permit a certain degree of hyperglycaemia, avoiding excessively high glucose levels that can affect immune function and induce osmotic diuresis, volume depletion and electrolyte loss.

Most observational and retrospective studies of hyperglycaemia conducted on patients during the perioperative period have demonstrated a strong association between SIH and poor clinical outcomes, including infections, cardiovascular morbidity, mortality, and overall complications.

Association does not indicate causality; therefore, before recommending a specific glucose-lowering strategy to surgical patients, the beneficial effects of this strategy must be assessed in randomized controlled trials.

The traditional view on glycaemic control in critically ill patients was that acute hyperglycaemia represented a normal, and perhaps beneficial, adaptive response that promoted cellular glucose uptake [45]. In fact, this view is still defended by some experts [19] and supported by some recent publications [46]. With this approach, the tolerant management of SIH (glucose <200 mg/dl) is recommended to avoid the adverse effects of hyperglycaemia and increased osmolarity on granulocyte function [45].

The Leuven trial, conducted in 2001 [47] on critically ill patients in a single centre intensive care unit with predominantly surgical patients, showed benefits of intensive insulin therapy (aiming for a glucose level of between 80 and 110 mg/dl) vs. a conventional approach (aiming for a glucose level of below 215 mg/dl) on mortality, mainly due to improvements in the rates of multiorgan failure with a proven septic focus and morbidity (bloodstream infections, acute renal failure, critical illness polyneuropathy and prolonged mechanical ventilation). However, these positive results have not been reproduced in subsequent trials [14]. Randomized controlled trials conducted after the Leuven trial have mainly evaluated the benefits and risks of strict blood glucose control (between 80 and 110 mg/dl) vs. somewhat more permissive blood glucose control (less than 180 mg/dl (10 mmol/l)) in a mixed surgical and medical population of patients showing no benefits of the intensive strategy [48] or even an increase in 90-day mortality [49]. Interestingly, another randomized, although not blinded, study [50] comparing the intensive approach vs. an even more permissive approach (blood glucose level of between 180 mg/dl and 200 mg/dl (10–11.1 mmol/l)) [10] has also found no benefit of the intensive strategy on either 28-day mortality or morbidity. Furthermore, all of these studies have uniformly shown robust increases in hypoglycaemic events in the intensive arm [51], a fact that might be important in view of the association found between hypoglycaemic events and mortality in critically ill patients [52].

Notably, all of these studies were performed on a mixed population of patients with and without previously diagnosed diabetes, with the proportion of non-diabetic patients ranging from 70 to 87 % [14]. This approach to a complex problem might cause confusion because the treatment effects cannot be assumed to be the same in both groups of patients. Patients with already established diabetes may harbour clinical or subclinical vascular damage that can affect the outcome of acute disease and the response to insulin treatment. Additionally, a certain degree of hyperglycaemia may reflect a substantially different degree of stress, depending on the glycaemic status before the onset of the acute disease. In fact, it can be inferred that patients with diabetes have a higher level of glycaemia than non-diabetic patients experiencing the same level of stress, making it difficult to interpret studies reporting that SIH is particularly detrimental in patients without previously established diabetes [12, 39].

Worldwide epidemiological data indicate that 30–50 % of the population has impaired glycaemic control (diabetes or prediabetes), and up to 30 % of individuals are unaware of their status [53, 54]. Thus, the glucose levels of patients undergoing preoperative evaluation must be checked because unrecognized impaired glycaemia may lead to hyperglycaemia during the intraoperative or postoperative period. Patients especially predisposed to diabetes should be carefully evaluated prior to surgery.

Nevertheless, there is no consensus among scientific societies with regard to the criteria to use to screen for diabetes or prediabetes in asymptomatic patients. The American Diabetes Association recommends screening for diabetes or prediabetes in all adults aged 45 years and at even younger ages in overweight patients with other risk factors such as physical inactivity, a first-degree relative with diabetes, a high-risk ethnicity (African-American, Pacific Islander, or Latino), delivery of a baby weighing >9 lb for females, or the presence of polycystic ovarian syndrome, dyslipidaemia, a history of impaired glycaemia or glycosylated haemoglobin (HbA1c), the presence of hypertension with other clinical conditions associated with insulin resistance, such as obesity or acanthosis, or a history of cardiovascular disease [55]. The US Preventive Services Task Force only recommends screening for diabetes in adults with a blood pressure of >135/80 mmHg [56]. The Endocrine Society Guidelines for the management of hyperglycaemia in hospitalized patients in non-critical care settings recommends laboratory blood glucose testing in all patients upon admission and bedside glucose monitoring with a point-of-care glucose metre in all non-diabetic patients with a blood glucose level of >140 mg/dl (7.8 mmol/l) for at least 24–48 h. The same recommendation applies to patients receiving therapies that promote hyperglycaemia, such as corticosteroids, octreotide and enteral or parenteral nutrition [57]. However, current perioperative recommendations do not advocate testing for diabetes mellitus prior to surgery, except for cardiac surgery [58].

Patients diagnosed with diabetes during the preoperative period must be evaluated by their general practitioner or diabetologist before surgery and treated during the perioperative period, as discussed in a specific chapter of this book on the perioperative management of patients with diabetes.

There is an absence of prospectively controlled studies specifically comparing patients with and without SHI; thus, no consensus has been reached on the intraoperative management of this condition in non-critical patients because no studies have distinguished these patients from previously diabetic patients. Regular monitoring of blood glucose and intravenous insulin therapy with variable rate infusion (VRIII) are the best methods for controlling hyperglycaemia in non-critically ill surgical patients. These methods result in added responsibilities and tasks for anaesthesiologists and nurses during surgical procedures. Guidelines for perioperative glycaemic control in all types of patients recommend defining and implementing a standard protocol for glucose control that must be implemented only after intensive training of all relevant staff [55, 59, 60].

It must be considered that multiple transient factors, such as pain, the type of surgery and the use of some drugs and anaesthetic agents, could modify glycaemia [61]. This issue is addressed in the chapter on the perioperative management of diabetic patients.

Monitoring glycaemia during anaesthesia is the only method available for diagnosing SIH during surgery. Ideally, blood glucose monitoring should be started while the patient is awaiting elective surgery and repeated intraoperatively, although there are no recommendations on the frequency of glycaemic monitoring on the operative day if insulin therapy is not prescribed. When VRIII is used hourly, blood glucose monitoring is mandatory.

Glycaemia may be monitored using a point-of-care glucose metre, which tests for capillary blood glycaemia using a blood gas/glucose analyser, or in the laboratory by performing measurements in whole arterial or venous blood, which is the recommended method by some scientific societies for critically patients and can be used if an arterial line is placed intraoperatively [62]. Levels measured in capillary samples using glucometers may differ by up to 20 % from those reported in laboratory results, and such a discrepancy is acceptable for hyperglycaemia, but not for hypoglycaemia. The accuracy of blood glucose monitoring is affected by various potential patient conditions, such as anaemia, oedema, skin hypoperfusion or concomitant use of drugs, such as dopamine, mannitol or noradrenaline. In these circumstances, the laboratory blood glucose level must be checked regularly.