**3. The stress hyperglycemia and adverse outcomes in surgical patients**

The hyperglycemic response to acute stress induced by surgery was initially considered a beneficial-adaptive response, being the raised blood glucose a ready "source of fuel" for several tissues including the neural and cardiac-muscle cells. However, retrospective studies in patients undergoing cardiac surgery have suggested that perioperative hyperglycemia was associated with an increased risk of post-operative infections and an increased mortality (50-52). Furthermore, these studies suggested that control of blood glucose reduced these complications. The severity of hyperglycemia depends on many factors as showed in Table 1. There are different mechanisms in which a variety of risk factors affect the glucose metabolism and insulin responsiveness (53). Specifically, on surgeryinvasiveness: the more invasive the surgery, the more intense the hyperglycemia (11, 54). Stress hyperglycemia has many deleterious effects, including vasodilatation, impaired

Fig. 3. The relationship between the abnormal glucose usage and physiological stress is exposed. Stress modifies the carbohydrate metabolism, the augmented glucose production and a diminished glucose uptake raises blood glucose levels, as well as the glucose intracellular metabolism is deviated.

reactive endothelial nitric oxide generation, decreased complement function, increased expression of leukocyte and endothelial adhesion molecules, increased cytokine levels, and impaired neutrophyle chemotaxis and phagocytosis, leading to increased inflammatory state and infection-vulnerability, and multiorgan system dysfunction (55). Others effects of excessive glucose levels include the impairment in hepatic functions, abolishment of ischemic preconditioning, and protein glycosylation (56).

Cardiac Surgery has been traditionally considered a highly-invasive procedure (57, 58) and taking in account that the hyperglycemic response is increased by anesthetics and the preoperative emotional stress (59), this major surgery, induces the release of several counterregulatory hormones and deeply modifies the metabolism of carbohydrates, causing increased hepatic gluconeogenesis, insulin resistance in various peripheral tissues, and the relative insulin production deficiency (60,61). This insulin resistance has been related to an increased risk of postoperative complications in cardiac surgery, regardless of the patient´s diabetic status (62).

These metabolic and physiological responses to surgical stress often cause maintaining euglycemia during a cardiac surgery, to become a very difficult goal. Nevertheless, the reports about association of hyperglycemia and adverse outcomes in cardiac surgery make

Non Glucosydic Substrates

**Physiological Stress**

**Alteration in post-receptor signaling**

Hepatic Gluconeogenesis /Glycogenolysis

**>140mg/dl (ACP/AACE**)

Fig. 3. The relationship between the abnormal glucose usage and physiological stress is exposed. Stress modifies the carbohydrate metabolism, the augmented glucose production

↑Glucolysis

Peripheral Resistance

reactive endothelial nitric oxide generation, decreased complement function, increased expression of leukocyte and endothelial adhesion molecules, increased cytokine levels, and impaired neutrophyle chemotaxis and phagocytosis, leading to increased inflammatory state and infection-vulnerability, and multiorgan system dysfunction (55). Others effects of excessive glucose levels include the impairment in hepatic functions, abolishment of

Cardiac Surgery has been traditionally considered a highly-invasive procedure (57, 58) and taking in account that the hyperglycemic response is increased by anesthetics and the preoperative emotional stress (59), this major surgery, induces the release of several counterregulatory hormones and deeply modifies the metabolism of carbohydrates, causing increased hepatic gluconeogenesis, insulin resistance in various peripheral tissues, and the relative insulin production deficiency (60,61). This insulin resistance has been related to an increased risk of postoperative complications in cardiac surgery, regardless of the patient´s

These metabolic and physiological responses to surgical stress often cause maintaining euglycemia during a cardiac surgery, to become a very difficult goal. Nevertheless, the reports about association of hyperglycemia and adverse outcomes in cardiac surgery make

and a diminished glucose uptake raises blood glucose levels, as well as the glucose

intracellular metabolism is deviated.

**↓Glucose Uptake**

**≠Glucose Usage**

**↑Glucose Production**

**↑Glycemia**

diabetic status (62).

ischemic preconditioning, and protein glycosylation (56).

the glycemic control, something indispensable. Cardiac surgery mortality, tightly correlated to glucose blood levels, becomes significant lower when glycemia reaches less than 150 mg/dl (63) and it raises to even 17% with every 1 mmole/l (18 mg/dl) over 6.8 mmole/l (110 mg/dl) (61,64). Hyperglycemia during cardiac procedures and pulmonary bypass is severe, particularly in diabetic patients - who comprise a significant percentage of the patient population that undergo cardiac surgery. As it was commented, this impairment in glucose metabolism is related considerably to the metabolic response to surgical trauma, but it is associated mostly to specific aspects of cardiopulmonary bypass, such as heparinization, hypothermia, and rewarming (65, 66).

Independently of controversy about the reports on tight control of glycemia during perioperative period, is well known than poor perioperative glycemic control is associated with an increased morbidity and mortality.

#### **4. Approaches on glycemic control during the perioperative period in cardiac surgery**

In 2001, van den Berghe and coworkers (67) published a "landmark study" named "The Leuven Intensive Insulin Therapy Trial". In this study, they demonstrated that in critically-ill patients –the majority of them undergoing cardiac surgery- the Tight Glycemic Control (TGC) (blood glucose between 80-110 mg/dl) using intensive insulin therapy (IIT), improved the general clinical outcome (significant reduction in mortality; 42%) (67). After this study was published, TGC became rapidly adopted as the reference standard of care in surgical ICUs throughout the world (63, 68). The publication of new randomized controlled trials has diminished the initial enthusiasm on TGC because it has also been linked with increased morbidity and mortality. In last decade, there have been reports about the IIT has led to an increased iatrogenic rate of hypoglycemia episodes, emerging as an important risk factor for mortality exceeding, in some cases, the mortality-risk associated with hyperglycemia. In fact, even moderate and short hypoglycemia events in the ICU can produce permanent brain damage (69). After van den Berghe's work, two multicenter-randomized European studies were prematurely discontinued due to an alarmingly high rate of hypoglycemia in the TGC arm, showing no mortality benefits (70, 71). Two additional single centers, randomized studies showed a trend towards a higher mortality in the TGC arm (72, 73). TGC is strongly associated with an even sixfold-increase in episodes of severe hypoglycemia (glucose levels < 2.2 mmole/l, 40 mg/dl) (20) and, as mentioned before, this state can have dramatically adverse effects such as coma or even death (74). The recent NICE-SUGAR study showed that an intensive glucose control increased mortality among ICU adults, and that an 81-108 mg/dl target was too ambitious and potentially dangerous (12).

On the other hand, glucose variability has emerged as another important factor associated with mortality (75). Glucose profiles from patients are characterized by important fluctuations, even during continuous intravenous insulin infusion. However, many of the reported trials have evaluated the effects of IIT based on the absolute glucose levels, although clinical effects of IIT should be interpreted using temporal courses (76, 77). From this point of view, we should consider simultaneously the combined and independent clinical impact of glycemia's sudden fluctuations, glycemia temporal trends, and glycemia variability during hospitalization. In this way of thought, in a study including over 7,000 critically ill patients was demonstrated that the standard deviation of glucose concentration is a significant independent predictor of ICU and hospital mortality (78). Recently, it has been reported a relationship between ICU mortality and glucose variability in a cohort of 5,728 patients managed with IIT (79).

Although there is agreement that both hyperglycemia and hypoglycemia are deleterious, and that we should consider the fluctuations in blood glucose levels, there is no a consensus on the target glucose values to enhance desirable clinical outcomes. In this regard, relatively recent guidelines have been published from different international study-groups, like the American College of Physicians (ACP), American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE) and the European Society of Cardiology (ESC) (80,81). The next section is related with recommendations about management of hyperglycemia in both patients with and without diabetes undergoing cardiac surgical, and the procedures that should be taken into account during the perioperative period, obtained from the Society of Thoracic Surgeons (STS) Practice Guideline series (81), which is derived in turns from evidence-based recommendations. We consider these guidelines as the most important work on the glucose management in cardiac surgery and we mention several paragraphs textually.

In summary, these useful guidelines offer some central ideas about the management of glycemia during cardiac surgery. The first of them is about detrimental effects of hyperglycemia in perioperative period, and they highlight that poor perioperative glycemic control is associated with increased morbidity and mortality, quoting the guidelines: "Collectively, these studies strongly suggest that increased fasting glucose levels during and immediately after cardiac surgery, are predictive of increased perioperative morbidity and mortality in patients with and without diabetes" (81). In this regard, the following central idea is about the beneficial effects of glycemic control on clinical outcomes during cardiac surgery, and afterwards, it recommends - after a review of the most important randomized trials - a glycemic control <180 mg/dl, mainly in patients with diabetes during cardiac surgery.

In the following paragraph, guidelines are focused about glycemic control in patients without diabetes during cardiac surgery, and they point –after analyzing several randomized trials of good quality- that "intraoperative glycemic control using intravenous insulin infusions is not necessary in cardiac surgery patients without diabetes, as well as glucose values remain < 180 mg/dl. This previous conclusion was obtained from the comparison between groups with TGC using IIT and without insulin finding no difference in the primary outcome, which consisted of the composite incidence of death, sternal wound infections, prolonged ventilation, cardiac arrhythmias, strokes, and renal failure within 30 days of surgery (82). There was also no difference in ICU or hospital stay between the groups. There was a tendency for more deaths (p=0.06) and strokes (p=0.02) in the IIT".

In the next section, the guidelines point to management of hyperglycemia using insulin protocols in the perioperative period considering that intravenous insulin therapy is the preferred method of insulin delivery during this period. It is used an evidence-based recommendations, depending on the procedure it is classified as beneficial, useful and effective (table 3; ref. 81). The recommendations class I are based on when glycemic control is best achieved with continuous insulin infusions rather than intermittent subcutaneous insulin injections or intermittent intravenous insulin boluses (level of evidence A). In addition, all patients with diabetes undergoing cardiac surgical procedures should receive an insulin infusion in the operating room, and for at least 24 hours postoperatively to maintain serum glucose levels 180 mg/dl (level of evidence=B; table 3).

Following the recommendations of the guidelines, the next part refers to the perioperative management and assessment for patients with diabetes. The next recommendations are classified after an exhaustive analysis of several trials with this kind of patients. Thus, we

been reported a relationship between ICU mortality and glucose variability in a cohort of

Although there is agreement that both hyperglycemia and hypoglycemia are deleterious, and that we should consider the fluctuations in blood glucose levels, there is no a consensus on the target glucose values to enhance desirable clinical outcomes. In this regard, relatively recent guidelines have been published from different international study-groups, like the American College of Physicians (ACP), American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE) and the European Society of Cardiology (ESC) (80,81). The next section is related with recommendations about management of hyperglycemia in both patients with and without diabetes undergoing cardiac surgical, and the procedures that should be taken into account during the perioperative period, obtained from the Society of Thoracic Surgeons (STS) Practice Guideline series (81), which is derived in turns from evidence-based recommendations. We consider these guidelines as the most important work on the glucose management in cardiac surgery and we mention several paragraphs textually. In summary, these useful guidelines offer some central ideas about the management of glycemia during cardiac surgery. The first of them is about detrimental effects of hyperglycemia in perioperative period, and they highlight that poor perioperative glycemic control is associated with increased morbidity and mortality, quoting the guidelines: "Collectively, these studies strongly suggest that increased fasting glucose levels during and immediately after cardiac surgery, are predictive of increased perioperative morbidity and mortality in patients with and without diabetes" (81). In this regard, the following central idea is about the beneficial effects of glycemic control on clinical outcomes during cardiac surgery, and afterwards, it recommends - after a review of the most important randomized trials - a

glycemic control <180 mg/dl, mainly in patients with diabetes during cardiac surgery.

maintain serum glucose levels 180 mg/dl (level of evidence=B; table 3).

Following the recommendations of the guidelines, the next part refers to the perioperative management and assessment for patients with diabetes. The next recommendations are classified after an exhaustive analysis of several trials with this kind of patients. Thus, we

In the following paragraph, guidelines are focused about glycemic control in patients without diabetes during cardiac surgery, and they point –after analyzing several randomized trials of good quality- that "intraoperative glycemic control using intravenous insulin infusions is not necessary in cardiac surgery patients without diabetes, as well as glucose values remain < 180 mg/dl. This previous conclusion was obtained from the comparison between groups with TGC using IIT and without insulin finding no difference in the primary outcome, which consisted of the composite incidence of death, sternal wound infections, prolonged ventilation, cardiac arrhythmias, strokes, and renal failure within 30 days of surgery (82). There was also no difference in ICU or hospital stay between the groups. There was a tendency for more deaths (p=0.06) and strokes (p=0.02) in the IIT". In the next section, the guidelines point to management of hyperglycemia using insulin protocols in the perioperative period considering that intravenous insulin therapy is the preferred method of insulin delivery during this period. It is used an evidence-based recommendations, depending on the procedure it is classified as beneficial, useful and effective (table 3; ref. 81). The recommendations class I are based on when glycemic control is best achieved with continuous insulin infusions rather than intermittent subcutaneous insulin injections or intermittent intravenous insulin boluses (level of evidence A). In addition, all patients with diabetes undergoing cardiac surgical procedures should receive an insulin infusion in the operating room, and for at least 24 hours postoperatively to

5,728 patients managed with IIT (79).


Modified from ref. 29: McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. *Crit Care Clin* 2001; 17: 107-24.

Table 2. Major actions of counterregulatory hormones and cytokines in stress hyperglycemia

Class I: Conditions for which there is evidence for and/or general agreement that the procedure is beneficial, useful, and effective.

Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment

Class IIA: Weight of evidence/opinion is in favor of usefulness/efficacy

Class IIB: Usefulness/efficacy is less well-established by evidence/opinion

Class III: Conditions for which there is evidence or general agreement that the procedure/treatment is not useful/effective, or both, and in some cases may be harmful

Level of Evidence – A: Data derived from multiple randomized clinical trials

Level of Evidence – B: Data derived from a single randomized trial or nonrandomized studies

Level of Evidence – C: Only consensus opinion of experts, case studies, or standard- ofcare

Modified from ref. 81: Lazar. *Ann Thorac Surg* 2009; 87: 663-669.

Table 3. Classification system used for evidence based recommendations from society of thoracic surgeons practice guidelines

have summarized the experience of these trials. Class I: a) "patients taking insulin should hold their nutritional insulin after dinner the evening prior to surgery (level of evidence=B). b) Scheduled insulin therapy, using a combination of long-acting and short-acting subcutaneous insulin, or an insulin infusion protocol, should be initiated to achieve glycemic control for in-hospital patients awaiting surgery (level of evidence=C; table 3). c) All oral hypoglycemic agents and noninsulin diabetes medications should be held for 24 hours prior to surgery (level of evidence=C). d) The hemoglobin A1c (HbA1c) level should be obtained prior to surgery in patients with diabetes or those patients at risk for postoperative hyperglycemia to characterize the level of preoperative glycemic control" (level of evidence=C; table 3). Class IIA. Prior to surgery, it is reasonable to maintain blood glucose concentration 180 mg/dl (level of evidence=C; table 3). Efforts should be made to optimize glucose control prior to surgery, because poor preoperative glycemic control has been associated with increased mortality, including a higher incidence of deep sternal wound infections and prolonged postoperative length of stay. In general, all oral diabetes medications should be withheld within 24 hours prior to surgery, especially sulfonylureas (eg, glipizide) and glinides (eg, nateglinide or repaglinide). These drugs can induce hypoglycemia in the absence of food. Patients who are taking insulin and who are admitted on the day of surgery should be instructed to continue their basal insulin dose (eg, glargina, determir or NPH) and hold their nutritional insulin (eg, lispro, aspart, glulisine, or regular) unless instructed otherwise by their primary physician. The NPH insulin may be reduced by one half or one third of the dose prior to surgery to avoid hypoglycemia.

"To achieve rapid control in hospitalized patient with hyperglycemia (glucose 180 mg/dl for more than 12 hours before surgery), insulin therapy -either with intravenous variablerate continuous infusion or subcutaneous basal plus rapid-acting insulin- should be used depending on the availability of either therapy. For the hyperglycemic patient in the preoperative area, on the day of surgery, IV insulin therapy is an effective way to achieve immediate control. Patients with a known history of diabetes (either type 1 or type 2) can be started immediately on IV therapy in the preoperative area. All preoperative medications should be reviewed to determine the potential for insulin resistance. These include steroids, protease inhibitors, and anti-psychotic drugs. Finally, patients with renal insufficiency should be identified, because insulin clearance is impaired and the risk for hypoglycemia is increased".

Next section is the "intraoperative control recommendations". Above recommendations are classified upon the level of evidence and quality of trials. Class I. a) Glucose levels 180 mg/dl that occur in patients without diabetes only during cardiopulmonary bypass may be treated initially with a single or intermittent dose of IV insulin as long as levels remain 180 mg/dl. However, in those patients with persistently elevated serum glucose ( 180 mg/dl) after cardiopulmonary bypass, a continuous insulin drip should be instituted, and an endocrinology consult should be obtained (level of evidence = B; table 3). b) If an intravenous insulin infusion is initiated in the preoperative period, it should be continued throughout the intraoperative and early postoperative period according to institutional protocols to maintain serum glucose 180 mg/dl (level of evidence = C; table 3).

Concerning glycemic control in the ICU, guidelines recommend the following procedures: Recommendation Class I. a) Patients with and without diabetes with persistently elevated serum glucose ( 180 mg/dl) should receive IV insulin infusion to maintain serum glucose 180 mg/dl for the duration of their ICU care (level of evidence = A; table 3). b) All patients who require 3 days in the ICU because of ventilatory dependency or requiring the need for inotropes, intra-aortic balloon pump, or left ventricular assist device support, antiarrhythmics, dialysis, or continuous veno-venous hemofiltration should have a continuous insulin infusion to keep blood glucose 150 mg/dl, regardless of diabetic status (level of evidence =B; table 3). b) Before intravenous insulin infusions are discontinued, patients should be transitioned to a subcutaneous insulin schedule using institutional protocols (level of evidence=B; table 3).

hours prior to surgery (level of evidence=C). d) The hemoglobin A1c (HbA1c) level should be obtained prior to surgery in patients with diabetes or those patients at risk for postoperative hyperglycemia to characterize the level of preoperative glycemic control" (level of evidence=C; table 3). Class IIA. Prior to surgery, it is reasonable to maintain blood glucose concentration 180 mg/dl (level of evidence=C; table 3). Efforts should be made to optimize glucose control prior to surgery, because poor preoperative glycemic control has been associated with increased mortality, including a higher incidence of deep sternal wound infections and prolonged postoperative length of stay. In general, all oral diabetes medications should be withheld within 24 hours prior to surgery, especially sulfonylureas (eg, glipizide) and glinides (eg, nateglinide or repaglinide). These drugs can induce hypoglycemia in the absence of food. Patients who are taking insulin and who are admitted on the day of surgery should be instructed to continue their basal insulin dose (eg, glargina, determir or NPH) and hold their nutritional insulin (eg, lispro, aspart, glulisine, or regular) unless instructed otherwise by their primary physician. The NPH insulin may be reduced by

"To achieve rapid control in hospitalized patient with hyperglycemia (glucose 180 mg/dl for more than 12 hours before surgery), insulin therapy -either with intravenous variablerate continuous infusion or subcutaneous basal plus rapid-acting insulin- should be used depending on the availability of either therapy. For the hyperglycemic patient in the preoperative area, on the day of surgery, IV insulin therapy is an effective way to achieve immediate control. Patients with a known history of diabetes (either type 1 or type 2) can be started immediately on IV therapy in the preoperative area. All preoperative medications should be reviewed to determine the potential for insulin resistance. These include steroids, protease inhibitors, and anti-psychotic drugs. Finally, patients with renal insufficiency should be identified, because insulin clearance is impaired and the risk for hypoglycemia is

Next section is the "intraoperative control recommendations". Above recommendations are classified upon the level of evidence and quality of trials. Class I. a) Glucose levels 180 mg/dl that occur in patients without diabetes only during cardiopulmonary bypass may be treated initially with a single or intermittent dose of IV insulin as long as levels remain 180 mg/dl. However, in those patients with persistently elevated serum glucose ( 180 mg/dl) after cardiopulmonary bypass, a continuous insulin drip should be instituted, and an endocrinology consult should be obtained (level of evidence = B; table 3). b) If an intravenous insulin infusion is initiated in the preoperative period, it should be continued throughout the intraoperative and early postoperative period according to institutional

Concerning glycemic control in the ICU, guidelines recommend the following procedures: Recommendation Class I. a) Patients with and without diabetes with persistently elevated serum glucose ( 180 mg/dl) should receive IV insulin infusion to maintain serum glucose 180 mg/dl for the duration of their ICU care (level of evidence = A; table 3). b) All patients who require 3 days in the ICU because of ventilatory dependency or requiring the need for inotropes, intra-aortic balloon pump, or left ventricular assist device support, antiarrhythmics, dialysis, or continuous veno-venous hemofiltration should have a continuous insulin infusion to keep blood glucose 150 mg/dl, regardless of diabetic status (level of evidence =B; table 3). b) Before intravenous insulin infusions are discontinued, patients should be transitioned to a subcutaneous insulin schedule using institutional protocols

protocols to maintain serum glucose 180 mg/dl (level of evidence = C; table 3).

one half or one third of the dose prior to surgery to avoid hypoglycemia.

increased".

(level of evidence=B; table 3).

Finally, the Glycemic control in the stepdown units and on the floor recommendations is the last part of the guidelines. Class I. a) A target blood glucose level 180 mg/dl should be achieved in the peak postprandial state (level of evidence = B; table 3). b) A target blood glucose level 110 mg/dl should be achieved in the fasting and pre-meal states after transfer to the floor (level of evidence = C; table 3). c) Oral hypoglycemic medications should be re-started in patients who have achieved target blood glucose levels if there are no contraindications. Insulin dosages should be reduced accordingly (level of evidence = C; table 3). d) According to the AACE, a reasonable goal for a noncritically ill patient on a regular hospital ward is 110 mg/dl and 180 mg/dl postprandial or randomly (83). The best method to realize this control is with scheduled subcutaneous basal and, or bolus insulin therapy, such as glargine or determir (basal) and lispro, aspart, or glulisine (bolus). Patients with type 2 diabetes who have used oral diabetes medications preoperatively can be restarted on those medications once they have reached their targeted glucose goals and are eating a regular diet. Metformin should not be restarted until stable renal function has been documented. In relation to preparation for hospital discharge, the guidelines recommend that prior to discharge, all patients with diabetes and those who have started a new glycemic control regimen, should receive in-patient education regarding glucose monitoring, medication administration (including subcutaneous insulin injection if necessary), nutrition, and lifestyle modification (level of evidence = C, table 3). Upon discharge, changes in therapy for glycemic control should be communicated to primary care physicians, and follow up appointments should be arranged with an endocrinologist when appropriate (level of evidence = C, table 3). All patients with hyperglycemia after cardiac surgery should be assessed by an inpatient diabetes team to decide on a glycemic control program after discharge.

The conditions that are important to consider are, in summary: avoidance of deep hypothermia, excessive blood losses, a prolonged preoperative fasting period and prolonged immobilization, because all these conditions augment perioperative insulin resistance. In addition, considering that most anesthetic agents cause hyperglycemia, the choice of anesthetic agent will be influenced by the severity of systemic diseases, such as coronary artery disease, nephropathy (with the concomitant risk of hyper/hypokalemia and other hidroelectrolytic disorders), and hypertension, and the choice of neuromuscular blocking agent will be affected by renal function.
