Metabolic syndrome represents a constellation of risk factors associated with increased incidence of cardiovascular disease and progression to diabetes mellitus. Insulin resistance, a state of decreased biologic response to physiologic concentrations of insulin, is a key component of this syndrome and seems to be the result of a primary defect at the skeletal muscle glucose transporter. Acute illness and the perioperative period are characterized by a state of insulin resistance that manifests as hyperglycemia and leads to various other metabolic and biochemical alterations that adversely affect end organ function. Hyperglycemia in acutely ill patients adversely affects outcome. Achieving euglycemia seems beneficial in certain clinical situations, but considerable disagreement exists regarding the target blood sugar levels, the duration of therapy, and the modality. Pharmacotherapy, exercise, and nutrition to improve insulin sensitivity seem promising but require further evaluation to confirm their efficacy for perioperative risk reduction. This review discusses the pathophysiology and the clinical implications of metabolic syndrome and insulin resistance in the acutely ill patient with an emphasis on perioperative modulation strategies.
METABOLIC syndrome represents a cluster of related cardiovascular risk factors that include central obesity, insulin resistance, atherogenic lipid profile, and hypertension. Several definitions of metabolic syndrome exist that share the core components but differ in the criteria required to diagnose the syndrome. Among these, the World Health Organization definitions and the National Cholesterol Education Program Adult Treatment Panel III (table 1) are widely accepted.1,2
The use of various criteria hampered comparison of data from different studies as each definition identified different sets of the population as having metabolic syndrome. Further, none of the definitions were found to be universally superior when applied to different populations. The International Diabetes Federation (IDF) thus recognized the need for a simple, easily applicable tool for the diagnosis of the syndrome that could be used universally. In 2006, the IDF consensus group proposed new criteria (essential and additional) for defining metabolic syndrome recognizing the ethnic variations in the identification of obesity and focused on the prediction of coronary vascular disease and diabetes.3Metabolic syndrome, which affects an estimated 20–25% of the general population, has been identified as the central player in the growing epidemic of diabetes and cardiovascular disease.3
Pathophysiology of Metabolic Syndrome
Central (Visceral) Obesity
Abnormal fat distribution plays a key role in the pathogenesis of metabolic syndrome. Obesity is associated with an increased risk of diabetes and cardiovascular disease. Furthermore, visceral fat by itself is a strong determinant of insulin sensitivity and B-cell function.3,4Waist circumference is found to be superior to the body mass index as a measure of visceral adiposity and is widely used to quantify central obesity in clinical practice.3Further, visceral adiposity as measured by waist circumference correlates better with the risk of diabetes or coronary vascular disease than total obesity as measured by body mass index.5,6Central obesity also shares a strong relation with other components of metabolic syndrome. The IDF definition draws attention to the fact that waist circumference may be population specific because differences have been observed between various ethnic groups and thus may warrant the use of different cutoff values while defining metabolic syndrome.3
Adipose tissue is an active endocrine organ that secretes numerous bioactive substances, including hormones, growth factors, and cytokines. Central (visceral) obesity represents dysfunctional adipose tissue whose dysregulated metabolism leads to increased free fatty acid (FFA) flux in the liver and muscle. This contributes to insulin resistance that further worsens the dyslipidemia.7Visceral fat also secretes proinflammatory cytokines interleukin 6 and tumor necrosis factor α. Together with the reduced secretion of adiponectin, it further aggravates insulin resistance.8
Insulin resistance can be defined as “a state where there is a reduced biologic effect for any given concentration of insulin.”9It is a central feature of metabolic syndrome, showing a strong association with most components of the syndrome.3,10The prevalence of insulin resistance in the general population has seen a phenomenal increase in the past decade.7It may be seen during pregnancy or starvation but is more widely recognized in patients with type II diabetes mellitus. Transient insulin resistance may often develop with surgical and nonsurgical trauma and critical illness.11
Insulin resistance manifests as a broad clinical spectrum evolving progressively from hyperinsulinemia to glucose intolerance and eventually to frank diabetes. Therefore, the diagnosis of insulin resistance in the various definitions of metabolic syndrome has required the presence of one or more features from this spectrum. Genetic susceptibility, along with environmental factors such as lifestyle, diet, stress, and smoking, can trigger the development of insulin resistance.8The metabolic consequences, hyperinsulinemia, hyperglycemia, and lipid and lipoprotein dysregulation, act in synergy to potentiate and sustain the pathologic state of insulin resistance. With the evolution of insulin resistance, endothelial dysfunction, inflammation, and atherosclerosis worsen progressively.7,12
The combination of increased triglycerides and reduced high-density lipoprotein (HDL) cholesterol together with increased apolipoprotein B and small–dense low-density lipoprotein (LDL) particles best describes the atherogenic lipid profile associated metabolic syndrome.3,7Alterations in the lipid and lipoprotein metabolism are closely linked with hepatic and peripheral insulin resistance. The small–dense LDL is highly atherogenic and therefore has become the main target for lipid lowering therapy.13
The mechanism of hypertension in metabolic syndrome is multifactorial and may be related, among other factors, to obesity and dietary thermogenesis.14Insulin-related alteration in renal sodium handling and salt sensitivity, central activation of the sympathetic nervous system, along with angiotensin II and endothelin 1–mediated vasoconstriction might also contribute.12
Metabolic syndrome predisposes to a prothrombotic state as a result of elevated fibrinogen levels along with decreased fibrinolytic activity due to increased plasminogen activator inhibitor 1. Platelet function is also disturbed, leading to increased aggregation and thrombin generation.15
Inflammation and Endothelial Dysfunction
Metabolic syndrome is a proinflammatory state. Insulin resistance and the atherogenic dyslipidemia cause up-regulation of inflammatory adipokine tumor necrosis factor α, interleukin 6, and C-reactive protein and a decrease in adiponectin.7Overexpression of the inflammatory proteins further interferes with insulin signaling pathways, enhances lipid peroxidation, and increases FFA flux.
Systemic Effects of Metabolic Syndrome
Patients with metabolic syndrome are at a greater risk of developing coronary artery disease and major adverse vascular events (table 2).16–18A threefold increase in the risk of myocardial infarction (MI) or stroke with twice the mortality from such an event is reported in patients with metabolic syndrome as compared with those without the syndrome.19While the individual components of metabolic syndrome have been recognized as independent risk factors of coronary vascular disease, clustering of these adverse metabolic factors may further intensify the risk.3
Patients with metabolic syndrome have fivefold higher risk for developing diabetes. Insulin resistance and altered glucose metabolism, the key component of the syndrome, may be responsible for this increased risk.20
Metabolic syndrome and its individual components are risk factors for acute stroke in the elderly. Stroke patients with metabolic syndrome exhibited an atherogenic profile with higher concentrations of triglycerides and lower HDL cholesterol.21Patients, especially women, with metabolic syndrome and atherosclerotic disease were at an increased risk for ischemic stroke or transient ischemic attack even in the absence of diabetes. Further, hypertension and fasting hyperglycemia were stronger predictors of cerebrovascular events than other components of metabolic syndrome.22
The individual components of metabolic syndrome adversely affect the kidney initiating loss of renal function. The constellation of the syndrome acts in synergy, the risk increasing progressively with the number of components involved, to accelerate renal damage from microalbuminuria to eventual end-stage renal disease.23Metabolic syndrome has also been identified as an important risk factor for diabetes mellitus, chronic renal graft dysfunction, and graft loss after renal transplantation.24
Metabolic syndrome has been shown to be associated with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.25Nonalcoholic steatohepatitis is characterized by hepatocellular inflammation and necrosis along with elevated transaminases and may progress to cirrhosis.7Insulin resistance may be the main causative factor because improving insulin sensitivity has been shown to decrease hepatic fat and inflammation, improve metabolic profile, and resolve the histologic changes.7,26
A retrospective study of a large cohort of pregnant women showed that features of metabolic syndrome before pregnancy were linked to a higher risk of placental dysfunction, including fetal growth retardation and demise. The study also found that this risk increased progressively with the number of components of metabolic syndrome involved, with the odds ratio increasing from 3.1 for one feature to 7.7 when three or four components were affected.27Metabolic syndrome has also been linked with an increased risk of adverse vascular events and venous thrombosis.17,28
The pathophysiology of metabolic syndrome may have important implications for the surgical patient. Obesity, hypertension, and diabetes mellitus are well-recognized perioperative risk factors that contribute to morbidity and mortality.29,30It is possible that the clustering of these cardiometabolic risk factors may further potentiate surgical risk and impact outcome. The incidence and degree of insulin resistance may also be related to the clustering of features of metabolic syndrome.10In the context of perioperative or acutely ill patients, insulin resistance may be one of the only features that is easily amenable to modulation and that may lead to an improvement in outcome.
Pathophysiology and Molecular Mechanisms of Perioperative Insulin Resistance
Insulin is secreted mainly in response to plasma glucose.31With the onset of insulin resistance, normoglycemia is achieved by increasing the secretion of insulin from pancreatic β-cells resulting in hyperinsulinemia. This state of “prediabetes” manifests clinically as impaired fasting glucose and/or impaired glucose tolerance.7,32Further resistance to insulin results in a failure to achieve normoglycemia despite increased insulin secretion, resulting in diabetes mellitus. Eventually, a “burnout” of β cells results, followed by decreased insulin levels along with further failure of glucose homeostasis7,31(fig. 1). Hyperinsulinemia, glucose intolerance, hyperglycemia, and frank diabetes thus represent a clinical continuum of abnormal glucose homeostasis and insulin resistance. Features of this clinical continuum often coexist, and it may not always be possible to dissect the effects of hyperglycemia per se from the state of insulin resistance.
The stress of acute illness and surgery induces transient but reversible acceleration of the progression of insulin resistance.33The magnitude of insulin resistance and the metabolic response to surgical stress may be linked to the invasiveness of the surgery. Blood loss may also have a direct and independent correlation with postoperative insulin resistance.33Whether the body cavity operated on influences the magnitude of insulin resistance is not known and remains open to speculation. Stress response may also be related to the duration of the surgical trauma, because glucose utilization seems to be reduced after prolonged surgery.34Physical status and postsurgery rehabilitation may further influence the development of insulin resistance by affecting skeletal muscle glucose uptake. Nutrition may be another contributing factor. A diet inadequate in calories, besides causing negative nitrogen balance, has been shown to alter the metabolic environment and give rise to insulin resistance.31Although the biochemical manifestation of this transient state of insulin resistance is obvious, the underlying mechanisms remain poorly understood.
Several alterations in the skeletal muscle, adipose tissue, hormones, and cytokines are proposed to explain the pathogenesis of perioperative insulin resistance. It is now increasingly recognized that perioperative insulin resistance is predominantly an extrahepatic phenomenon, primarily affecting the skeletal muscle. It is characterized by a decrease in peripheral glucose uptake with an increase in endogenous glucose production.11,33Insulin facilitates glucose entry in insulin sensitive tissues such as muscle and adipose tissue by increasing the number of GLUT4 transporters.31These receptors are stored in intracellular vesicles, and insulin-mediated activation of phosphoinositol-3-kinase causes fusion of the vesicles with the cell membrane, thereby resulting in insertion of the transporter into the cell membrane and increasing glucose entry into the cell. A defect at this GLUT4 transporter prevents insulin-stimulated glucose uptake and subsequent glycogen synthesis in skeletal muscle. This is now considered the principal abnormality underlying insulin resistance.11,33,35,36Studies on muscle biopsies from patients undergoing hip replacement seem to corroborate the role of skeletal muscle GLUT4 transporter in the pathogenesis of peripheral insulin resistance.36Furthermore, with insulin resistance there is upregulation of insulin-independent GLUT1–3 transporters that are found in neurons, renal cells, erythrocytes, and immunocytes, exposing them to excess glucose load and glucotoxicity (fig. 2).11Skeletal muscles also contain a subpopulation of GLUT4 transporters that translocate to the cell membrane in response to exercise and enhances glucose uptake independent of insulin. Limitation of physical exercise results in down-regulation of these GLUT4 transporters, aggravating insulin resistance.31,37
Lipid and lipoprotein dysregulation are closely linked to the insulin-resistant state. Defects in FFA storage and metabolism result in increased FFA flux in primary insulin sensitive tissues like the liver and skeletal muscle. The FFAs and their metabolites decrease phosphoinositide-3-kinase activity that ultimately leads to failure of GLUT4 translocation and insulin signaling mechanisms. The resulting insulin-resistant state further enhances lipolysis, setting up a vicious cycle (fig. 3).7
Insulin resistance and the inflammatory stress response seem to be interlinked. Plasma insulin levels and interleukin 6 follow a similar pattern during the perioperative period.38Whereas inflammatory cytokines such as interleukin 6 seem to inhibit insulin sensitivity by their effects on lipid peroxidation, and FFA flux, and GLUT4 expression, adipokines such as tumor necrosis factor α and resitin decrease insulin sensitivity by modulating lipid metabolism and GLUT4 activity.7,31,38
Insulin-like growth factors (IGFs) and their binding proteins may also play a role in the pathophysiology of perioperative insulin resistance. IGFs are polypeptides secreted by the liver that mediate the anabolic effects of growth hormone. Most IGF-1 in the plasma is bound to IGF-binding proteins 1–6. Free IGF-1 binds specifically to IGF receptors and weakly to insulin receptors, both of which are tyrosine kinases that enhance glucose uptake.31,33Levels of IGF-binding protein 1 are elevated in the perioperative period, whereas IGF-1 levels remain unchanged or even decrease, resulting in altered bioavailability of IGFs in the perioperative period.33The neuroendocrine system also contributes to the development of insulin resistance. Elevated circulating cortisol, growth hormone, and catecholamines seen during surgical stress exert an antiinsulin effect resulting in enhanced hepatic glucose output.39
Insulin Resistance and Hyperglycemia
There is mounting evidence attesting to the detrimental effects of hyperglycemia on outcomes in diverse clinical settings (table 3).40,41–48The impact of hyperglycemia on outcome in critically ill patients was first evaluated prospectively in the Leuven study by van den Berghe et al. 40It was found that tight glycemic control (blood glucose <110 mg/dl or 6.1 mm) reduced morbidity and mortality among surgical intensive care patients irrespective of their diabetic status.40Among medical intensive care patients, van den Berghe et al. reported that intensive insulin therapy to achieve blood glucose levels of 80–110 mg/dl (4.4–6.1 mm) while reducing morbidity did not affect mortality. However, a reduction in mortality with intensive insulin therapy was observed in patients who required intensive care for more than 3 days.49An observational study involving critically ill patients showed that glycemic control and not insulin dosage seemed to explain mortality benefits of intensive insulin therapy.46Therefore, the primary benefits of intensive insulin therapy may be related to its glucose-decreasing effect and maintenance of normoglycemia.46,50
Hyperglycemia is a frequent metabolic disturbance observed in patients with MI. Stress-induced insulin resistance mediates decreased availability of glycolytic substrate, and increased fatty acid utilization may impair myocardial contractility and increase oxygen requirements, promoting arrhythmias and pump failure.51A meta-analysis reviewing the risk of in-hospital mortality after MI in patients with stress hyperglycemia found that nondiabetic patients with blood glucose in the range 6.1–8 mm (100–140 mg/dl) had 3.9-fold increased risk of death than patients who had blood glucose of 6.1 mm (100 mg/dl) or less. Admission hyperglycemia corresponded with the risk of in-hospital mortality, congestive cardiac failure, and cardiogenic shock after MI in both diabetic and nondiabetic patients, with more pronounced effects in the latter.52A prospective study involving nondiabetic patients with acute MI reported increasing mortality with fasting glucose levels of 6.1 mm (110 mg/dl) or greater. Fasting glucose was also found to be better at predicting short-term mortality after acute MI than admission glucose levels.53Patients without previous history of diabetes with admission hyperglycemia (fasting glucose >7 mm [>125 mg/dl] or random >11.1 mm [>200 mg/dl]) on general surgical and medical wards were found to have higher mortality and poorer outcome as compared with normoglycemic patients. Further, these patients had higher rates of intensive care unit admissions and greater risk of infection and acute neurologic events.54The American Diabetes Association and the American Association of Clinical Endocrinologists have subsequently issued guidelines recommending fasting glucose level less than 6.1 mm (110 mg/dl) in hospitalized patients irrespective of their clinical history.55
The insulin resistance and hyperglycemia frequently observed during cardiac surgery occurs as a result of release of inflammatory cytokines during cardiopulmonary bypass, use of heparin, release of stress hormones, and iatrogenic catecholamine use, among others. Hyperglycemia during cardiopulmonary bypass and after cardiac surgery has been associated with increased mortality among both diabetics and nondiabetics.48,56,57In a study involving diabetic patients undergoing coronary artery bypass graft, plasma glucose levels greater than 175 mg/dl (9.7 mm) were related to higher mortality principally from cardiac causes. Achieving glycemic control with continuous insulin infusion improved survival in these patients by reducing cardiac mortality.58Others have reported similar improvements in morbidity and mortality using insulin infusion to achieve tight glycemic control.40,59
The potential diabetogenicity of uremia and peritransplant therapy may be aggravated further by surgical stress. Glucose uptake into renal tubular cells is insulin independent, making them vulnerable to glucotoxicity related to hyperglycemia.11Perioperative hyperglycemia has been shown to be associated with acute rejection in known diabetics.60Thomas et al. ,61however, reported that 71% of nondiabetic renal transplant recipients whose postoperative blood glucose levels were greater than 8 mm (144 mg/dl) developed acute rejection. Acute hyperglycemia due to insulin resistance may enhance ischemia–reperfusion injury and antigen presentation, escalating the inflammatory response that mediates graft rejection.61
Insulin resistance seems to play a central role in the pathophysiology of the glucose intolerance commonly observed in brain-dead donors. Detrimental effects include osmotic diuresis, electrolyte disturbances, and impairment of end-organ function. Insulin therapy to maintain blood glucose levels between 4.4 and 8.3 mm (80 and 150 mg/dl) and avoidance of hypotonic dextrose solutions have been recommended. Treatment of insulin resistance during the process of graft harvest and transplantation may improve the number and viability of the organs procured.62
Persistent hyperglycemia 48 h after thromboembolic stroke seems to increase mortality, whereas achieving euglycemia seems to improve outcome. Normoglycemia was reported to be an independent predictor of survival after stroke. This effect seemed to be independent of the method used for blood glucose control.63Hyperglycemia has also been reported to be associated with poor neurologic outcome after traumatic brain injury in both adults and children.47,64
Hyperglycemia has been shown to have detrimental effects on the immune system. Acute hyperglycemia impairs monocyte activation and oxidative burst as well as phagocytic capacity of macrophages.65,66It may also lead to glycosylation of immunoproteins.11Another effect observed is an exaggeration of injury-induced inflammatory response. These effects, in conjunction with the enhanced protein breakdown caused by insulin resistance, may predispose to systemic and surgical site infections, impair wound healing, and delay recovery.40,59,67Amelioration of hyperglycemia may partly account for the beneficial immunomodulating effects of insulin therapy.
Assessment of Insulin Resistance
Hyperinsulinemic euglycemic clamp remains the accepted standard for assessment of insulin resistance.68With this method, blood glucose is “clamped” at a predetermined level by titrating glucose infusion against a fixed rate of insulin infusion. The degree of insulin resistance is inversely related to the amount of glucose required to maintain the target concentration when steady state is achieved. The clamp technique provides a quantitative measure of insulin-mediated glucose disposal and also defines the site of insulin resistance.68In the insulin-resistant state, the insulin-mediated glucose disposal curve is typically shifted to the right, often with reduction in the maximal effect of insulin (fig. 4). This is reflected in clinical practice by increasing insulin requirements to achieve blood glucose control.9
Several other validated tests are available for the assessment of insulin resistance and are summarized in table 4. These are useful research tools and may provide valuable input for clinical management. Insulin resistance may be quantified by mathematical models, clamp techniques, insulin infusion tests, or by glucose tolerance tests.9,68Due consideration should be given to the method of assessment of insulin resistance when comparing different studies.
Strategies for Metabolic Management
The complex cellular and molecular mechanisms underlying insulin resistance and metabolic syndrome may be further altered by the dynamics of surgical trauma and the associated stress response, analgesia, nutritional status, and bed rest, among other factors. Active modulation of the altered metabolic status may improve outcome after a surgical injury.
Insulin Therapy and Glucose Control
Insulin, endogenous and exogenous, has long been recognized as a metabolic hormone. Its primary effect is on glucose homeostasis, i.e. , enhanced peripheral glucose uptake with inhibition of glycogenolysis and hepatic gluconeogenesis. It promotes protein anabolism while also inhibiting fatty acid breakdown. The nonmetabolic effects of insulin are increasingly being recognized. It is believed to have an antiinflammatory effect while enhancing phagocyte function and opsonic activity. It may maintain fibrinolytic activity, prevent platelet activation, and improve vascular reactivity and endothelial function. These effects may act in synergy with the metabolic effects to promote and maintain organ function.11However, it should be noted that persistent hyperinsulinemia might be associated with detrimental effects, such as such as coronary stenosis in transplanted hearts.16
Insulin therapy for the management of insulin resistance and the potential benefits of glycemic control among acutely ill subjects has been well studied (table 5).40,42,49Although data from heterogenous surgical populations are sparse, several authors have addressed the effect of insulin therapy in cardiac surgery.40,58,59,69Furthermore, in practice, the glycemic target, timing, and duration of therapy vary widely. A common method of insulin therapy in acutely ill patients is intravenous insulin infusion. Other methods used include glucose–insulin–potassium infusions, subcutaneous injections, dextrose infusions with insulin boluses, and insulin clamp techniques.
The Leuven study by van den Berghe et al. 40was a prospective, randomized controlled trial of surgical intensive care patients, more than two thirds of whom had had cardiac surgery. It showed that intensive insulin therapy to maintain glucose at or below 110 mg/dl (6.1 mm) was associated with a reduction in morbidity and mortality. Furthermore, there was reduced mortality from multiorgan failure irrespective of a history of diabetes, reduced duration of stay in intensive care, and lower requirement for mechanical ventilation and renal replacement therapy. Intensive insulin therapy was also associated with reduced episodes of septicemia and lower levels of inflammatory markers.40However, intensive insulin therapy to achieve blood glucose levels below 110 mg/dl (6.1 mm) was associated with increased mortality among medical intensive care patients who required intensive care for less than 3 days.49Lazar et al. 59showed that tight glycemic control (defined as blood glucose ≤11.1 mm or 200 mg/dl) with glucose insulin potassium infusion improved perioperative outcome, increased survival, and decreased incidence of ischemic events and wound infection in diabetic patients undergoing coronary artery bypass graft.
Furnary et al. 58conducted a large retrospective study involving more than 3,000 diabetic patients undergoing coronary artery bypass graft and found that patients receiving continuous insulin infusion achieved tighter blood glucose control as compared with patients managed with intermittent subcutaneous insulin injections. Furthermore, the perioperative mortality was significantly lower in the continuous insulin infusion group (2.5% vs. 5.3%; P <0.0001). The decrease in mortality was primarily from a reduction in the incidence of cardiac related deaths. The authors proposed that continuous insulin infusion improves myocardial glycometabolic function by insulin-induced stimulation of pyruvate dehydrogenase activity and enhanced glycolysis that replenishes cytoplasmic adenosine triphosphate stores required for phosphorylation of extracellular glucose, stabilization of membrane function, and maintenance of cellular integrity. Enhanced glycolysis is also believed to inhibit lipolysis and mitochondrial β oxidation, preventing accumulation of toxic FFA metabolites.58
The IDF currently recommends treatment of individual components of metabolic syndrome in patients where lifestyle modification alone is insufficient or the patient is at high risk of cardiovascular disease (table 6).3In clinical practice, many of the drugs used in the secondary intervention may have complementary effects and modulate more than one component of the syndrome.
Insulin Secretagogues: Sulfonylureas and Glinides.
Sulfonylureas close adenosine triphosphate–sensitive potassium (KATP) channels on the pancreatic β cells depolarizing the cell and consequently releasing insulin. KATPchannels are tetradimeric molecules that exhibit adenosine triphosphatase activity. KATPchannel isoforms that differ in the composition of the individual subunits are also found on the cell membranes of cardiomyocytes and vascular myocytes, among others, as well as the inner mitochondrial membrane (mito KATPchannels). Sulfonylureas differ in their selectivity for the pancreatic and cardiovascular isoforms of KATPchannels, with glibenclamide being one of the least selective (table 7).70–72Newer sulfonylureas, such as glimepiride, exhibit greater selectivity to the pancreatic KATPchannels.73
The KATPchannels in the cardiac sarcolemma and the mitochondria are now believed to play a central role in the phenomenon of ischemic preconditioning—a phenomenon whereby brief periods of ischemia and reperfusion before prolonged ischemia protects the myocardium from the consequent deleterious effects.74These KATPchannels are also believed to mediate a similar phenomenon, called anesthetic preconditioning, whereby volatile anesthetics protect the myocardium against the effects of ischemia.75
The effects of sulfonylurea use on both animal and human myocardium have been extensively researched, and the compound most often studied is glyburide (also known as glibenclamide). An increase in vascular tone, decreased tolerance to ischemic injury mediated by an inhibition of ischemic preconditioning, and an antiarrhythmic effect, among others, have been reported.71However, the clinical significance of these effects is uncertain. Besides, the proposed subtype selectivity of sulfonylureas has also not been addressed. Sulfonylureas may also adversely affect anesthetic preconditioning. Glibenclamide has been shown to prevent isoflurane-induced anesthetic preconditioning during cardiac surgery in diabetic subjects. Further, preoperative use of insulin instead of glibenclamide seemed to restore the protective effect of anesthetic preconditioning.76Sulfonylureas may thus not be appropriate agents in an acute care setting considering the potentially harmful myocardial effects of sulfonylureas, their inability to achieve metabolic control due to stress-induced insulin resistance after an acute illness, and the potential benefits of tight glycemic control with insulin.41
The University Group Diabetes Program study, a placebo-controlled, multicenter, clinical trial, reported in 1970 an increased risk of cardiovascular mortality in patients with type II diabetes treated with tolbutamide.77The findings resulted in the termination of the tolbutamide arm of the study and the publication of a US Food and Drug Administration warning.71These findings have been criticized because a subsequent analysis showed that the excess cardiovascular mortality purportedly related to tolbutamide was in fact restricted to a group with poorly controlled diabetes.78The United Kingdom Prospective Diabetes Study (UKPDS), a large prospective study of newly diagnosed type II diabetics, restored confidence in sulfonylureas, showing no increase in cardiovascular mortality. They further reported that intensive glycemic control either with sulfonylureas or insulin reduced microvascular but not macrovascular disease among type II diabetics.79Apart from the side effects of weight gain and hypoglycemia, sulfonylureas do not influence other components of metabolic syndrome.73
Another class of insulin secretagogues introduced recently are the glinides. These molecules resemble the nonsulfonylurea portion of glibenclamide and have a similar mechanism of action. They differ from sulfonylureas in their poor protein binding and shorter duration of action. Their role in clinical management of diabetes is yet to be established.70,73
Metformin, the only drug among the biguanide class in clinical use, decreases blood glucose levels by sensitizing target tissues to insulin, especially the liver, inhibiting hepatic glucose production and increasing peripheral glucose uptake. It has good oral bioavailability and negligible protein binding and is almost exclusively excreted unchanged by the kidneys.80It has modest effects on lipid metabolism, including decreasing triglycerides and LDL cholesterol, increasing HDL cholesterol, and promoting weight loss.80It may also improve endothelial dysfunction.73
The United Kingdom Prospective Diabetes Study (UKPDS 34) showed that addition of metformin to diet-controlled overweight type II diabetics significantly reduced microvascular and macrovascular disease. Metformin did not induce weight gain and was also associated with fewer episodes of hypoglycemia. The additional benefits observed with metformin monotherapy could not be accounted for by the improvement in glycemic control alone but were suggested to be due to decreases in plasminogen activator inhibitor 1 and enhanced fibrinolysis.81A population based retrospective study showed that metformin use either alone or in addition to sulfonylureas in newly treated diabetics reduced all-cause and cardiovascular mortality in comparison to sulfonylurea monotherapy.82Combinations of metformin with other oral hypoglycemic and insulin-sensitizing agents have also been shown to be safe and effective.80,83Adjuvant metformin therapy in type I diabetes improves insulin sensitivity, diabetic control, body composition, and patient well-being.84
A retrospective investigation of diabetic patients undergoing cardiac surgery reported that allowing metformin therapy until the night before surgery and early resumption postoperatively did not increase cardiac morbidity (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1–1.7), neurologic morbidity (OR, 0.9; 95% CI, 0.3–2.6), or in-hospital mortality (OR, 0.5; 95% CI, 0.1–2.0) as compared with other oral hypoglycemic agents. Metformin-treated patients, however, required a shorter course of tracheal intubation and had lower infection-related morbidity (OR, 0.2; 95% CI, 0.1–0.7) and overall morbidity (OR, 0.4; 95% CI, 0.2–0.8).85
Thiazolidinediones are insulin-sensitizing agents that bind to the nuclear γ isoform of peroxisome proliferator–activated receptor (PPAR-γ). These receptors are primarily expressed in adipose tissues but also find expression in the skeletal myocytes, hepatocytes, and vascular endothelial and smooth muscle cells. PPAR-γ activation results in the transcription of several genes encoding various insulin-sensitive proteins, including lipoprotein lipase and GLUT4. They have a slow onset, requiring up to 12 weeks to reach maximum effect.73Thiazolidinediones enhance insulin sensitivity in adipose tissue, skeletal muscle, and the liver. They are highly protein bound and undergo extensive hepatic metabolism, in the case of pioglitazone to active metabolites.80
Thiazolidinediones also increase expression of genes that encode proteins that enhance adipogenesis in the subcutaneous adipose tissue. The net result is believed to be a redistribution of fat stores from the muscle and visceral adipose tissue resulting in a decreased visceral-to-subcutaneous adipose tissue ratio.80Thiazolidinediones differ in their effects on the lipid profile. Whereas pioglitazone alters the profile favorably by decreasing triglycerides, rosiglitazone was associated with an increase in LDL cholesterol and total plasma cholesterol. The mechanism of this differential alteration in lipid profile and its clinical significance are as yet unclear.86
Thiazolidinediones have favorable effects on markers of atherosclerosis.80They decrease thrombotic risk especially on atherosclerotic areas by inhibiting plasminogen activator inhibitor 1. Further, they decrease the serum high-sensitivity C-reactive protein, tumor necrosis factor-α, and inerleukin-6 levels. While some of the antiatherogenic effects could be associated with improvement of glucose metabolism, thiazolidinediones seem to prevent progression of atherosclerosis independent of their effects on glucose metabolism. Nitric oxide, an important regulator of vascular endothelial function, is inactivated by superoxide (O2−) free radicals. PPAR-γ agonists are believed to promote endothelial function by suppression of NADPH oxidase, a major superoxide generating enzyme while inducing the superoxide scavenging cytosolic superoxide dismutase.87The antioxidant properties of PPAR-γ agonists may also restore the function of KATPchannels that are impaired by high glucose concentrations.88
In animal models, thiazolidinediones seems to limit infarct size and attenuate postinfarct left ventricular remodeling and failure.89,90In comparison with other oral hypoglycemic agents, thiazolidinediones significantly reduces microalbuminuria. However, it remains unclear whether this is mediated primarily via improvement in glycemic control, insulin sensitivity, or endothelial dysfunction or is independent via its the blood pressure–decreasing effect.91A prospective study to assess the ability of rosiglitazone to reduce the incidence of diabetes mellitus in subjects with impaired fasting glucose and/or impaired glucose tolerance reported an absolute risk reduction of 14.4% (number needed to treat = 7) at the end of a median follow-up period of 3 yr. That the study reported 70–80% increased likelihood of return to normoglycemia may suggest that thiazolidinediones treat dysglycemia as well as prevent diabetes.92
The PROactive study, a large European multicenter study involving 5,238 patients, showed no significant reduction in the composite primary endpoints with pioglitazone. However, the study found a significant reduction in the secondary endpoints of all-cause mortality, MI, or stroke. This improvement, observed in a group of high-risk patients, was in addition to that with their normal medical care, including antihyperglycemic, antiplatelet, antihypertensive, and lipid-lowering therapies. Glycemic control and lipid profile was better with pioglitazone compared with placebo, despite an increased use of metformin and insulin in the placebo group. They also had a better blood pressure profile at the end of the study than at the beginning.93However, considerable controversy surrounds the methodology and statistical analysis of the PROactive study. It is suggested that the results need to be confirmed and that they are seen as hypothesis-generating only.94
A meta-analysis of 22 trials that randomly assigned approximately 6,200 people to pioglitazone therapy for at least 24 weeks showed no evidence of benefit with respect to patient-oriented outcomes such as mortality, morbidity, adverse effects, cost, and health-related quality of life. Further, metabolic control (hemoglobin A1c) was found to be no better when compared with other oral antidiabetic drugs. However, the analysis reported a higher incidence of edema with pioglitazone and concluded that the risk–benefit ratio was unclear until further results were available. It also highlighted the different prescribing indications by the US Food and Drug Administration and the European Medicines Agency.94Common side effects reported with thiazolidinediones include weight gain (up to 4 kg), fluid retention, and heart failure.86,92–94They are contraindicated in New York Heart Association class III or IV heart failure, and the American Heart Association recommends that patients and physicians be aware of the risk of heart failure associated with their use in type II diabetes patients.95
Statins are inhibitors of β-hydroxy-β-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in the synthesis of cholesterol. They interrupt cholesterol synthesis in the liver and activate hepatocyte LDL receptors and decrease LDL.
Statins have proved beneficial in primary and secondary prevention of adverse cardiovascular events.96,97Furthermore, intensive decreasing of LDL cholesterol with high-dose atorvastatin therapy (80 mg) has also been shown to significantly reduce adverse vascular events in high-risk patients with both coronary heart disease and metabolic syndrome.13They are recommended in the early treatment of patients with unstable angina and MI.98
Evidence suggests that statins, besides their effects on lipids, reduce endothelial dysfunction, inhibit inflammatory responses, stabilize atherosclerotic plaques, and modulate procoagulant activity and platelet function, the so-called pleiotropic effects.99Statins may reduce the risk of severe sepsis and infection-related mortality independent of their lipid-lowering effect.100The effect of withdrawal of chronic statin therapy during acute coronary syndromes has been studied prospectively. Statin therapy was associated with a reduced rate of nonfatal MI or death at the end of 30 days. Requirement for revascularization procedures was reduced, as was hospital stay. However, among patients whose chronic statin therapy was withdrawn after hospital admission, the incidence of death and nonfatal MI increased when compared not only with patients whose statin therapy was continued, but also with patients who did not receive any statin therapy at all.101It is hence suggested that statins should be continued uninterrupted in acute coronary syndrome and intensive care patients to maintain their beneficial pleiotropic effects.102
A large observational study based on administrative data found that preoperative lipid-lowering therapy primarily with statins reduced the odds of in-hospital mortality after major noncardiac surgery by 38%. The study also reported that the number needed to treat to prevent a postoperative death was 30 among patients with a higher cardiac risk.103A recent meta-analysis of perioperative statin therapy concluded that while statins may confer a survival benefit, their effect of postoperative cardiovascular morbidity was inconclusive. The paucity of prospective data and heterogeneity of retrospective data were also highlighted. The authors suggest that with current data preoperative statin therapy be restarted as early as possible postoperatively.104
Fibrates are lipid-modulating drugs that act as ligands to the α isoform of PPAR nuclear receptors that activates the transcription genes encoding for proteins involved in lipoprotein metabolism. Fibrates induce synthesis of the major HDL apolipoproteins (apoA-I and apoA-II). By inducing lipoprotein lipase, fibrates stimulate lipolysis and decrease triglyceride synthesis and very-low-density lipoprotein secretion.105Gemfibrozil has been shown to reduce the risk of major cardiovascular events in middle-aged men with dyslipidemia.106But the FIELD study investigating the effects of fenofibrate on cardiovascular events in type II diabetes showed only a weak reduction in cardiovascular risk. However, it did show that fibrates were associated with less albuminuria progression and retinopathy and a significant reduction in incidence of nonfatal MI in low-risk patients.107Fibrates are associated with a 5.5-fold increase in the risk of rhabdomyolysis when compared with statin monotherapy. When combined with fibrates, statins further double this risk.108The IDF recommends fibrates as an option in the management of atherogenic dyslipidemia but highlights the risk of complications when combined with statins.3
Intensive treatment of diastolic hypertension has been shown to reduce the incidence of adverse cardiovascular events, with diabetic patients deriving most benefit.109The IDF recommends that antihypertensive therapy be introduced early and at much lower blood pressure (≥130/≥80 mmHg) in diabetic patients as compared with nondiabetic patients (≥140/≥90 mmHg).3Tight blood pressure control with either angiotensin-converting enzyme inhibitors or β-blockers has been associated with reduced incidence of microvascular and macrovascular complications in diabetic patients.110
No particular agent has been identified as being preferable for hypertensive patients with metabolic syndrome. Instead, current data suggest that the benefits associated with antihypertensive therapy are largely due to their blood pressure–decreasing effect rather than the drug type.3,110However, it has recently been suggested that drugs that block the renin–angiotensin system may prevent or delay the development of diabetes and thus confer cardiovascular benefit.111–113
Exercise and Mobilization
Increased physical activity has been recommended in the primary management of metabolic syndrome because of its beneficial effects on the various components of the syndrome.2,3Exercise induces the insertion of glucose transporters that do not depend on insulin into the skeletal muscle membrane.31Immobilization may thus induce insulin resistance with reduction in skeletal muscle glucose uptake and glycogen synthesis. In diabetic patients, physical rehabilitation and exercise may improve insulin sensitivity and glucose control.2Early postoperative mobilization as part of an enhanced recovery protocol has been shown to be associated with minimal postoperative insulin resistance.114
Fasting represents an extreme state of nutritional stress, and its adverse effects include depletion of glycogen stores and breakdown of proteins and fat to provide energy. It also impairs mononuclear phagocytic system, increases bacterial translocation, and enhances oxidative stress injury.115,116Studies in experimental animal models have shown that feeding before acute injury preserves energy stores, maintains bacterial homeostasis in the gut, and aids endotoxin clearance.116Therefore, the issue of preoperative fasting must be addressed from a metabolic perspective. Preoperative intake of carbohydrate-rich beverage has been shown to maintain insulin sensitivity in surgical patients.117Improvement in insulin sensitivity with preoperative carbohydrate treatment may also decrease nitrogen losses and promotes protein synthesis.118However, the effects of preoperative carbohydrate loading on postoperative morbidity and mortality have not been evaluated.
Anesthesia and Analgesia
Volatile anesthetics protect the myocardium against the effects of ischemia, a phenomenon closely resembling ischemic preconditioning. This phenomenon, called anesthetic preconditioning, is also believed to be mediated by KATPchannels in the myocardial sarcolemma and the mitochondrial membrane.75Hyperglycemia is believed to adversely affect preconditioning. High blood glucose concentrations have been shown to attenuate the protective effects of ischemic and anesthetic preconditioning in both diabetic and nondiabetic animal models.119,120In doses used for anesthesia, intravenous induction agents have no effect on circulating metabolite and hormone concentrations, except for etomidate, which has been shown to inhibit cortisol synthesis.121
In healthy volunteers, acute pain has been shown to induce insulin resistance and decrease nonoxidative glucose disposal.122Therefore, it seems logical that effective analgesia may potentially attenuate insulin resistance. High-dose opioids have been shown to attenuate the stress response to surgery, but this response lasts only till the high levels are maintained.123Epidural anesthesia has been shown to attenuate stress response, prevent intraoperative hyperglycemia, and reduce protein breakdown, which also lasts only for the duration of continuous blockade.124,125The effect of neuraxial blockade on sympathetic efferents to the liver, adrenals, and pancreas may mediate these effects. Decreased hepatic sympathetic efferent tone may reduce glucose output from the liver, whereas a reduced sympathetic stimulation of the adrenals attenuates release of catecholamines and cortisol, promoting peripheral glucose clearance.39Neuraxial blockade may also reduce hepatic perfusion and hence the supply of gluconeogenic precursors to the liver.125Furthermore, effective analgesia provided by neuraxial blockade may attenuate reduction in pain-mediated insulin resistance.123Children demonstrate similar responses to surgical stress that is attenuated by epidural blockade.126Continuous neural blockade has also been shown to improve insulin sensitivity after major joint surgery in subjects previously known to be insulin resistant.127Whether effective neuraxial blockade in patients with metabolic syndrome impacts perioperative morbidity or mortality is as yet unknown.
Metabolic syndrome, a rapidly growing global epidemic, is a cluster of cardiovascular risk factors that is associated with a heightened risk of morbidity and mortality. Lifestyle modification and pharmacotherapy targeting individual components of the syndrome have been recommended as primary and secondary prevention strategies. Insulin resistance and central obesity are increasingly recognized as being central to the pathogenesis of metabolic syndrome. Insulin resistance commonly manifests as hyperglycemia during acute illness and in the perioperative period. Management of insulin resistance to achieve glycemic control improves outcome. It is suggested that preoperative statins be continued uninterrupted or at least reinstated as soon as feasible to harness the benefits derived from its pleiotropic effects. Early postoperative mobilization and exercise have shown some promise, but their role must be defined clearly. Modulation of the other components of the syndrome in the acute phase of illness and in the perioperative period needs further evaluation. Perioperative physicians must identify patients at risk of insulin resistance and metabolic syndrome, and strategies aimed at modulating the altered metabolic milieu should be identified.
The authors thank Joel G. Ray, M.D., M.Sc., F.R.C.P.C. (Departments of Medicine, Obstetrics and Gynecology and Health Policy Management and Evaluation, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada), for kindly providing copies of his published studies.