To which of the following diabetic patients should you administer oral glucose

Curr Pharm Des. Author manuscript; available in PMC 2013 May 2.

Published in final edited form as:

PMCID: PMC3641560

NIHMSID: NIHMS464280

Abstract

Hyperglycemia is associated with increased mortality and morbidity in critically ill patients. Surgical patients commonly develop hyperglycemia related to the hypermetabolic stress response, which increases glucose production and causes insulin resistance. Although hyperglycemia is associated with worse outcomes, the treatment of hyperglycemia with insulin infusions has not provided consistent benefits. Despite early results, which suggested decreased mortality and other advantages of “tight” glucose control, later investigations found no benefit or increased mortality when hyperglycemia was aggressively treated with insulin. Because of these conflicting data, the optimal glucose concentration to improve outcomes in critically ill patients is unknown. There is agreement, however, that hypoglycemia is an undesirable complication of intensive insulin therapy and should be avoided. In addition, the risk of increased glucose variability should be recognized, because of the associated increased risk for worse outcomes. Patients with diabetes mellitus experience chronic hyperglycemia and often require more intensive perioperative glucose management. When diabetic patients are evaluated before surgery, appropriate management of oral hypoglycemic agents is necessary as several of these agents warrant special consideration. Current recommendations for perioperative glucose management from national societies are varied, but, most suggest that tight glucose control may not be beneficial, while mild hyperglycemia appears to be well-tolerated.

Keywords: Hyperglycemia, diabetes, glucose management

INTRODUCTION

Hyperglycemia is associated with worse outcomes in critically ill hospitalized patients [1, 2]. Patients who are hyperglycemic following stroke have worse functional recovery and higher mortality [3, 4]. Critically ill patients who have suffered myocardial infarction are more likely to experience cardiogenic shock, congestive heart failure, or die, if they were hyperglycemic during hospital admission [5]. In surgical patients, perioperative hyperglycemia increases risk of postoperative mortality, and cardiovascular, respiratory, neurologic, and infectious morbidity [6–9]. Despite the fact that hyperglycemia increases risk for adverse outcome in many clinical conditions, treatment of hyperglycemia has not consistently improved outcomes. In fact, certain aggressive treatments of severe hyperglycemia have not provided a survival benefit and, in some instances, have even increased mortality [10–12]. Because the risk of serious adverse outcomes associated with hyperglycemia is considerable, it is essential that the clinician understand the risks and benefits of a glucose management strategy. Further, a thorough understanding of the issues surrounding glucose control will allow the clinician to improve patient care by aiming insulin therapy toward the most favorable “target” glucose concentration in order to optimize patient outcomes. Although the primary focus of this review will be glucose management of the surgical patient during the perioperative period, most of the evidence regarding glucose control has been acquired from investigations in critically ill patients. Thus, glucose management of the critically ill patient will be discussed and, where applicable, information will be generalized to the surgical patient.

ADVERSE AFFECTS OF HYPERGLYCEMIA

Patients who experience major trauma, illness, or surgery often develop a hypermetabolic stress response, which is characterized by hyperglycemia and insulin resistance. This response involves an increased level of endogenous hepatic glucose production while insulin-stimulated peripheral glucose uptake is reduced. This hyperglycemic response has been referred to as “stress hyperglycemia”. Initially, this response was considered to be a beneficial adaptation to critical illness because an additional glucose supply was available as a source of energy. However, an increasing body of evidence indicates that acute severe hyperglycemia causes numerous immediate adverse effects and is associated with serious adverse clinical outcomes.

Hyperglycemia is common during major surgery because of the hypermetabolic stress response. The severity of the hyperglycemic response to major surgery may be affected by an individual's ability to control blood glucose [13] and the magnitude of the surgery [14]. In other words, patients who have glucose intolerance or diabetes and experience a more invasive surgical procedure would be expected to develop more profound hyperglycemia.

Hyperglycemia adversely affects morbidity and mortality in surgical and critically ill patients [3–6]. The development of these adverse effects is likely related to the numerous adverse cellular and biochemical events that occur as a result of hyperglycemia. For example, risk of infection is increased with severe hyperglycemia, because of abnormalities of monocyte and polymorphonuclear neutrophil function, decreased intracellular bactericidal activity, and glycosylation of immunoglobulins [15, 16]. Blood coagulation is activated by hyperglycemia, as circulating prothrombin fragments and D-dimers are increased, and platelet aggregation and thrombosis occur[17]. Inflammation and activation of proinflammatory cytokines is also induced by hyperglycemia. Hyperglycemia also abolishes intrinsic myocardial protective mechanisms, such as ischemic preconditioning [18]. Thus, hyperglycemia interacts at the cellular and biochemical level in numerous ways, which may be responsible for the adverse effects associated with hyperglycemia.

THE USE OF INSULIN INFUSIONS TO IMPROVE OUTCOMES IN CRITICALLY ILL PATIENTS

Insulin is the sole therapy currently available to treat acute hyperglycemia. In addition to its glucose-lowering effects, insulin also has multiple metabolic and cellular actions that could benefit outcomes. For example, insulin plays a crucial role in maintaining normal cell metabolism by increasing glucose uptake and adenosine triphosphate (ATP) production by glycolysis. Of its nonmetabolic effects, insulin provides protection from endothelial dysfunction, which may prevent organ failure and death [19]. Insulin also has anti-inflammatory effects, which decrease levels of proinflammatory cytokines, adhesion molecules, and acute phase proteins. Insulin has anti-thrombotic, anti-atherogenic properties [20–22]. Insulin treatment causes arterial vasodilation and capillary recruitment, via activation of the nitric oxide pathway [23] and improves myocardial perfusion [24]. Although it is difficult to distinguish whether these benefits arrive directly from insulin therapy rather than treatment of hyperglycemia, the inotropic and direct cardioprotective effects of insulin, specifically, anti-apoptotic properties, have been found to be independent of glucose concentrations [25].

Use of insulin therapy to improve outcomes during critical illness began with the use of glucose-insulin-potassium (GIK) infusions for treatment of myocardial ischemic events. GIK provided purported benefits of increased myocardial glucose uptake and utilization, which is expected to increase myocardial efficiency and improve contractile function following acute myocardial ischemia [26–29]. In addition, fatty acid oxidation is inhibited by GIK; thus, myocardial oxygen consumption is improved and production of arrhythmogenic substrates is decreased [30, 31]. Investigations of GIK have reported improved outcomes following myocardial infarction [31, 32] and cardiac surgery [33], although some investigations did not find a beneficial effect [34–36]. It is possible that the adverse effects of hyperglycemia, which may occur with GIK, negated the benefits of insulin therapy in some investigations.

Further research on glucose control using conventional insulin infusions was focused on critically ill patients and patients who recently had cardiac surgery. Furnary and colleagues reported that the use of insulin infusions to treat hyperglycemia in diabetic patients decreased risk of mortality and sternal wound infection following cardiac surgery [37, 38]. Although these studies were criticized because of their use of a historical control group, they suggested that a relatively simple intervention of insulin infusions may positively impact outcomes. In 2001, the publication of a landmark investigation reported a significant decrease in morbidity and mortality in critically ill and cardiac surgical patients when intensive insulin therapy was used to achieve normoglycemia (glucose target between 80 and 110 mg/dL) [1]. Van den Berghe and colleagues reported a lower risk of bloodstream infections, renal failure, blood transfusions, critical illness polyneuropathy, shorter requirement for mechanical ventilation, and a 30% decrease in mortality when critically ill patients, most of whom had recent cardiac surgery, received intensive insulin therapy aiming for normoglycemia, also referred to as “tight” glucose control. The results from this investigation were met with great enthusiasm, and tight glucose control became the standard of care in many institutions. This investigation did have some important limitations, however, which may have affected the validity of the results. For example, patients involved in this investigation were subjected to early and aggressive parental nutrition, a practice that differs from many institutions, because of associated hypertriglyceridemia, insulin resistance, and increased risk of infection and mortality [39]. It is possible that the control patients, who did not receive intensive insulin therapy but did receive parental nutrition, suffered adverse affects from parental nutrition-induced hyperglycemia. Also, this study had a relatively low event rate and was stopped early because of benefit, raising concerns that the reported treatment effect was larger than the `true' treatment effect [39]. Nevertheless, the publication of many retrospective studies following this landmark investigation consistently found that severe hyperglycemia was associated with worse outcomes [2, 40], which reinforced the belief that aggressive treatment was needed to correct hyperglycemia. Further, national organizations, including the American College of Endocrinology, published guidelines in 2004 that recommended “tight” glucose control for both surgical and nonsurgical patients in the critical care setting. These guidelines stated that the upper limit for blood glucose concentration in the intensive care unit (ICU) setting should be no higher than 110 mg/dL. This was a fairly aggressive stance considering the limited number of studies supporting the benefit of this intervention at the time [41].

Within a few years, several randomized controlled trials and meta-analyses were published that contrasted with the initial landmark publication by Van den Berghe. These later trials of intensive glucose control in critically ill medical and surgical patients found no benefit when intensive insulin therapy was used to achieve normoglycemia. Further, the risk of hypoglycemia was significantly higher when “tight” glucose control was implemented [10, 11]. One large randomized controlled trial found that “tight” glucose control provided no benefit on mortality rate or mean score for organ failure. In addition to no survival benefit, the rate of severe hypoglycemia (defined as glucose ≤ 40 mg/dL) and the rate of serious adverse events was higher in the tight glucose control group [10]. In addition, a meta-analysis of 29 randomized controlled trials found no difference in mortality between “tight” glucose control (<110 mg/dL) and “moderately tight” (<150 mg/dL) control [42]. However, a reduced risk of sepsis was found in patients who received tighter glucose control, albeit with a higher risk of hypoglycemia [42]. Importantly, the largest and most definitive randomized controlled trial, entitled NICE SUGAR, enrolled over 6000 critically ill patients, and found increased mortality in patients who received intensive insulin therapy in both medical and surgical patients [12]. (Fig. 1) Importantly, patients who received “tight” glucose control had a significantly higher incidence of hypoglycemia with intensive glucose treatment. Why these recent trials found dissimilar results to the initial landmark investigation published in 2001 is unclear. It is possible that the standard of care for glucose management has changed over the years, and the control group in these later trials suffered less severe hyperglycemia and thus less severe outcomes. Nevertheless, most now believe that “tight” glucose control does not have a beneficial effect on mortality, and likely increases risk for serious adverse events including hypoglycemia.

Probability of Survival and Odds Ratios for Death, According to Treatment Group

Panel A shows Kaplan–Meier estimates for the probability of survival, which at 90 days was greater in the conventional-control group than in the intensive-control group (hazard ratio, 1.11; 95% confidence interval, 1.01 to 1.23; P = 0.03). Panel B shows the odds ratios (and 95% confidence intervals) for death from any cause in the intensive-control group as compared with the conventional-control group, among all patients and in six predefined pairs of subgroups. The size of the symbols indicates the relative numbers of deaths. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score can range from 0 to 71, with higher scores indicating more severe organ dysfunction. Reprinted with permission. New England J Med. 2009; 360: 1283.

PREOPERATIVE GLUCOSE MANAGEMENT OF DIABETIC PATIENTS

Approximately 27% of all people aged 65 years or older in the US are estimated to have diabetes mellitus.1 The high prevalence of this disease indicates that many patients who present for surgery each year will have a diagnosis of diabetes. Diabetes is characterized by the development of significant insulin resistance or insulin deficiency, resulting in elevated fasting glucose concentrations and an inadequate response to a glucose load. Because the diabetic patient is unable to produce an adequate insulin response, hyperglycemia results. Although hyperglycemia requiring treatment occurs commonly in the perioperative period in diabetic patients, they are also at risk for the occurrence of hypoglycemia related to treatment with anti-diabetic medications during fasting state or during inadequate oral intake. Thus, a thorough understanding of the glucose management issues in diabetic patients beginning in the preoperative period is necessary.

Perioperative management of blood glucose concentrations in diabetic patients requires adjustment of the patient's usual diabetic medication regimen, which often includes oral hypoglycemic agents, the mainstay of glucose control therapy for patients with type 2 diabetes. Preoperatively, oral hypoglycemic agents, especially those that stimulate insulin secretion, such as sulfonylureal and meglitinide agents, have potential for producing hypoglycemia during fasting prior to surgery. In addition, the long half-life of many of these drugs make titration in the setting of rapidly changing clinical parameters difficult. Thus, oral hypoglycemic medications should be continued up to the night prior to surgery, then held on the morning of surgery, with consideration of the fact that stopping antidiabetic therapy too early may compromise glucose control. Maintenance of preoperative glucose concentrations of 150 to 180 mg/dL or less is a reasonable goal. Oral hypoglycemic agents should not be restarted until the patient has resumed adequate and regular oral intake. Until adequate oral intake occurs, short- or medium duration insulin may be used to treat hyperglycemia until oral hypoglycemic agents can be restarted. Insulin therapy allows an improved ability to titrate to changing glucose concentrations compared with oral hypoglycemic agents.

In addition to their ability to treat hyperglycemia, several oral hypoglycemic agents, including the sulfonylurea agents and metformin, have important extrapancreatic effects, which may affect postoperative outcomes. The sulfonylurea agents (e.g. glipizide, glyburide, glimepiride) are commonly prescribed oral hypoglycemic agents for the treatment of type 2 diabetes. These agents bind to the ATP-dependent potassium (KATP) channel in the pancreatic ß-cells, leading to closure of these channels, stimulating insulin release. Thus, pancreatic β-cells are increasingly responsive to glucose concentrations and insulin release is augmented. However, in addition to closure of the pancreatic KATP channel, cardiac KATP channels are also affected by these agents. Closure of the cardiac KATP channel may increase risk for myocardial ischemic injury by blocking an intrinsic mechanism of cardioprotection, termed “ischemic preconditioning”. Ischemic preconditioning provides myocardial protection by the application of brief episodes of ischemia, which renders the myocardium more resistant to injury. Sulfonylurea agents block this process by interfering with cardiac KATP channel opening, which may adversely affect cardiovascular outcomes. Indeed, sulfonylurea use was associated with in-hospital mortality in patients undergoing percutaneous coronary intervention following myocardial infarction [43]. Further, ischemic preconditioning was blocked by glyburide in non-diabetic patients undergoing angioplasty [44]. Thus, sulfonylurea agents should be held for 24 hours prior to elective surgery because of the risk of adverse effects resulting from closure of the cardiac KATP channels in addition to the risk of hypoglycemia [45]. Because the meglitinides (nateglinide, repaglinide), act by a similar mechanism involving closure of the KATP channels, it is recommended that these drugs should also be held for 24 hours prior to surgery.

Metformin, a biguanide oral hypoglycemic agent, is commonly used for treatment of type II diabetes mellitus. Metformin is effective at lowering blood glucose levels by decreasing hepatic glucose production and intestinal glucose absorption, and increasing peripheral glucose uptake and utilization [46]. Because of chemical similarities to its predecessor, phenformin, which was associated with high risk of lactic acidosis and approximately 50% mortality [46], concern has been raised of the possibility of life-threatening lactic acidosis occurring with metformin. In addition, surgical patients are already at increased risk for lactic acidosis because of predisposing conditions, including renal insufficiency, congestive heart failure, hypoxemia and hypovolemia. Perioperative metformin-associated lactic acidosis has been reported [47, 48]; thus some recommend that metformin be discontinued for 24 hours or more prior to surgery [47, 48], although perioperative administration of metformin has been reported without increased risk of adverse outcome [49]. Metformin may be restarted following surgery after adequate oral intake has resumed. Metformin should not be restarted in patients with renal insufficiency, hepatic impairment, or heart failure because of the increased risk of metabolic acidosis.

For diabetic patients who are treated with insulin, preoperative instructions should include adjustment of the usual insulin dose. Longer-acting insulins (e.g. Ultra-lente, Lantus, Levemir) should be reduced to half of the usual dose the morning of surgery. Patients who use 70/30 or 75/25 (pre-mixed) insulin, should replace this dose with NPH on the morning of surgery. The NPH dose should be half of the mixed insulin dose. Patients with type I diabetes who maintain glucose control with an insulin pump may need continuation of a basal insulin rate with their insulin pump the morning of surgery. Measurement of serum glucose concentrations should be made immediately upon admission to the hospital with administration of intravenous glucose or insulin titrated to serum glucose concentrations. Maintaining blood glucose concentrations of 180 mg/dL or less is recommended.

Although hyperglycemia is associated with more severe illness and worse outcomes in both diabetic and nondiabetic patients, it is unclear whether the presence of diabetes exacerbates or mitigates this association. Some reports have found that diabetes mellitus alters the impact of glucose concentrations on outcomes in critically ill patients. For example, the only group of critically ill patients that did not receive a survival benefit from treatment of hyperglycemia with intensive insulin therapy were diabetic patients [50]. The authors speculated that rapid normalization of blood glucose concentrations may have been deleterious to patients that were use to higher blood concentrations. In contrast, the presence of diabetes did not affect the association of perioperative glucose concentrations on outcomes in cardiac surgical patients. Although diabetic patients were at increased risk of mortality, the effect of hyperglycemia on postoperative mortality was not modified by diabetic status. In contrast, diabetic critically ill patients were at less risk for mortality with hyperglycemia compared to nondiabetic critically ill patients [51, 52], and diabetic patients did not gain the same benefit from insulin therapy as nondiabetic patients [50, 52]. Others found that hyperglycemia was strongly associated with outcome in nondiabetic, but not diabetic, critically ill patients [53]. It is possible that significant pathophysiologic differences exist between diabetic and nondiabetic patients which may influence the effect of mean glucose concentrations on outcomes.

INTRAOPERATIVE GLUCOSE MANAGEMENT OF THE DIABETIC AND NONDIABETIC PATIENT

Hyperglycemia develops in both diabetic as well as nondiabetic patients undergoing surgery, because of stress hyperglycemia. Other factors may also contribute to hyperglycemia during the perioperative period, including administration of dextrose-containing fluids (used to mix antibiotics, vasoactive medications, etc.), hypothermia [54], increased substrate availability in the form of lactate, and decreased exogenous insulin activity [55]. Additional factors contribute to hyperglycemia in patients undergoing cardiac surgery, including heparin administration [56] and administration of glucose-containing cardioplegic solutions [57].

Although some suggest that intraoperative glucose concentrations do not impact outcomes because of the short duration of insulin therapy [58], the results of several investigations provide evidence that intraoperative glucose levels are associated with postoperative outcomes. For example, in cardiac surgical patients, severe hyperglycemia occurring during surgery was a strong predictor of mortality and multi-system morbidity [7]. Others report that intraoperative hyperglycemia, defined as the measurement of four consecutive blood concentrations greater than 200 mg/dL, was associated with significantly higher risk of mortality, as well as increased risk for cardiovascular, respiratory, renal, neurologic morbidity [6]. (Fig. 2) Duncan and colleagues found that, although severe intraoperative hyperglycemia (average glucose concentration greater than 200 mg/dL) was associated with high risk of morbidity and mortality, glucose concentrations closest to normoglycemia (average glucose of 140 mg/dL or less) were also associated with increased mortality and morbidity [9]. In fact, the range of glucose values with the lowest risk of adverse outcome ranged between 141 and 170 mg/dL. These results suggested that mild hyperglycemia was well-tolerated and “tight” glucose control during cardiac surgery was not associated with improved outcomes. Interestingly, the lowest glucose concentrations during the intraoperative period were associated with an increase in complications. This differed markedly from the pattern of the postoperative period, where the risk of adverse outcomes consistently declined with decreasing glucose concentrations (Figs. 3 and ​4).

Incidence of severe in-hospital morbidity between patients in whom intraoperative glycemic control was poor (4 consecutive glucose levels > 200 mg/dL) or tight. CV = cardiovascular morbidity; Inf: infectious morbidity; Neuro = neurologic morbidity; Resp = respiratory morbidity. *P<0.05 versus tight control. Reprinted with permission. Anesthesiology 2005; 103:687–94.

Univariate analysis comparing risk of adverse outcome between decreasing incremental mean glucose levels during the intraoperative period. *P≤0.001 overall between mean glucose levels for each individual outcome. #P≤ 0.001 between glucose > 200 mg/dL and glucose 141 −170 mg/dL. Reprinted with permission. Anesthesiology 2010; 112: 860.

Univariate analysis comparing risk of adverse outcome between decreasing incremental mean glucose levels during the initial postoperative period. *P≤0.001 overall between mean glucose levels for each individual outcome. #P≤ 0.001 between glucose > 200 mg/dL and glucose 141 −170 mg/dL. Reprinted with permission. Anesthesiology 2010; 112: 860.

An important randomized controlled trial investigated the benefits of intraoperative intensive insulin therapy in surgical patients [59]. This report found that efforts to maintain normoglycemia during cardiac surgery did not improve clinical outcomes. Unexpectedly, patients who received intensive insulin therapy to target glucose concentrations between 80 and 110 mg/dL had a higher incidence of mortality and postoperative stroke, providing evidence to suggest that “tight” glucose control during the intraoperative period of cardiac surgery did not benefit mortality or morbidity.

A few studies have examined glucose control in noncardiac surgery. For example, insulin infusions were reported to decrease risk of myocardial infarction in vascular surgery patients [60]. And neurosurgical patients who receive intensive insulin treatment have shorter ICU length of stay and less infections, though they did have more hypoglycemia [61]. Differences between cardiac and noncardiac surgery may explain why glucose control could impact these surgeries differently. The intraoperative course of cardiac surgery is complicated by myocardial ischemia and reperfusion injury related to aortic cross-clamping and release. It is possible that glucose concentrations may play a unique role during this period, since increased glucose uptake and metabolism during ischemia, rather than fatty acids, results in lower myocardial oxygen consumption, greater myocardial efficiency [26, 62], decreased arrhythmogenic substrates [30, 31], and preserved myocardial function [63]. One possible explanation may include that patients with “tight” glucose control may experience inadequate myocardial utilization of glucose and possibly contributing to increased postoperative complications. Whether the management of blood glucose concentrations should be specific to the type of surgery has not been investigated.

GLUCOSE VARIABILITY

Increased glucose variability, defined as greater fluctuation of glucose concentrations, has been associated with increased risk for adverse outcome. In cardiac surgical patients, postoperative glucose variability was significantly higher in nonsurvivors compared with survivors, and increased postoperative glucose variability was found to be an important risk factor for adverse postoperative outcomes [9]. Interestingly, significant intraoperative glucose variability was similar in both survivors and nonsurvivors, and was not associated with mortality. Intraoperative glucose variability is expected to be increased because of the acute development of insulin resistance exacerbated by frequent intraoperative administration of glucose-containing cardioplegia. The reasons for an association between increased glycemic variability and mortality could be related to activation of an oxidative stress effect due to excessive glucose fluctuations [64]. Other reports also found an association between increased glucose variability and increased morbidity and mortality in critically ill patients [65–67]. In fact, some have suggested that measures of glucose variability may be a better predictor of adverse outcome than mean glucose concentrations [65]. It is possible that methods aimed at decreasing postoperative glucose variability may improve outcomes. Fortunately, the use of continuous insulin infusions to treat hyperglycemia also decreases glucose variability compared to intravenous or subcutaneous insulin administration techniques.

HYPOGLYCEMIA

Hypoglycemia may occur with any insulin administration, but risk is increased when aggressive insulin therapy is implemented to target normoglycemia. Hypoglycemia is obviously an undesirable complication, which can result in death or severe neurological injury, and should be avoided. Indeed, several reports have found hypoglycemia to be an independent risk factor for death [11, 66, 68]. A recent meta-analysis of 21 trials in critically ill medical and surgical patients found no consistent evidence showed that tight glucose control reduced mortality, infection rates, length of stay, or the need for renal replacement therapy [69]. However, this trial and others found a five-fold or more greater risk for severe hypoglycemia when intensive insulin therapy was implemented [39, 69]. Interestingly, a few investigations have found a strong association of tight blood glucose control with worse outcomes despite rare hypoglycemia [9, 59], which suggests that factors other than hypoglycemia could contribute to poor outcomes in patients receiving intensive insulin therapy. Known risk factors for hypoglycemia are common in surgical patients, including diabetes, renal insufficiency, mechanical ventilation, high severity of illness, and receiving tight glucose control [70]. Although the consequences of hypoglycemia in hospitalized patients are unclear because few studies reviewed reported adverse effects and few studies examined the long-term consequences of hypoglycemia. However, some question whether hypoglycemia is a causative factor for excessive mortality, or whether it may be merely a marker for more severe disease [39].

CURRENT RECOMMENDATIONS

Although initial investigations suggested that intensive glycemic control improved outcomes in critically ill patients, subsequent trials failed to show a benefit or have even shown increased mortality associated with use of an intensive target for glucose control (glucose concentrations 80–110 mg/dL) compared to a more moderate target (glucose 140–180 mg/dL) for glucose concentrations. Thus, management of glucose concentrations has undergone drastic changes in the past decade, which are reflected by significant changes in recommendations for glucose management from national organizations with extensive expertise in glucose control. (Table 1) For example, the American Diabetes Association and the American Association of Clinical Endocrinologists currently recommend starting insulin infusions for critically ill patients with persistent hyperglycemia (glucose greater than 180 mg/dL) and aiming for a target blood glucose range of 140 – 180 mg/dL [71], while the American College of Physicians recommends a target of 140 to 200 mg/dL for insulin therapy in critically ill patients [39]. The fact that these two national societies differ in their recommended threshold for insulin treatment emphasizes the fact that the upper limit for treatment of glucose concentrations is unknown. However, both societies agree that adverse outcomes, including death and hypoglycemia, are increased in patients that receive intensive insulin therapy [9, 10, 12, 59]. Thus, tight glucose control is not recommended. Instead, toleration of mild hyperglycemia appears to benefit outcomes.

Table 1

Recommendations for Target Blood Glucose Concentrations

Recommendations for glucose control in the surgical patients are based largely on evidence accumulated from investigations of postoperative glucose management in the ICU [1, 72]. The Society of Thoracic Surgeons has issued recommendations for intraoperative glucose control, where insulin therapy for patients undergoing cardiac surgery with glucose concentrations that remain persistently greater than 180 mg/dL is recommended and, if initiated in the operating room, insulin therapy should be continued throughout the early postoperative period [73]. In patients who remain in the intensive care unit greater than 3 days, maintenance of glucose less than 150 mg/dL is recommended [73]. Less information is available for noncardiac surgical patients. However, these recommendations may also be applied to patients undergoing major surgery, such that glucose concentrations persistently higher than 180 mg/dL may benefit from glucose control with insulin infusions. However, the evidence to support this guideline in noncardiac surgical settings is limited.

Effective insulin therapy algorithms should be used to treat severe perioperative hyperglycemia; however, efforts to avoid serious consequences of hypoglycemia are necessary. Intravenous insulin infusion protocols are more useful than simple sliding-scale infusion protocols in controlling blood glucose levels while maintaining relatively low rates of hypoglycemia [74] and decreasing blood glucose variability. Insulin treatment algorithms should incorporate factors that titrate insulin according to the current blood glucose level, the rate of change of glucose level, and insulin infusion rate. Low-dose insulin infusions, small insulin boluses, and adjusting insulin dose for rate of change of glucose levels over time, do contribute to the safety of an insulin infusion technique. Intraoperatively, arterial blood gas analysis is the gold standard for measuring blood glucose concentrations, however, if an arterial line is not used intraoperatively, point-of-care glucometer devices will provide capillary blood glucose measures useful for titration of insulin. However, during periods of hypotension or poor tissue perfusion, capillary blood glucose measures may not be accurate. During cardiac and other major surgery, especially in diabetic patients, blood glucose measurements should be performed frequently and routinely in order to avoid hypoglycemia, which has been identified as a risk factor for mortality [10, 70]. In addition, simple interventions, such as using normal saline rather than dextrose as a carrier solution for administering antibiotics and other medications, will contribute to improved blood glucose control.

ACKNOWLEDGEMENT OF FUNDING

The manuscript was supported by NIH 1K23HL093065-01A2.

Footnotes

CONFLICT OF INTEREST The author confirms that this article content has no conflicts of interest.

1This information was obtained from the Centers for Disease Control and Prevention (CDC) web site: http://www.cdc.gov/diabetes/pubs/estimates11.htm#1 accessed on May 12, 2011.

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