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*Department of Anesthesiology and Internal Medicine, University of Wisconsin, Madison, Wisconsin; and
Department of Anesthesiology and Critical Care, Wake Forest University, Winston-Salem, North Carolina
Address correspondence and reprint requests to Douglas B. Coursin, MD, Department of Anesthesiology, B6/319 UW CSC, Madison, WI 53792-3272. Address e-mail to dcoursin{at}facstaff.wisc.edu
Anesthesiologists are increasingly expected to achieve new standards of perioperative glucose control (1–8). Although attention is often focused on the nearly 30,000 children, adolescents, and young adults newly diagnosed each year with Type 1 diabetes mellitus (DM) (attributed to pancreatic islet cell failure and an absolute deficiency of insulin that results in an obligate need for insulin), this incidence has not changed in more than 50 yr (9). By contrast, there is an epidemic of Type 2 DM, which manifests as a spectrum of glucose dysregulation secondary to a combination of relative insulin deficiency, peripheral insulin resistance, and excessive hepatic gluconeogenesis (10,11). Type 2 DM is managed with diet, oral hypoglycemic drugs, and insulin preparations, alone or in combination (9,10). The number of newly diagnosed Type 2 diabetics is approaching 1 million cases annually, and this incidence has doubled in the past decade. Obesity, inactivity, excessive carbohydrate ingestion, and chronic inflammation all contribute to the increasing prevalence, and although it is most often diagnosed in the elderly, Type 2 DM is increasing in younger individuals as well (9–11). Despite, or perhaps because of, these epidemic proportions, one third of Type 2 diabetics still go undiagnosed. Thus, anesthesia preoperative assessment may need to include routine fasting glucose screening or measurement of glycosylated hemoglobin (hemoglobin A1c) in inactive, obese, high-risk patients. Earlier diagnosis and proper treatment may delay or prevent the onset of renal, vascular, ophthalmic, and cardiac disease (4,12).
The DM alarm is ringing loudly, with reports by Narayan et al. (13) suggesting that a male child born in 2000 has approximately a 30% chance and a female child a 40% likelihood of developing DM during his or her lifetime. DM is currently the number 6 cause of death in the United States and is frequently present in patients who have cardiovascular disease and stroke, the first and third leading causes of death in this country, respectively (14,15). Cardiac disease is especially common in diabetics and is the most common cause of death in this population (12). Not surprisingly, therefore, 28% of patients undergoing coronary artery surgery are diabetic (7).
Diabetic patients have more frequent, more prolonged, and more expensive hospitalizations that result in more morbidity and mortality than nondiabetics (9,16). Diabetics also require more frequent surgical interventions and are more often admitted to an intensive care unit (ICU). Furthermore, it is common for even nondiabetic surgical and ICU patients to develop acute hyperglycemia mediated by the release of proinflammatory cytokines (such as tumor necrosis factor-
and interleukin-6) and increasing concentrations of catecholamines, growth hormone, glucagon, and glucocorticoids (17).
What can and should be done to manage hyperglycemia during hospitalization? The work by Carvalho et al. (18) in this issue of the journal highlights the rediscovery of a clinically superior method for insulin and glucose administration to maintain endocrine homeostasis throughout a particularly challenging period: during and immediately after cardiopulmonary bypass (19). Previous efforts to tightly control blood glucose in this population through the traditional approach of monitoring blood sugar and then responding with escalating doses of regular insulin have simply proven unsuccessful and may predispose patients to delayed and significant hypoglycemia (20). It appears that Carvalho et al. (18) have identified a better way.
Although the methodology for administering insulin and glucose may be debated, the clinical end-point is well accepted. Convincing evidence suggests that clinical outcome is improved in cardiac surgery patients treated to maintain blood glucose 
110 mg/dL (<7 mmol/dL) (2,7,21). Van den Berghe et al. (21) achieved postoperative euglycemia with aggressive infusions of regular insulin in a surgical ICU population of whom two thirds had just undergone cardiac surgery. Although only 13% of these patients were known diabetics, almost all study patients required insulin infusions to normalize blood glucose to the target range of 80–110 mg/dL (5–7 mmol/dL) (21). Subgroup analysis demonstrated significantly improved outcomes when cardiac surgery patients required ICU care for 
5 days and euglycemia was maintained (21). In another study of 520 surgical ICU patients (>80% of whom underwent cardiac surgery), Finney et al. (2) reported similar survival benefits when glucose was maintained <145 mg/dL (9 mmol/dL). Even historical standards support these findings. In a longitudinal 15-yr study that reviewed diabetic patients undergoing coronary artery surgery, Furnary et al. (7) reported a significant improvement in survival as increased glucose concentrations were treated more aggressively. Their most recent protocol advocated continuous insulin infusions starting the morning of surgery and continuing until the time of ICU discharge, with a target glucose concentration (100–150 mg/dL, or 6.2–9.6 mmol/dL) that is nearly consistent with current standards (7). Surprisingly, outcome data related to glucose control are mostly limited to cardiology and cardiac surgery patients (2,6,7,21,22). Thus, a legitimate question is whether similar strategies for glucose management are beneficial to medical and pediatric patients or even patients from other surgical disciplines. At least one recent (but retrospective) review of 1800 adult, noncardiac surgical patients reported that mean and maximal glucose concentrations at the time of ICU admission were highly predictive of outcome and that the higher the glucose level, the more frequent the mortality rate (1).
Both Van den Berghe et al. (21) and Finney et al. (2) ascribed the benefits in outcome to glucose control and not to insulin therapy. This conclusion is controversial (22–24). Furnary et al. (7) and others (22) speculate that glucose, insulin, and potassium help to limit the deleterious free fatty acid metabolism associated with myocardial ischemia or infarction. However, this may require even larger doses of glucose, insulin, and potassium, and no one has measured the free fatty acid response to aggressive insulin therapy during cardiac procedures (8).
In summary, aggressive perioperative control of glucose appears appropriate for both diabetic and nondiabetic cardiac surgery patients. The study by Carvalho et al. (18) demonstrates that a continuous infusion of insulin initiated before cardiopulmonary bypass reduces the variation and improves the precision of glucose control during the intra- and postoperative periods. Their approach is convincing, in that euglycemia can be safely achieved throughout the perioperative period in this challenging patient cohort. Institutions considering any aggressive glucose control protocol must recognize that it is labor intensive and associated with significant resource utilization (Pam Roberts, MD, Wake Forest University, personal communication, 2004). Indeed, it is noteworthy that the patients in the study of Carvalho et al. had their blood glucose measured every 5 min to ensure euglycemia. Other issues remain unclarified. The first is the need to determine the ideal glucose range to optimize outcome while minimizing the risk of hypoglycemia. The second is whether tight glucose control is equally beneficial in other patient populations beyond those undergoing cardiac surgery. Finally, we need to elucidate the biochemical mechanisms by which the benefit of normoglycemia is conferred. In the meantime, we applaud the efforts of Carvalho et al. in illuminating an effective strategy to monitor and control glucose during cardiac surgery. We have some answers, but many questions remain.
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