Perioperative glucose control James Krinsley

Transcription

1 Perioperative glucose control James Krinsley Purpose of review Hyperglycemia occurs commonly among acutely ill patients owing to a combination of counterregulatory and stress responses, as well as insulin resistance and deficiency, and is associated with increased morbidity and mortality in a variety of different patient populations. This manuscript reviews the adverse consequences of hyperglycemia in these different settings and focuses on perioperative glycemic management. Recent findings Hyperglycemia has a number of effects on the native immune system that may explain its role in increasing the risk of infection. Insulin may exert its beneficial effects by altering lipid metabolism as well as by modulating endothelial function through several mechanisms. Hyperglycemia during cardiac surgery is associated with increased risk of postoperative complications, including death. Several interventional studies have concluded that intensive glycemic management is beneficial, but there are limited data available from general surgical populations. Summary Hyperglycemia is associated with adverse outcomes in acutely ill adult patients and its treatment has been shown to improve mortality and morbidity in a variety of different settings. Additional studies are needed in heterogeneous populations of critically ill patients as well as in other populations of acutely ill patients, especially general surgical patients, to confirm the early studies and define the correct glycemic target. Keywords glucose, hyperglycemia, intensive care unit, intensive insulin therapy, mortality, surgery Curr Opin Anaesthesiol 19: # 2006 Lippincott Williams & Wilkins. Department of Critical Care, Stamford Hospital, Department of Medicine, Columbia University College of Physicians and Surgeons, Stamford, Connecticut, USA Correspondence to J Krinsley MD, Director of Critical Care, Stamford Hospital, 190 West Broad Street, Stamford, CT 06902, USA Tel: ; fax: ; jkrinsley@stamhealth.org Current Opinion in Anaesthesiology 2006, 19: Abbreviations ADMA asymmetric dimethylarginine AMI acute myocardial infarction GIK glucose insulin potassium ICU intensive care unit # 2006 Lippincott Williams & Wilkins Introduction Poorly controlled diabetes mellitus has long been associated with an increased risk of organ system dysfunction and failure. Hyperglycemia that occurs in acutely ill patients, both diabetic and nondiabetic, has been recognized in a growing body of literature to be both a marker and a cause of adverse outcomes in a variety of different clinical contexts. This manuscript summarizes information about the mechanisms of the harmful effects of hyperglycemia, reviews recently published observational and interventional studies of hyperglycemia in acutely ill patients, focusing on the surgical population, and highlights gaps in the medical literature regarding perioperative glucose control. Why is hyperglycemia deleterious? A number of recent studies [1,2,3,4,5,6,7,8,9,10, 11 ], including several excellent review articles, have helped to elucidate the different mechanisms of the deleterious effects of hyperglycemia in acutely ill patients and the beneficial effect of glycemic control in various populations. Broadly speaking, these include evaluations of the glycemic and nonglycemic metabolic effects of insulin, as well as the role of hyperglycemia in modulating the innate immune system and the effect of intensive insulin therapy on reversing these changes. A brief synopsis of some of the most current important work follows. Turina et al. [5 ] summarized some of the most important effects of hyperglycemia on immune defenses. These include in part the microvascular response, the adhesion and transmigration of leukocytes, the complement cascade, the cytokine network, chemokine formation, chemotaxis, phagocytosis, the generation of reactive oxygen species, and neutrophil apoptosis, accounting for the increase in infections and multisystem dysfunction seen among critically ill patients with hyperglycemia. A beneficial effect on lipid metabolism is one possible important consequence of intensive insulin therapy [6, 7,8 ]. Mesotten et al. [6 ] found that intensive insulin therapy correlated with an increase in the activity of two enzymes necessary for the peripheral uptake of glucose: skeletal muscle glucose transporter 4 and hexokinase. Moreover, intensive insulin therapy affected the lipid profile of the patients: mortality correlated with increasing triglyceride level as well as with a decrease 111

2 112 Intensive care in high-density lipoprotein and low-density lipoprotein levels below a threshold. These investigators hypothesized that low levels of high-density lipoprotein and lowdensity lipoprotein may contribute to increased infection risk by adversely affecting scavenging of endotoxin in the circulation. Siroen et al. [9 ] and Nirjveldt et al. [10] have also evaluated the effect of intensive insulin therapy on modulators of endothelial function in two recent studies. Microvascular dysfunction associated with a diminished availability of gaseous nitric oxide may explain the multiorgan system dysfunction and failure that occurs in the most critically ill patients [9 ]. Asymmetric dimethylarginine (ADMA) inhibits the enzyme nitric oxide synthetase, which produces nitric oxide, and has been found to be an independent predictor of mortality in critically ill patients [9 ]. Siroen et al. [9 ] measured ADMA level in a subset of patients from the Leuven study (see below). ADMA levels increased significantly among patients in the control group during the first 2 days of intensive care unit (ICU) stay, whereas they did not change in the patients treated with continuous intravenous insulin. Moreover, ADMA levels were higher among nonsurvivors than among survivors, regardless of the treatment received. Endothelial activation is associated with the expression of several adhesion molecules, including E- and P- selectin, intracellular adhesion molecule and vascular cell adhesion molecule (VCAM), on the cell surface [11 ]. These activated molecules recruit leukocytes; subsequent leukocyte aggregation and adhesion lead to microvascular obstruction as well as increased microvascular permeability, important features of multiorgan system dysfunction. Nitric oxide helps modulate the interaction between the endothelium and leukocytes. Langouche et al. [11 ] investigated local activation of the endothelium and its relation to insulin therapy and outcomes. They found that intensive insulin therapy lowered circulating levels of intracellular adhesion molecule 1 and E-selectin, and led to decreased circulating nitric oxide levels by suppressing inducible nitric oxide synthetase gene expression; these mechanisms may help protect the vascular endothelium from injury and prevent organ system dysfunction. Observational studies The relationship between hyperglycemia and outcomes has been investigated recently among patients with neurologic illness [12,13,14,15,16 ], acute myocardial ischemia and infarct [17 19,20,21], trauma [22,23 ], and peripheral vascular disease [24]. Intraoperative hyperglycemia correlated with death or significant organ dysfunction among patients undergoing cardiovascular surgery [25 ]. There are fewer reports describing the relationship between hyperglycemia and outcomes of populations of general ICU patients. A series of 1826 consecutive admissions [26] to a mixed medical-surgical ICU found a striking relationship between mean glucose level during ICU stay and the rate of hospital mortality. An observational study of 523 patients, 85% who had had cardiac surgery, confirmed a strong relationship between glycemic control and mortality [27]. Finally, pre-icu glucose control, reflected by hemoglobin A 1C level, may help predict a patient s glycemic response to ICU admission [28 ]. Interventional studies Van den Berghe et al. [29,30] performed a single-center randomized, controlled prospective trial among 1548 surgical ICU patients receiving mechanical ventilation at the University of Leuven in Belgium, 63% following cardiovascular surgery. The therapeutic goal in the treated group was maintenance of euglycemia mg/ dl using a continuous intravenous infusion of insulin. There was a 34% reduction in mortality among the treated patients and a 40 50% reduction in important comorbidities. The Leuven trial has catalyzed the development of glucose-management protocols in ICUs worldwide and is cited in practice standards promulgated by leading organizations [31,32 ]. Moreover, the Joint Commission on Accreditation of Hospitals and Organizations [33] is considering glycemic control as a core measure for hospital performance. Nevertheless, Bellomo et al. [34] have raised several issues regarding this study: the study was not blinded, raising the possibility of bias; the study population precludes generalizability of the findings; and the very high dextrose administration is not typical of ICU treatment and may have actually contributed to the high (5.1%) mortality of the cardiovascular surgery patients in the control group. Finally, the loose level of glycemic control in the control group (glycemic target mg/dl) would be difficult to justify in 2006 in view of accumulating data demonstrating the deleterious effect of glucose levels significantly below this treatment threshold. The only other published study of intensive glucose management was performed in a community hospital setting among a mixed population of medical and surgical patients, none following cardiovascular surgery [35 ]. This before-and-after study compared the outcomes of 800 patients admitted just prior to the institution of the protocol with those of the first 800 patients treated with the protocol. The noncontrolled, nonrandomized design is the main limitation of the study. The treatment goal

3 Perioperative glucose control Krinsley mg/dl was less strict than was used in the Leuven trial. There was a 29% reduction in hospital mortality of the treated patients, from 20.9 to 14.8%, as well as a reduction in the development of new renal insufficiency and in the number of patients who required red blood cell transfusions. Since completion of the published study, the subsequent 1200 patients admitted to the ICU sustained a 13.6% hospital mortality rate (Krinsley, unpublished observation). Two recent studies have investigated the effect of insulin and glucose administration among patients with acute myocardial infarction (AMI). The DIGAMI 2 study [36 ] followed the DIGAMI 1 study [37] of glucose insulin potassium infusion (GIK) among diabetics with AMI, which had demonstrated a reduction in 1- year mortality from 28 to 19% in the treated group. The new study, involving 1253 patients with type 2 diabetes, was hindered by a lack of appropriate funding and by small patient enrollment spread across a large number of centers [38]. Mortality did not vary among the two treatment and one control groups; glycemic control was, however, no better in the two treatment groups than in the control group. The CREATE- ECLA trial evaluated the effect of GIK infusion in AMI in patients from 470 centers worldwide [39 ]. GIK infusion did not have an effect on mortality, cardiac arrest or the development of cardiogenic shock. The treated group actually demonstrated worsened glycemic control; it is possible that this may have blunted any potential benefit of insulin. There was a strong relationship between 30-day mortality and baseline glucose level among the entire group. The messages of these two studies are, first, that GIK infusion cannot be recommended as a therapy for AMI and, second, that the strong relationship between glycemic levels and mortality in AMI was confirmed. There are only a few published studies involving glycemic management protocols in postoperative populations; most involve cardiovascular patients. Furnary et al. [40,41 ] have, since 1992, implemented intensive glycemic management using continuous intravenous insulin infusions among diabetic patients undergoing cardiovascular surgery. This pioneering work has demonstrated a strong association between glycemic control and deep sternal wound infections as well as mortality. This work has been criticized because of its observational, noncontrolled design, but, to this reviewer, these objections are overwhelmed by the size of the population studied and the strength and consistency of the findings. Lazar et al. [42 ] evaluated GIK therapy in a small series of cardiovascular surgery patients. The treated group achieved better glycemic control than did the control group. Beneficial outcomes included decreases in the infection rate, atrial fibrillation, the use of inotropic support, length of stay, and duration of mechanical ventilation, as well as improved 2-year survival and a lower incidence of recurrent ischemia. There are several limitations to this study. It was completed in an unblinded manner in a single institution and involved a small number of patients. More importantly, the liberal glycemic target (250 mg/dl in the control group) does not correspond to the standard of care in In other words, we have learned that severe hyperglycemia is deleterious, but this trial does not help determine the correct glycemic target. Moreover, although Lazar et al. s study does not answer whether the observed benefit was attributable to glucose, potassium or insulin, the AMI studies noted above suggest that the insulin administration was determinative. A group of investigators from Vanderbilt University [43] performed a before-and-after trial of the effect of a glycemic management protocol on the outcomes of patients admitted to a trauma ICU who required mechanical ventilation. This study reports no change in the incidence of ventilator-associated pneumonia, surgical site infection or mortality between the two groups. However, glycemic control was nearly identical between the two groups. Hyperglycemia was associated with adverse outcomes in both groups. Once again, it is difficult to demonstrate beneficial outcomes of a glycemic management protocol that does not produce significant differences in glycemic control between the treatment and the control group. There are no studies in the literature specifically evaluating the effect of tight glucose control on populations of general surgical patients. Outcome data [29] from the small number of general patients enrolled in the Leuven trial are difficult to interpret in the absence of severity adjustment. The Stamford Hospital 1600 patient before-and-after study [35 ] included a total of 335 patients with general surgical diagnoses; among this group, there was a 48.8% relative reduction in mortality, from 16.8 to 8.6% (P = 0.04). One small randomized study [44], involving only 61 patients, reported a significant decrease in nosocomial infections in the treated group; the protocol in this case did lead to a significant improvement in glycemic control. Enthusiasm about these positive results must be tempered by the small sample size of the study group. Protocol implementation Several groups have recently reported their experience promulgating intensive glycemic management protocols among cardiovascular surgery patients, with targeted

4 114 Intensive care blood glucose ranges of mg/dl [45], mg/dl [46] and mg/dl [47]. All groups reported improvements in glycemic control without the development of clinically significant hypoglycemia. Most glycemic management protocols rely heavily on the bedside measurement of glucose using point-ofcare devices. These chemistry-based analyzers were developed for the outpatient diabetic population; their accuracy in the ICU setting is worth validating. Finkielman et al. [48 ] performed a retrospective review of the records of 1192 consecutive ICU admissions to identify instances when simultaneous glucose measurements were made using a bedside chemistry analyzer. The limits of agreement between the two measurements, defined by the authors as 2 SD, were mg/dl and 27.1 mg/dl. In other words, if the plasma glucose level measured by the central analyzer yielded a result of 150 mg/dl, the concomitant blood glucose value obtained by the point-of-care chemistry analyzer would, 95% of the time, be within the large range of mg/dl. These data are sobering in an era when many ICUs are attempting to institute protocols targeting euglycemia. Future directions and needs This review article on perioperative glucose control has, by necessity, a major omission the absence of any data evaluating the effect of intensive glucose-management protocols on populations of general surgical patients. These data do not yet exist. It is not proven that the benefits of intensive glycemic management reported in the two ICU studies [29,35 ] necessarily extend to general surgery patients. Moreover, the appropriate glycemic target needs to be determined. Data from the Leuven study [30] demonstrate that mortality and morbidity were lowest among patients who maintained mean glucose levels <110 mg/dl, intermediate among patients with mean glucose levels of mg/dl and highest among patients with mean glucose levels >150 mg/dl. The Stamford Hospital study targeted 140 mg/dl, not 110 mg/dl, but a large observational series from the same ICU [26] reported that the lowest mortality occurred among patients with a mean glucose during ICU stay of mg/dl; this rate was better than seen even in those patients with a mean glucose during ICU stay of mg/dl. New data on the effect of intensive glycemic management among a heterogeneous population of critically ill patients will be available in the near future. The Australian and New Zealand Intensive Care Society Clinical Trials Group is currently performing a large prospective multicenter study (NICE Normoglycemia in Intensive Care Evaluation); glycemic targets are mg/dl in the treatment group and mg/dl in the control group [49 ]. Note how much this control-group target has changed since publication of the Leuven study. Completion of these new trials is eagerly awaited to confirm those data we currently have on the effect of intensive glucose management in critically ill patients. Finally, two new studies document the potential cost savings accruing from the implementation of intensive glycemic management. The authors of the Leuven [50 ] and Stamford Hospital [51] studies have found that the decreases in mortality and morbidity enjoyed by their patients were accompanied by substantial reductions in the cost of patient care. These additional bottom-line benefits of this relatively simple intervention will likely provide additional impetus to the adoption of tight glycemic control as a standard of care among acutely and critically ill patients. References and recommended reading. Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Digman C, Borto D, Nasraway SA Jr. Hyperglycemia in the critically ill. Nutr Clin Care 2005; 8: This review article provides an excellent starting point for those wishing to review the clinical studies observational as well as interventional that have involved intensive glycemic management, as well as some of the mechanisms of the deleterious effects of hyperglycemia. 2 Taylor JH, Beilman GJ. Hyperglycemia in the intensive care unit: no longer just a marker of illness severity. Surg Infect (Larchmt) 2005; 6: Butler SO, Btaiche IF, Alaniz C. Relationship between hyperglycemia and infection in critically ill patients. Pharmacotherapy 2005; 25: Another excellent overview. 4 Coursin DB, Connery LE, Ketzler JT. Perioperative diabetic and hyperglycemic management issues. Crit Care Med 2004; 32:S116 S Turina M, Fry DE, Polk HC. Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med 2005; 33: An outstanding review of the various immune mechanisms impacted by hyperglycemia. The authors place their findings in the context of the recent clinical studies of intensive glycemic management and caution that not every mechanism discussed has been proved to be relevant to the critically ill population. 6 Mesotten D, Swinnen JV, Vanderhoydonc F, et al. Contribution of circulating lipids to the improved outcome of critical illness by glycemic control with intensive insulin therapy. J Clin Endocrinol Metab 2004; 89: This study evaluates the effect of intensive insulin therapy on lipid metabolism and its relationship to improved outcomes with treatment. 7 Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? J Clin Invest 2004; 114: Vanhorebeek I, Langouche L, Van den Berghe G. Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness? Curr Opin Crit Care 2005; 11: An excellent summary of the metabolic and nonmetabolic effects of insulin in critical illness. 9 Siroen MP, van Leeuwen PA, Nijveldt RJ, et al. Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: a possible explanation of reduced morbidity and mortality? Crit Care Med 2005; 33: This provocative manuscript reports experimental data supporting a central role of ADMA in the development of multiorgan failure, and a role of insulin in ameliorating its effects.

5 Perioperative glucose control Krinsley Nijveldt RJ, Teerlink T, Van Der Hoven B, et al. Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality. Clin Nutr 2003; 22: Langouche L, Vanhorebeek I, Vlasselaers D, et al. Intensive insulin therapy protects the endothelium of critically ill patients. J Clin Invest 2005; 115: This investigation evaluates the effect of insulin therapy in mitigating the excessive release of nitrogen oxide and its relationship to the development of multiorgan failure. 12 Juvela S, Siironen J, Kuhmonen J. Hyperglycemia, excess weight, and history of hypertension as risk factors for poor outcome and cerebral infarction after aneurysmal subarachnoid hemorrhage. J Neurosurg 2005; 102: Hyperglycemia is an important risk factor for poor outcome after aneurysmal subarachnoid hemorrhage. 13 Kernan WN, Viscoli CM, Inzucchi SE, et al. Prevalence of abnormal glucose tolerance following a transient ischemic attack or ischemic stroke. Arch Intern Med 2005; 165: Dora B, Mihci E, Eser A, et al. Prolonged hyperglycemia in the early subacute period after cerebral infarction: effects on short term prognosis. Acta Neurol Belg 2004; 104: Alvarez-Sabin J, Molina CA, Ribo M, et al. Impact of admission hyperglycemia on stroke outcome after thrombolysis: risk stratification in relation to time to reperfusion. Stroke 2004; 35: Another important contribution that relates admission hyperglycemia to poor outcomes, especially among patients with early reperfusion. 16 Jeremitsky E, Omert LA, Dunham CM, et al. The impact of hyperglycemia on patients with severe brain injury. J Trauma 2005; 58: Hyperglycemia is a marker of worsened outcomes in the setting of severe brain injury. 17 Suleiman M, Hammerman H, Boulos M, et al. Fasting glucose is an important independent risk factor for 30-day mortality in patients with acute myocardial infarction: a prospective study. Circulation 2005; 111: This prospective evaluation of patients with acute myocardial infarction confirms the association of admission glucose values with impaired outcome in nondiabetics as well as diabetics. 18 Kosuge M, Kimura K, Ishikawa T, et al. Persistent hyperglycemia is associated with left ventricular dysfunction in patients with acute myocardial infarction. Circ J 2005; 69: Persistent hyperglycemia 24 h after symptom onset was associated with left ventricular dysfunction in patients with recanalized anterior AMI. 19 Choi KM, Lee KW, Kim SG, et al. Inflammation, insulin resistance, and glucose intolerance in acute myocardial infarction patients without a previous diagnosis of diabetes mellitus. J Clin Endocrinol Metab 2005; 90: Previously undiagnosed diabetes and impaired glucose tolerance were common in Korean patients with AMI and correlated with serum markers of inflammation. 20 Cao JJ, Hudson M, Jankowski M, et al. Relation of chronic and acute glycemic control on mortality in acute myocardial infarction with diabetes mellitus. Am J Cardiol 2005; 96: Timmer JR, van der Horst IC, Ottervanger JP, et al. Prognostic value of admission glucose in non-diabetic patients with myocardial infarction. Am Heart J 2004; 148: Laird AM, Miller PR, Kilgo PD, et al. Relationship of early hyperglycemia to mortality in trauma patients. J Trauma 2004; 56: Sung J, Bochicchio GV, Joshi M, et al. Admission hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma 2005; 59: Admission hyperglycemia is identified in this report as an important predictor of worsened outcomes in a population of trauma patients. 24 Vriesendorp TM, Morelis OJ, Devries JH, et al. Early post-operative glucose levels are an independent risk factor for infection after peripheral vascular surgery. A retrospective study. Eur J Vasc Endovasc Surg 2004; 28: Gandhi GY, Nuttall GA, Abel MD, et al. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc 2005; 80: Intraoperative hyperglycemia correlated with worsened postoperative outcomes in this series of over 400 cardiovascular surgery patients from the Mayo Clinic. 26 Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc 2003; 78: Finney SJ, Zekveld C, Elia A, et al. Glucose control and mortality in critically ill patients. JAMA 2003; 290: Cely CM, Arora P, Quartin AA, et al. Relationship of baseline glucose homeostasis to hyperglycemia during medical critical illness. Chest 2004; 126: This study demonstrates that suboptimal preadmission blood glucose control, as reflected in hemoglobin A 1C levels, is correlated with deleterious outcomes among critically ill medical patients. 29 Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345: Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003; 31: American College of Endocrinology Position Statement on Inpatient Diabetes and Metabolic Control. Endocr Prac Jan-Feb 2004; 10: This document provides a consensus statement from a leading association about inpatient management of diabetes. 32 Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004; 32 3: Review. Erratum in: Crit Care Med 2004; 32 6:1448. Correction of dosage error in text. Crit. Care Med 2004; 32: This comprehensive document, crafted by a group of critical-care leaders, lists intensive glucose management among its practice guidelines for sepsis. 33 American Association of Respiratory Care. AARC provides JCAHO with guidance Bellomo R, Egi M. Glycemic control in the ICU: why we should wait for NICE SUGAR. Mayo Clin Proc (in press). 35 Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 2004; 79: This large before-and-after study among a mixed population of medical and surgical patients remains the only ICU trial of intensive glucose management published since Van den Berghe s trial [29]. 36 Malmberg K, Ryden L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005; 26: This study may be misinterpreted as showing no benefit of intensive glycemic control in this cohort of diabetic patients with AMI. The absence of a difference in glycemic control among the treatment groups, however, vitiates this conclusion. Instead, there are additional compelling data supporting the strong association between hyperglycemia and deleterious outcomes in this clinical context. 37 DIGAMI Study Group, Malmberg K, Rydén L, et al. A randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction: effects on mortality at 1 year. J Am Coll Cardiol 1995; 26: Hirsch IB. Were we wrong about insulin and acute myocardial infarction? 39 Mehta SR, Yusuf S, Diaz R, et al. Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial. JAMA 2005; 293: The authors present compelling data from a very large prospective cohort demonstrating the absence of benefit of GIK infusion, which in their hands led to worsened glycemic control in the treatment group. Once again, a strong association between increasing glycemic level and mortality was demonstrated. 40 Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 2003; 125: Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocr Pract Mar Apr 2004; 10 (Suppl. 2): An excellent overview of more than a decade of intensive glucose management among cardiovascular surgery patients by the visionary Furnary group. 42 Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation 2004; 109: Lazar et al. s randomized, prospective study provides evidence of improved outcomes among diabetic patients undergoing coronary artery bypass grafting surgery with intensive glucose management. 43 Collier B, Diaz J Jr. Forbes R, et al. The impact of a normoglycemic management protocol on clinical outcomes in the trauma intensive care unit. JPEN J Parenter Enteral Nutr 2005; 29:

6 116 Intensive care 44 Grey NJ, Perdrizet GA. Reduction of nosocomial infections in the surgical intensive-care unit by strict glycemic control. Endocr Pract Mar Apr 2004; 10 (Suppl.2): Goldberg PA, Sakharova OV, Barrett PW, et al. Improving glycemic control in the cardiothoracic intensive care unit: clinical experience in two hospital settings. J Cardiothorac Vasc Anesth 2004; 18: Mirian A, Korula G. A simple glucose insulin regimen for perioperative blood glucose control: the Vellore regimen. Anesth Analg 2004; 99: Carvalho G, Moore A, Qizilbash B, et al. Maintenance of normoglycemia during cardiac surgery. Anesth Analg 2004; 99: Finkielman J, Oyen LJ, Afessa B. Agreement between bedside and plasma glucose measurement in the ICU setting. Chest 2005; 127: This important manuscript demonstrates the frequent lack of agreement between the bedside glucose monitor used in the study and the hospital s central laboratory analyzer, an important finding in the context of the proliferation of glycemic protocols targeting euglycemia. 49 The NICE/SUGAR trial. ISRCTN /0/ html. This large randomized controlled trial of intensive glucose management in critically ill adult medical and surgical patients will serve as a welcome follow-up of the Leuven and Stamford trials. 50 Van den Berghe G, Wouters PJ, Kesteloot K, et al. Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients. Crit. Care Med. 2006: htm;jsessionid=D0KdXRRfLz11thTNf01qMfXAMC VRW9ZMnA08A1id71wTSI11OC59! ! !9001!-1 [Accessed 15 th February 2006] This economic analysis of the Leuven trial finds significant economic benefit to intensive glycemic management, complementing the benefits observed in the clinical trial. 51 Krinsley JS, Jones R, Grissler B. Cost analysis of intensive glycemic control in critically ill adult patients. Chest (in press).