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Does Tight Blood Glucose Control during Cardiac Surgery Improve Patient Outcome?

Greet Van den Berghe, MD, PhD
[+] Article, Author, and Disclosure Information

From Catholic University of Leuven, Leuven, Belgium.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Greet Van den Berghe, MD, PhD, Catholic University of Leuven, Department of Intensive Care Medicine, University Hospital Gasthuisberg, B-3000 Leuven, Belgium; e-mail, greta.vandenberghe@med.kuleuven.be.

Ann Intern Med. 2007;146(4):307-308. doi:10.7326/0003-4819-146-4-200702200-00012
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Intensive insulin therapy to maintain normal levels of blood glucose (4.4 to 6.1 mmol/L [80 to 110 mg/dL]) during intensive care improves survival and reduces morbidity of critically ill patients after complicated, high-risk, or extensive surgery or trauma (1). Clear benefit from this intervention requires maintenance of tight blood glucose control for at least a few days (2). The mechanism by which maintaining normoglycemia prevents adverse outcomes is not fully understood. One possibility is that avoiding sustained cellular glucose overload and toxicity in certain cell types reduces the likelihood for vital organ dysfunction (3). Avoiding glucose toxicity seems to prevent damage to the mitochondrion, the organelle that generates energy for cellular functions (4).

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Tight Blood Glucose Control with Insulin: Unmasking Previous Safety Concerns.
Posted on February 25, 2007
Mohamed Y Rady
Department of Critical Care Medicine, Mayo Clinic Hospital, Arizona
Conflict of Interest: None Declared

In a recent editorial, the excess death and stroke (harm) from tight blood glucose control with insulin therapy was explained as a lack of benefit from that intervention during cardiac surgery (1). The deleterious outcome from hypoglycemia and tight blood glucose control are most frequently related to cardiac and/or neurologic adverse events (2-4). The variability of the hypoglycemic threshold associated with increased risk for adverse events and death is largely influenced by patient age, pre- existing comorbidities, acute illness characteristics and concurrent medications. In fact, the Center for Medicare and Medicaid Services national collaborative for the prevention of surgical site infections selected a much higher glucose target (<200 mg/dl) because of safety concerns from strict postoperative blood glucose control (5). A prospective, randomized, controlled, multi-center European study comparing insulin use to achieve glycemic control ranges (80 to 110) mg/dl versus (140 to180) mg/dl in the intensive care unit was terminated early because of safety issues arising from high rate of hypoglycemic events in patients randomized to the lower glycemic control range (6). It is imperative to exercise clinical judgment before adopting tight glucose control with insulin to avoid attributable death and morbidity in the critically ill.

1. Van den Berghe G. Does Tight Blood Glucose Control during Cardiac Surgery Improve Patient Outcome? Ann Intern Med. 2007;146:307-308.

2. Wintergerst KA, Buckingham B, Gandrud L, Wong BJ, Kache S, Wilson DM. Association of Hypoglycemia, Hyperglycemia, and Glucose Variability With Morbidity and Death in the Pediatric Intensive Care Unit. Pediatrics. 2006;118:173-179.

3. Pinto DS, Skolnick AH, Kirtane AJ, et al. U-Shaped Relationship of Blood Glucose With Adverse Outcomes Among Patients With ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol. 2005;46:178-180.

4. Svensson A-M, McGuire DK, Abrahamsson P, Dellborg M. Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. Eur Heart J. 2005;26:1255- 1261.

5. Dellinger EP, Hausmann SM, Bratzler DW, et al. Hospitals collaborate to decrease surgical site infections. Am J Surg. 2005;190:9- 15.

6. Glucontrol Study: Comparing the Effects of Two Glucose Control Regimens by Insulin in Intensive Care Unit Patients. ClinicalTrials.gov Identifier NCT00107601. http://www.glucontrol.org/ and http://clinicaltrials.gov/ct/show/NCT00107601?order=1. Accessed February 25 2007.

Conflict of Interest:

None declared

Insulin effect and protein glycosylation/glycation
Posted on March 2, 2007
Marvin A. McMillen
Beth Israel Medical Center
Conflict of Interest: None Declared

In the extraordinary growth of our pharmacologic and basic science ability to control protein production, we may ignore post-translational modification events such as glycosylation or glycation to our peril. We wonder whether tight control of glucose might therefore alter protein receptor and soluble protein function in critically ill patients in a beneficial manner. (Or rather, poor control alter the same proteins in a harmful fashion.)

The rat ocular angiogenesis model is sometime discussed as a surrogate for vascular remodelling and collateralization. In the course of our efforts to define the angiogenic role of endothelin (Bek EL, McMillen MA, Endothelins are angiogenic, J. Cardiovasc. Pharm, 2000,, S135 -S139) we asked what effect inducing diabetes in the assay rat might have. Endothelin and interleukin-8-mediated angiogenesis was inhibited, but vascular endothelial growth factor-mediate angiogenesis was not (Bek EL, McMillen MA, Scott P, Anug LD, and Shaftan GW, Clinical Science, 2002, 424S-429S.)

As endothelin receptor glycosylation variation has been shown to alter both receptor immunogenicity as well as receptor function, we assumed that our data suggested that poorly controlled diabetes altered some aspect of some angiogenesis-mediating substances, but not all. These factors are almost certainly important in patients healing wounds and recovering from surgery. We have perceived the clinical studies on tight glucose control, despite the controversy, to be strongly suggestive that protein receptor glycosylation or glycation may have protean beneficial effects in healing intensive care unit patients.

Conflict of Interest:

None declared

Tight Glucose Control -- A Panacea for All?
Posted on April 10, 2007
Michael J Murray
Mayo Clinic
Conflict of Interest: None Declared

Dear Editor,

We were surprised by the editorial, "Does Tight Blood Glucose Control during Cardiac Surgery Improve Patient Outcome," in the February 2007 issue of the Annals. After we read Gandhi et al.'s article (1), we concluded that intensive intraoperative insulin therapy should be administered with caution if not avoided altogether. However, Dr. Van den Berghe's conclusion, based on her 2001 study (2), is that intensive insulin therapy to maintain blood levels of glucose at 4.4-6.1 mmol/L (80- 110 mg/dL) during intensive care improves survival and reduces morbidity of critically ill patients after complicated, high risk or extensive surgery, or trauma. Because the patients in Dr. Gandhi's study had intensive insulin therapy not only in the operating room, but also in the intensive care unit (ICU), no benefit could be seen because, according to Dr. Van den Berghe, "Postoperative tight glucose control has such a strong effect on the outcome of cardiac surgical patients that any additional effect of tight blood glucose control initiated only a few hours earlier, during an operation, is likely to be quite small." Interestingly, in examining the tables in her 2001 study, general surgery patients and trauma patients had worse outcomes if blood glucose levels were tightly controlled.

The original ICU study by Dr. Van den Berghe et al. is the only prospective, randomized, controlled study that has shown that the benefits of intensive insulin therapy in the ICU outweigh the risks (2). And yet several groups, including the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and the American College of Endocrinology, have accepted and promulgated intensive insulin therapy as the standard of care.

We find this of concern because several other prospective, randomized control trials have not shown improvement in mortality in noncardiac surgical patients (Van den Berghe's medical intensive care unit study [3], the European GluControl study [4], and the German VISEP study [5]). After 2,000 patients had been enrolled in the NICE-SUGAR study (6), an interim analysis showed no effect either on outcome or complications, and the study is still underway. The NICE-SUGAR investigators have concluded that perhaps 6000 to 8000 patients may have to be enrolled to see an effect, if indeed one exists. Within the United States, there is enough concern about the potential conflicts between the outcomes of these different studies that the Society of Critical Care Medicine is conducting a survey to determine what physicians' practices are. Several editorials have concluded that changes in practice should not be based on a single, prospective, randomized, controlled trial, and that more research needs to be done (7-12). Unfortunately, it is unlikely that Van den Berghe's original study will ever be duplicated because the mortality rate in the control group at over 5% was excessive, and no one is going to administer 300 gm of glucose intravenously over a 24-hour period to artificially raise blood glucose levels (6). Our own Institutional Review Boards would never allow us to conduct such a study.

Does blood glucose control during cardiac surgery improve patient outcome? The large longitudinal database from the Portland Diabetic Project would strongly support the concept that improved perioperative glucose control starting at the onset of surgery, prior to the induction of anesthesia, and continuing for the first 2 days postoperatively, improves outcome in coronary artery bypass patients (12). This appears to be dependent, in part, on institutional approach, resource availability, glucose goal, and recognition of potentially unforeseen effects while attempting to meet this goal. Does tight blood glucose control in the ICU improve outcome? Perhaps, but this remains a complex and unresolved question. We need to know the type of patients who benefit and the glucose level that confers benefit, while minimizing side effects and costs. We are not nihilistically calling for a return to a more laissez faire approach to glucose control (say maintain glucose < 10.0-12.2 mmol/L [< 180-220 mg/dL]), but are concerned about widespread application or misapplication of practice guidelines based on limited data or data from one critically ill population being applied more globally. While Dr. Van den Berghe concludes that the Ghandi et al. study did not show benefit because of the use of intensive insulin therapy in the operating room, we conclude as do Ghandi et al. from their study that the increased incidence of death and stroke raise concern about intensive insulin therapy with a goal to maintain glucose at 4.4-5.1 mmol/L (80 to 100 mg/dL).


1. Gandhi GY, Nuttall GA, Abel MD, et al: Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery. Ann Intern Med 2007; 146:233-243.

2. Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359-1367.

3. Van de Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:449-461.

4. Devos P: European glucose control study. www.glucontrol.org. Accessed March 28, 2007

5. Brunkhorst FM, Kuhat E, Engel C, et al: Intensive insulin therapy in patients with severe sepsis and septic shock in associated with an increased rate of hypoglycemia"”results from a randomized multicenter study (VISEP). Infection 2005; 33:19.

6. NICE-SUGAR study: http://www.thegeorgeinstitute.org/iih/index.cfm?CBEB61E0-D192-95-F9-9C1E- 6A2474B45DCC. Accessed April 9, 2007.

7. Angus DC, Abraham E: Intensive insulin therapy in critical illness. Am J Resp Crit Care Med 2005; 172:1358-1359.

8. Bellomo R, Egi M: Glycemic control in the intensive care unit: Why should we wait for NICE-SUGAR. Mayo Clin Proc 2005; 80:1546-1548.

9. Cryer PE: Hypoglycaemia: the limiting factor in the glycaemic management of the critically ill? Diabetologia 2006; 49:1722-1725.

10. Malhotra A: Intensive insulin in intensive care. N Engl J Med 2006; 354:516-518.

11. Watkinson P, Barber VS, Young JD: Strict glucose control in the critically ill. BMJ 2006; 332:865-866.

12. 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; 125:1007-1021.

Michael J. Murray, M.D., Ph.D., FCCM Department of Anesthesiology Mayo Clinic Jacksonville, FL

Douglas B. Coursin, M.D. Department of Anesthesiology and Medicine University of Wisconsin School of Medicine and Public Health Madison, WI

Conflict of Interest:

None declared

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