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From the Mayo Clinic College of Medicine, Rochester, Minnesota.
ClinicalTrials.gov registration number: NCT00282698.
Acknowledgments: The authors thank Nicole Henderson, Laurie Olsen, and Lisa Schrader for recruitment of study participants, data collection and entry, and project management; Victor Montori, MD, MSc, for providing methodological expertise; and Darrell Schroeder, MS, for statistical support.
Potential Financial Conflicts of Interest:Consultancies: R.A. Rizza (Abbott, Takeda, Symphony Capital, Eli Lilly Inc.), M.M. McMahon (Baxter Healthcare); Honoraria: R.A. Rizza (Merck & Co. Inc., Novo Nordisk, Takeda, Mankind, Eli Lilly Inc.); Stock ownership or options (other than mutual funds): R.A. Rizza (Diobex); Grants received: H.V. Schaff (AstraZeneca, Atricure Inc., Avant Immunotherapeutics Inc., Baxter, Boston Scientific, Cryolife Inc., Edwards Lifesciences, Jarvik Heart Inc., Medtronic Inc., Sorin Group/Carbomedics, St. Jude Medical, Thoratec Corporation, TransTech Pharma Inc., W.L. Gore and Associates Inc.).
Requests for Single Reprints: Gunjan Y. Gandhi, MD, MSc, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Gandhi, Nuttall, Abel, Mullany, Schaff, O'Brien, Williams, Rizza, and McMahon; Mr. Johnson, Ms. Cutshall, and Ms. Mundy: Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905.
Author Contributions: Conception and design: G.Y. Gandhi, G.A. Nuttall, M.D. Abel, P.C. O'Brien, A.R. Williams, S.M. Cutshall, L.M. Mundy, R.A. Rizza, M.M. McMahon.
Analysis and interpretation of the data: G.Y. Gandhi, G.A. Nuttall, P.C. O'Brien, R.A. Rizza, M.M. McMahon.
Drafting of the article: G.Y. Gandhi, R.A. Rizza, M.M. McMahon.
Critical revision of the article for important intellectual content: G.Y. Gandhi, G.A. Nuttall, M.D. Abel, C.J. Mullany, P.C. O'Brien, A.R. Williams, R.A. Rizza, M.M. McMahon.
Final approval of the article: G.Y. Gandhi, R.A. Rizza, M.M. McMahon.
Provision of study materials or patients: C.J. Mullany, H.V. Schaff.
Statistical expertise: P.C. O'Brien, M.G. Johnson.
Obtaining of funding: A.R. Williams, R.A. Rizza, M.M. McMahon.
Administrative, technical, or logistic support: G.A. Nuttall, M.D. Abel, C.J. Mullany, H.V. Schaff, S.M. Cutshall, L.M. Mundy.
Collection and assembly of data: G.Y. Gandhi.
To our knowledge, this is the first randomized, controlled trial to assess the effect of strict intraoperative glycemic control during cardiac surgery on clinically significant outcomes when added to rigorous postoperative glycemic control. When intensive intravenous intraoperative insulin therapy was administered in a controlled setting by using standardized protocols, it maintained glucose concentrations close to normal during surgery without appreciably increasing the risk for hypoglycemia. In contrast to previous observational studies that showed that intraoperative hyperglycemia strongly predicted adverse postoperative outcomes after adjustment for the effects of postoperative glucose levels, our study showed that lowering glucose concentrations to near normal levels intraoperatively by intravenous insulin infusion did not reduce short-term death, morbidity, or length of stay in the ICU or hospital. On the other hand, increased incidence of death and stroke in the intensive treatment group raises concern about routine implementation of this intervention.
CPB=cardiopulmonary bypass; ICU=intensive care unit. To convert glucose values to mmol/L, multiply by 0.055.
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As a practitioner of both anesthesiology and critical care, I read with interest Dr. Gandhi's study of intensive insulin therapy for cardiac surgery as well as the accompanying editorial by Dr. Van den Berghe. Since Dr. Van den Berghe's landmark study in 2001 (Van den Berghe, NEJM, 2001) there has been widespread implementation of tight glycemic control protocols in the intensive care unit, as well as pressure to extend that practice into the operating room. I have resisted this pressure on the basis of lack of literature to support it. If Dr. Van den Berghe needed several days of insulin therapy to show benefit (Van den Berghe, Diabetes, 2006), I was skeptical that several hours in the operating room would provide sufficient benefit to outweigh the risk of unrecognized hypoglycemia in an anesthetized patient. Dr. Gandhi's findings should instill in all of us a bit of humility when considering the translation of literature from one clinical setting to another.
Gandhiand Colleagues did not discuss the medications used in the induction of anesthesia specifically if etomidate was used. This would be important for two reasons: 1) Edelman and colleagues  showed that etomidate administration in humans resulted in cerebral deoxygenation and enhanced hypoxic risk in the setting of cerebral ischemia , 2) The adrenal counterregulatory hormones inhibition by etomidate which can last 8-12 hours  could have contributed to more morbidity especially in the intensive insulin treated group where the brain is more vulnerable at lower blood sugar levels .
1. Gandhi, G.Y., et al., Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial. Ann Intern Med, 2007. 146(4): p. 233-43.
2. Edelman, G.J., W.E. Hoffman, and F.T. Charbel, Cerebral hypoxia after etomidate administration and temporary cerebral artery occlusion. Anesth Analg, 1997. 85(4): p. 821-5.
3. Jackson, W.L., Jr., Should we use etomidate as an induction agent for endotracheal intubation in patients with septic shock? A critical appraisal. Chest, 2005. 127(3): p. 1031-8.
4. Auer, R.N., Progress review: hypoglycemic brain damage. Stroke, 1986. 17(4): p. 699-708.
The results of a nicely planned and performed randomized controlled trial have been recently published in the article by Gandhi and colleagues (1). This study has a relevant message for routine clinical practice, preventing clinicians from introducing tight blood glucose control during cardiac surgery. We agree with the main conclusions drawn from the study about the lack of benefit of the intensive insulin therapy during cardiac surgery, although it is not a surprising finding as stated by Van den Berghe (2). As already pointed out (2), the increase in mortality is not significant and may be attributable to chance. Further, the study was not designed nor powered to answer such a question. However, when carefully looking at the data, some concern arises on some differences in the baseline characteristics of the two study groups that may explain, at least in part, the occurrence of a higher number of deaths and strokes in the intervention group. The main difference is in the use of aspirin: 89 (48%) in the intensive group versus 112 (60%) in the conventional one. This difference is statistically significant (p<0.025) and may have some relationship with the different event rate detected. Furthermore, if taken together, there are some additional differences between the groups that, although not statistically significant, may have a relevant influence on the outcome: in the intensive group more male patients were included (134 versus 123), fewer of them received angiotensin-converting enzyme inhibitors (65 versus 72) and b-blockers (96 versus 103), and more subjects had a history of previous cerebrovascular disease (20 versus 13). Among patients with diabetes, 20 (versus 11 in the control group) were previously treated only with oral drugs. The heterogeneity in the baseline characteristics of the study groups is most likely due to a random effect, but we feel that an important part of the excess event rate reported in the intensive treatment group may be explained by this fact. We strongly believe that further clinical research insight on this important issue is warranted.
1. Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, O'Brien PC, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery. Ann Intern Med 2007; 146: 233-43.
2. Van den Berghe G. Does tight blood glucose control during cardiac surgery improve patient outcome? Ann Intern Med 2007; 146: 307-8.
Gandhi et al. (1) report the results of a randomized controlled trial (RCT) on the effect of intensive intraoperative insulin therapy after on- pump cardiac surgery. The authors conclude that the application of an insulin sliding scale that fails to consistently maintain blood glucose between 4.4 and 5.6mmol/L does not reduce mortality or morbidity in non- diabetic and diabetic patients after a variety of cardiac procedures. An increased incidence of death and stroke in the treatment group prompted the authors to caution against the routine use of insulin therapy during cardiac surgery.
Several aspects of this manuscript merit further comment. A study paradigm supposedly designed to examine the clinical value of a therapeutic concept in the operating room without taking into account important principles of surgical and anesthetic care is prone to flaws. Gandhi's paper does not provide the required information for interpretation and understanding of outcomes observed in a relatively small number of patients undergoing interventions of such high surgical, physiological and pharmacological complexity as operations on the heart. What exactly were the surgical procedures performed? What was the patients' baseline cardiac function and risk assessment? Which anesthetics and narcotics were used and how was inotropic and vasopressor therapy decided upon? Was there an attempt to reduce aortic manipulation and embolization? What were the methods of cardioprotection and did they differ by group, surgeon, and procedure? What cardioplegia solutions were used? Was it administered cold, warm, antegrade, retrograde, or both? How was temperature management decided upon? What were the details of the cardiopulmonary bypass circuitry? Was cardiotomy suction blood reinfused directly or was it processed through a "cell saver" prior to reinfusion? What were the nadir hematocrits? What was the transfusion requirement? What was the extent and incidence of bleeding and reoperation? How was heparin therapy managed? Were antifibrinolytics administered and at what dosages? Were patients' blood volume hemoconcentrated or ultra-filtered? Did patients receive perioperative antibiotics or steroids? What was the incidence of intraoperative pacing or mechanical assistance?
The authors chose the primary and secondary study outcomes because of their "clinical relevance". We think that selecting parameters that are potentially modifiable by insulin therapy would have increased the clinical relevance of the study results. Atrial fibrillation, heart block, stroke and postoperative ventilation are outcomes with primarily a surgical or anesthetic cause. It seems very unlikely, for example, that normoglycemia would shorten the action of anesthetics/analgesics, counteract the functional consequences of the type or size of aortic valve inserted (3), or the placement of an aortic cross-clamp over an unknown ascending aortic atheroma, arguably one of the most important risk factors for poor cerebrovascular outcome (4).
We must emphasize that the authors did not achieve normoglycemia. Furthermore, they did not prevent hyperglycemia using an insulin sliding scale based on "blood glucose measurements every 30 min", i.e. mean blood glucose after separation from cardiopulmonary bypass was 6.7 Â±1.3(SD) mmol/L in non-diabetic and 7.3 Â±1.6(SD) mmol/L in diabetic patients. Considering the well documented evidence on the importance of tight glycemic control (blood glucose of 4.4 to 6.1mmol/L) (2) and the authors' ambitious goal to maintain glycemia between 4.4 and 5.6mmol/L one would have expected a more aggressive insulin regimen including more frequent blood glucose measurements. It is therefore debatable whether insulin therapy was intensive as stated in the title.
Gandhi's paper is accompanied by an editorial written by van den Berghe, the principal author of the so-called Leuven trial demonstrating superior survival with strict glycemic control in critically ill patients, most after cardiac surgery (2). As all patients in the Leuven study received parenteral or enteral nutrition it remains unknown whether reduced mortality in the treatment group was due to the benefits of feeding while maintaining normoglycemia using insulin or to the harm inflicted with hyperalimentation and hyperglycemia in the conventional group (5). The results of Gandhi's study in context with the current body of literature on glycemic control and glucose insulin potassium (GIK) infusions, clearly emphasize the need for trials designed to dissect the clinical effects of insulin therapy, nutrition and normoglycemia in cardiac surgery. Until the results of such studies are available we are hesitant to accept that a therapy, which appears to be effective in critical care postoperatively, can be harmful intraoperatively. However, we believe that the efficacy of metabolic therapies depends on the nutritional state of the subjects studied, i.e. whether they are fed or not. As of now it is too early to speculate what diet, if any, is best for patients undergoing open heart surgery but we do know that studies conducted during surgery are not performed in a black box also known as the operating theatre.
1. Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, O'Brien PC, et al. Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery. A randomized trial. Ann Intern Med. 2007;146:233-43.
2. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359-67.
3. Bridges CR, O'Brien SM, Cleveland JC, Savage EB, Gammie JS, Edwards FH, et al. Association between indices of prosthesis internal orifice size and operative mortality after isolated aortic valve replacement. J Thorac Cardiovasc Surg. In press.
4. Djaiani GN. Aortic arch atheroma: Stroke reduction in cardiac surgical patients. Seminars Cardiothorac Vasc Anesth. 2006;10:143-57.
5. Cheung NW, Napier B, Zaccaria C, Fletcher JP. Hyperglycemia is associated with adverse outcomes in patients receiving total parenteral nutrition. Diabetes Care. 2005;28:2367-71.
The well planned trial by Gandhi and Colleagues (20 February issue) concludes that benefit of intensive insulin therapy is lacking and, moreover, more deaths and strokes occur in the intensive treatment group. It contradicts not only the results from Van den Berghe et al on postoperative tight blood glucose control (1), but also those obtained in a different context such as intensive insulin treatment of acute myocardial infarction in type 2 diabetes (DIGAMI 1), although it was the tight blood glucose control, the prevention of glucose toxicity and the shift of fatty acid toward glucose oxidation, and not the amount of insulin administered, to explain the benefits of insulin therapy (2).
The 20 patients with diabetes on intensive insulin versus 11 in the control group of Gandhi and Colleagues were previously treated with oral drugs only, a fact reminiscent of that in DIGAMI 1, when insulin substituted pre-treatment with glyburide, that interferes with ischemic preconditioning and explained the results of DIGAMI 2 (3).
What, however, we want to comment is not the use of insulin in critical care intraoperative and postoperative setting, but the use of any types of insulin in obese (BMI 30 and over, as in intensive treatment group of Gandhi and Colleagues) type 2 diabetes (DM2). The great majority of DM2 are associated with insulin resistance, "compensatory" hyperinsulinemia and visceral obesity (4). Insulin resistance differentially affects PI 3-K and MAP-K: the former mediates metabolic effects and becomes dramatically resistant (also defined "metabolic insulin resistance"), whereas the latter, linked to proliferative and mitogenic effects, remains fully sensitive and, being exposed to high insulin levels, explains their atherogenic effects (5). It is absolutely true that hyperglycemia (and HbA1c) is associated with both micro- and macro-angiopathy, and that insulin is an anti-inflammatory and anti- atherogenic hormone; however, these effects are lost when insulin stimulation of PI 3-K is absent (5). When basal glycemia is more than 300 mg/dl at onset, initial insulin administration can remove glucotoxicity and allow transition to oral drugs after 6-8 weeks (4). Lowering hyperglycemia and HbA1c lowers the risk of vascular complications, but the means of achieving this result with insulin is wrong (5). This concept is likely to apply also to intensive insulin therapy during cardiac surgery.
1. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359-67.
2. Van den Berghe G. Insulin vs. strict blood glucose control to achieve a survival benefit after AMI? Eur Heart J 2005;26:63941.
3. Bloomgarden ZT. DIGAMI 2: results and questions. Medscape Conference Coverage, 40th Annual Meeting of EASD, 2004. http://www.medscape.com/viewarticle/496161 (accessed 30 December 2004).
4. DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM: A balanced overview. Diabetes Care 1992;15:318-68.
5. Wang CCL, Goalstone ML, Draznin B. Molecular mechanism of insulin resistance that impact cardiovascular biology. Diabetes 2004;53:3735-40.
We thank Drs. Assaly and Habib, Drs. Carvalho and Schricker, and Doctor Rius for their interest and excellent comments on our recent publication.
Drs. Carvalho and Schricker ask for numerous details regarding the surgical interventions which pertain to the applicability of study findings to other settings rather than to the validity of results. It is important to realize that the degree of intraoperative glycemic control was the only difference in study intervention between the two groups. The beauty of randomization with allocation concealment is that all known as well as unknown prognostic variables should be equally distributed among the two study groups. Specific surgical details can be provided by personal communication but are beyond the scope of this response. Although we appreciate the concerns of Drs. Assaly and Habib, we did not use etomidate for induction of anesthesia in our study patients.
We chose the study outcomes not only because of clinical relevance but also as other studies showed that glycemic control and/or insulin use affected them: mortality(1, 2), stroke(3), prolonged mechanical ventilation(1, 2, 4), acute renal failure(2, 4), sternal wound infections(2), atrial fibrillation(2), heart block requiring pacing(2).
We never claimed to have achieved normoglycemia during cardiac surgery. We were able to achieve as strict a glucose control as safely feasible with monitoring glucose levels every 30 minutes in the operating room (intense by most standards). A hyperinsulinemic normoglycemic clamp can achieve normoglycemia(5) but measurement of glucose concentration every 5 minutes with constant titrating of dextrose levels to clamp glucose levels at goal would not be practically feasible outside a study protocol. While a more aggressive insulin infusion protocol may have further lowered intraoperative glucose concentrations, it also may have resulted in a greater frequency of hypoglycemia. Identification of hypoglycemic symptoms is especially challenging in an unconscious patient and the prognosis of hypoglycemia remains unclear.
Doctor Rius noted a difference in some patient characteristics between the two study groups at baseline (e.g. aspirin use) which may be a reasonable explanation of the increased incidence of strokes and deaths in this group. The small number of events makes it difficult to draw firm conclusions about stroke and death even though this reached statistical significance. So the issue in the interpretation of the data, we believe, is not whether the distribution of events is too extreme to have occurred by chance alone, but rather whether such small number of events should drive clinical policy. We clearly think this would be misguided until more trials or a much larger trial become available.
1. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359- 67.
2. Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS. Tight glycemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and decreases recurrent ischemic events. Circulation. 2004;109(12):1497-502.
3. Bucerius J, Gummert JF, Borger MA, et al. Stroke after cardiac surgery: a risk factor analysis of 16,184 consecutive adult patients. Ann Thorac Surg. 2003;75(2):472-8.
4. Gandhi GY, Nuttall GA, Abel MD, et al. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc. 2005;80(7):862-6.
5. Carvalho G, Moore A, Qizilbash B, Lachapelle K, Schricker T. Maintenance of normoglycemia during cardiac surgery. Anesth Analg. 2004;99(2):319-24.
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