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J Thorac Cardiovasc Surg 2002;123:928-935
© 2002 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

The Insulin Cardioplegia Trial: Myocardial protection for urgent coronary artery bypass grafting

From the Division of Cardiovascular Surgery, Toronto General Hospital and Sunnybrook and Women's College Health Centre, University of Toronto, Toronto, Ontario, Canada.

Supported by the Medical Research Council of Canada (grant MT13513) and the Heart and Stroke Foundation of Ontario (grants NA3767 and NA4189).

Received for publication May 29, 2001. Revisions requested July 11, 2001; revisions received Nov 2, 2001. Accepted for publication Nov 12, 2001. Address for reprints: Vivek Rao, MD, PhD, Division of Cardiovascular Surgery, EN 14-222, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4 (E-mail: Vivek.Rao{at}uhn.on.ca).

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 
Background: Small, nonrandomized clinical trials have demonstrated a beneficial effect of solutions containing insulin and glucose on the recovery of myocardial metabolism and ventricular function after cardioplegic arrest and reperfusion. However, no large, blinded, randomized study has yet determined the effects of insulin-enhanced cardioplegia on clinical outcomes after coronary artery bypass grafting.
Methods: The Insulin Cardioplegia Trial was designed to evaluate the clinical impact of insulin-enhanced cardioplegia on patients at high risk undergoing isolated coronary artery bypass grafting for unstable angina. A total of 1127 patients were randomly assigned at operation to receive cardioplegic solution supplemented with 10 IU/L insulin (n = 557) or placebo (n = 570). All personnel with direct patient contact were blinded to randomization group.
Results: Overall operative mortality was 2.2%, with no significant differences between groups. The prevalences of postoperative low output syndrome (insulin 10.4%, placebo 9.7%, P = .7) and enzymatic myocardial infarction (insulin 21.0%, placebo 18.8%, P = .3) were not different between groups. The primary composite outcome of low output syndrome and/or enzymatic myocardial infarction revealed no difference between groups (insulin 30.0%, placebo 26.3%, P = .2).
Conclusions: Despite encouraging results from smaller, nonrandomized studies, the Insulin Cardioplegia Trial failed to demonstrate a clinical benefit of insulin-enhanced cardioplegic solution for patients undergoing high-risk isolated coronary artery bypass grafting.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 
See related article on page 842

Several reports from large database registries have documented the improved clinical results after isolated coronary artery bypass grafting (CABG). ^1,2 However, certain groups of patients continue to face increased risk of morbidity and mortality after this operation. These include patients with left ventricular dysfunction, elderly patients, and patients who undergo urgent operations because of unstable angina or critical coronary anatomy. ^3-5

Improved methods of myocardial protection may improve the results of surgery in these high-risk populations. Demonstration of incremental benefits for conventional clinical outcomes such as mortality and Q-wave myocardial infarction (MI), however, would require prohibitively high numbers of patients to achieve clinical and statistical significance. We have previously demonstrated that postoperative low cardiac output syndrome (LOS) is an alternative objective outcome that may be used to evaluate alternate methods of myocardial protection. ⁶ In addition, determining the area under the curve of creatine kinase MB isoenzyme fraction (CKMB) over time provides a more sensitive measure of enzymatic myocardial injury. ^7,8 In the Warm Heart Trial, ⁷ the largest prospective evaluation of myocardial protection to date, the incidence of postoperative LOS and enzymatic MI was more than 20% among patients undergoing urgent operations. Any clinical evaluation of a new cardioplegic intervention should therefore be targeted toward the reduction of LOS and enzymatic MI in those patients with unstable angina who require urgent, isolated CABG.

In 1965, Sodi-Pollares and colleagues ⁹ first described the beneficial effects of a glucose-insulin-potassium infusion on the electrocardiographic changes during acute MI. The use of glucose-insulin solutions during heart operations has produced conflicting results. ^10,11 One potential confounding factor in the early studies of glucose-insulin-potassium solutions was the routine use of moderately hypothermic (25°C-28°C) cardiopulmonary bypass. In retrospect, metabolic stimulation of the heart may not have been effective at temperatures that inhibit normal enzyme function. The advent of normothermic or warm heart surgery has prompted a renewed interest in myocardial protection. ⁷ We believe that a reassessment of myocardial metabolic stimulation is required at systemic and myocardial temperatures that more closely reflect current standards of practice and in patients who may receive the most potential benefit. The Insulin Cardioplegia Trial was designed as a large, double-blinded, prospective randomized trial to evaluate the impact of insulin-enhanced cardioplegia on objective clinical outcomes after isolated, urgent CABG for unstable angina or critical coronary anatomy.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 
Patient population
A total of 3301 patients underwent urgent isolated CABG at Toronto General Hospital (n = 2382) or Sunnybrook and Women's College Health Science Centre (n = 919) between June 1996 and July 1999. There were 1271 patients screened for possible entry into this study, 1127 (34%) of whom were eventually randomly assigned to receive either insulin-enhanced cardioplegic solution (n = 557) or placebo (n = 570). Exclusion criteria for the study included any potential for concomitant surgery (eg, left ventricular aneursymectomy or mitral valve repair), failure to obtain consent, refusal to participate, or inclusion in a competing clinical trial. A demographic comparison between study participants and nonparticipants has demonstrated no differences in postoperative LOS or perioperative MI.

The requirement for urgent surgery at the University of Toronto is determined by a combination of symptoms and coronary anatomy. Patients with angina refractory to intravenous medical therapy or those with critical left main coronary artery stenosis are recommended to undergo surgery within 72 hours of cardiac catheterization on an urgent basis. All patients enrolled in the study signed a written consent form approved by the respective institution's investigational review board.

Surgical technique
A computer-generated randomization schedule was created and stratified by institution and surgeon to allow participants to conduct the surgical procedure according to individual preference. All patients received uniform perioperative anesthetic care, which has been described in detail previously elsewhere. ^12,13 Before anesthetic induction, a perfusionist not involved in the study case would open a sealed randomization envelope and proceed to prepare the study cardioplegic solution. Patients randomly assigned to the insulin group received a final concentration of 10 IU/L of Humulin R (Eli Lilly Canada; Mississauga, Ontario, Canada), whereas the placebo group received an equal volume of the inactive vehicle solution (courtesy of Eli Lilly Canada). All personnel with direct patient contact both during and after surgery remained blinded to the randomization group. The final cardioplegic solution has been described previously and represented an 8:1 mixture of oxygenated blood to crystalloid solution to achieve the following final concentrations: 6 mEq/L magnesium sulfate, 50 mmol/L glucose, and either a low (8 mEq/L) or a high (30 mEq/L) concentration of potassium chloride. ¹⁴ All patients received an initial infusion of the high-potassium solution followed by maintenance with the low-potassium formulation.

Surgeons were permitted to use antegrade delivery of cardioplegic solution, retrograde delivery, or a combination of antegrade and retrograde delivery. Similarly, the cardioplegic temperature and the degree of systemic hypothermia were left up to surgeon preference. All proximal and distal anastomoses were completed during a single crossclamp period in most cases. Measurements of arterial blood gases, hematocrit, serum glucose, and serum potassium were performed every 20 minutes during the crossclamp period. Treatment of perioperative hypoglycemia or hyperglycemia is described in detail here and was standardized, as was the treatment of hyperkalemia.

Treatment of hypoglycemia, hyperglycemia, and hyperkalemia
A strict protocol was developed for the treatment of abnormal serum glucose levels because of possible neurologic concerns related to hyperglycemia or hypoglycemia. Normal values in our laboratory range from 3 to 7 mmol/L. Because of the increased concern about hypoglycemia versus hyperglycemia, patients were given intravenous dextrose (25-g boluses) for any blood sugar value less than 5 mmol/L in the first four hours after the operation. In a pilot study, we observed that those patients with a blood sugar less than 10 mmol/L before leaving the operating room were at risk for development of hypoglycemia in the early postoperative period. ¹⁴ Patients were therefore given a 25-g intravenous bolus of dextrose if their last intraoperative blood sugar was less than 10 mmol/L. Because of the neurologic concerns of severe hyperglycemia, all patients with a blood sugar greater than 20 mmol/L in the first 4 postoperative hours were given a 5- to 10-IU intravenous bolus of Humulin R. In cases of insulin-dependent diabetes or persistent hyperglycemia, an intravenous insulin drip was administered until the patient reverted to the usual preoperative insulin regimen.

Patients with hyperkalemia during the crossclamp period were treated with furosemide or intravenous insulin. If the serum potassium level rose above 5.5 mmol/L, a 20-mg intravenous bolus of furosemide was administered. If the serum potassium climbed above 6.0 mmol/L, a 10-IU bolus of insulin was given intravenously.

Study outcomes
The composite primary end point of the trial was the development of enzymatic MI, postoperative LOS, or both. Enzymatic MI was determined after obtaining serial measurements of CKMB. Measurements of CKMB were performed at 0, 2, 4, 8, 24, and 48 hours after arrival into the intensive care unit. Integration of the CKMB release over time curve was performed in all patients with at least 4 samples (n = 962, 85%). An integrated value greater than 1000 IU · h was used as a binary cutoff for the determination of enzymatic MI. ⁸ To account for survivors with fewer than 4 samples, an analysis was repeated with two different end points for enzymatic MI: peak CKMB greater than 20 and peak CKMB/creatine kinase ratio greater than 5%.

Clinical records of all patients who received intra-aortic balloon pump or postoperative inotropic support were flagged and reviewed by an independent outcomes committee blinded to treatment group. Each record was reviewed by at least three individuals (see Appendix 1 for outcomes committee members), and a determination of LOS was made by majority opinion.

All other clinical outcomes were recorded by the respective institution's clinical database manager. Stroke was defined as any new gross neurologic deficit or abnormal computed tomographic scan result. A description of the primary study end points is provided in Appendix 2.

Statistical analysis
All data were collected prospectively and entered into a trial database. The SAS statistical software package (version 6.0 for Windows; SAS Institute, Inc, Cary, NC) was used for all statistical analyses. Categorical variables were analyzed with the ² test or Fisher exact test as appropriate and are expressed as absolute or percentage frequencies. Continuous data were analyzed with the Student t test and are expressed as mean ± SD. Stepwise logistic regression analyses were performed to determine the independent predictors of LOS, MI, and the primary composite endpoint. Exact probability values are reported to enable the reader to discern clinical and statistical significance.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 
Patient demographic characteristics
Table 1 compares the preoperative demographic characteristics in the insulin and placebo groups. Despite the randomized nature of the trial, patients in the insulin group were more likely to have depressed ventricular function (P = .02) and left main coronary artery stenosis (P < .001). In addition, patients in the insulin group were more likely to have symptoms of congestive heart failure (P < .001).

View larger version (18K): [in this window] [in a new window]   Fig. 1. Requirement for exogenous insulin to treat hyperkalemia or hyperglycemia was higher in placebo group (white bars). Requirement for intravenous glucose to treat hypoglycemia was higher in insulin cardioplegia group (black bars). Asterisk indicates P < .05; double asterisk indicates P < .001.

View larger version (18K): [in this window] [in a new window]   Fig. 2. Prevalences of LOS, enzymatic MI, and primary composite end point of LOS and/or MI (LOS/MI) in the Insulin Cardioplegia Trial. There were no statistically significant differences in any objective clinical outcomes between placebo group (white bars) and insulin cardioplegia group (black bars).

View larger version (26K): [in this window] [in a new window]   Fig. 3. Subgroup analysis for Insulin Cardioplegia Trial. Prevalence of primary composite end point (LOS and/or MI) is shown in each cardioplegic group. Patients proceeding to surgery from intensive care unit (ICU) had higher rate of primary composite end point than did those housed on regular floor (37% vs 28%, P = .01). There was no effect of either left ventricular ejection fraction (LVEF) or congestive heart failure (CHF) on rate of LOS and/or MI. There were no differences between groups when stratified for preoperative status (intensive care unit vs floor), left ventricular function (left ventricular ejection fraction <40% or >40%), or presence of congestive heart failure.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Prevalences of LOS, MI, and primary composite end point (LOS, MI, or both, LOS/MI), are shown for each cardioplegic study group and temperature range. There were no differences between groups even when stratified by cardioplegic temperature. Incidence of enzymatic MI was lower in placebo group in those patients who received cold cardioplegia. Asterisk indicates P < .05.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 
Despite the well-documented improvements in surgical outcomes after CABG, certain subgroups continue to be at high risk for perioperative morbidity and mortality. ^1-6 Improvements in myocardial protection may improve the results of surgery in these high-risk subgroups, but documentation of a clinically significant effect has become increasingly difficult. The current mortality rate associated with isolated CABG (2%) necessitates the recruitment of thousands of patients to demonstrate even a 50% reduction in death. We have previously shown that postoperative LOS is a more sensitive measure of ischemic injury that correlates with mortality, MI, and other objective clinical outcomes. ⁶ The Insulin Cardioplegia Trial was therefore designed to prospectively evaluate the ability of preischemic metabolic enhancement to improve the results of surgery in high-risk patients undergoing urgent, isolated CABG for unstable angina.

Previous, smaller studies have documented metabolic, functional and clinical benefits of glucose-insulin-containing solutions. Lazar and colleagues ^15,16 completed two prospective randomized trials in patients with diabetes and in patients undergoing urgent surgery for unstable angina. In contrast to our results, they reported improvements in clinical outcomes, including a reduction in postoperative atrial fibrillation and shorter ventilation, intensive care unit stay, and hospital stay. Unfortunately, these studies were not blinded and only included a small number of patients (n = 30). Another important distinction is the use of intravenous insulin therapy for 24 hours after the operation. In the Insulin Cardioplegia Trial, insulin was given only in the cardioplegic solution and was not continued into the postoperative period. Our previous blinded study of patients undergoing elective CABG demonstrated a metabolic and functional benefit of insulin cardioplegia that lasted for 4 hours after crossclamp removal. ¹⁴ It is therefore conceivable that a combination approach in which insulin cardioplegia is supplemented with postoperative intravenous therapy might afford substantial clinical benefit.

There were several controversial details in the design of this trial. First, contamination with insulin in the placebo group may have confounded the overall results. Almost a third of the patients in the placebo group received insulin to treat hyperglycemia or hyperkalemia. Extrapolation of the data of Lazar and coworkers implicates this contamination as a possible cause for the relatively low rate of LOS in the placebo group. We repeated our analysis and eliminated the 190 patients in the placebo group who received intravenous insulin, but we still failed to demonstrate any beneficial effect of insulin therapy. In the Warm Heart Trial, ⁷ normothermic cardioplegia resulted in a 33% reduction in the incidence of LOS, from 9% to 6% (P < .05). Despite restriction of the trial to high-risk patients with unstable angina, the overall LOS rate of 10% in the Insulin Cardioplegia Trial approached that of the Warm Heart Trial. The combined rate of LOS and/or MI in the Warm Heart Trial was 20%, compared with 28% in Insulin Cardioplegia Trial, which is reflective of the higher risk patient population. The study was sufficiently powered to detect a 50% reduction in LOS (94% power) and a 25% reduction in either enzymatic MI (82% power) or the composite primary outcome (89% power).

Table 1 illustrates that roughly 30% of patients in both groups received postoperative inotropic support. However, only 5% of patients required intra-aortic balloon pump support, and the total rate of LOS (as determined by committee) was only 10%. Thus two thirds of the patients who received inotropic support received either low-dose dopamine for renal perfusion or transient levophed for low systemic vascular resistance in the setting of high cardiac output.

Another possible confounding effect was related to the differences in cardioplegic technique among the participating surgeons. We deliberately stratified the study by surgeon to assess the effect of insulin enhancement in a wide variety of cardioplegic strategies. We believe that this decision improved the generalizability of this study to all cardiac surgeons, irrespective of their individual cardioplegic technique. A subgroup analysis failed to demonstrate any effect of either cardioplegic temperature or direction on the development of LOS, although the prevalence of enzymatic MI was higher among the patients who received normothermic blood cardioplegia. In an analysis by cardioplegic temperature or direction, there was no group effect on the prevalence of the primary composite outcome. Finally, the use of alternate end points might have demonstrated differences between groups. The study of Lazar and colleagues ¹⁵ used an inotrope score that revealed a reduction in inotropic support in those patients who received intravenous insulin.

Summary of study limitations
The following are limitations of the study: high use of intravenous insulin in the placebo group, short-term (intraoperative) administration of study drug, variability in cardioplegic temperature and delivery, and relatively low rate of adverse events. The evaluation of metabolic enhancement before anticipated ischemia required reexamination in the contemporary era of blood cardioplegia and relative normothermia. This prospective, randomized, double-blind trial failed to demonstrate any meaningful clinical benefit to those patients who received insulin-enhanced cardioplegia. The results of CABG are affected by intraoperative technical factors, such as the quality of the coronary arteries and conduits. That is not to say that intraoperative myocardial protection is no longer important to the outcome of CABG. Rather, a novel intervention concentrated during a short period of cardioplegic arrest no longer has a meaningful impact on clinical outcomes when one uses contemporary methods of myocardial protection. However, perioperative support with glucose-insulin-containing solutions may yet prove useful when used both in the operating room and in the intensive care unit. In addition, other high-risk subgroups, such as those with poor left ventricular function or diabetic cardiomyopathy, may derive benefit from this form of metabolic therapy. The results of several studies now in progress should further define the role of metabolic enhancement during CABG.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 
Insulin Cardioplegia Trial (ICT) Investigators
Steering Committee: George T. Christakis, MD, Joan Ivanov, PhD, C. David Naylor, MD, DPhil, Vivek Rao, MD, PhD, and Richard D. Weisel, MD. Trial Coordinators: Michael A. Borger, MD, Gideon Cohen, MD, PhD, Vania DeSouza, MD, and Barbara Weller, RN. Safety, Monitoring, and Outcomes Committee: Davey Cheng, MD, Jacek Karski, MD, Keyvan Karkouti, MD, C. David Mazer, MD, Terry M. Smith, MD, Bill I. Wong, MD, and Terrence M. Yau, MD. Biochemical Support: Frank Merante, PhD, Donald A.G. Mickle, MD, Molly K. Mohabeer, and Laura C. Tumiati. Participating Surgeons: Gopal Bhatnagar, MD, George T. Christakis, MD, Stephen E. Fremes, MD, and Bernard S. Goldman, MD, Sunnybrook and Women's College Health Science Centre; and Robert J. Cusimano, MD, Tirone E. David, MD, Christopher M. Feindel, MD, Lynda L. Mickleborough, MD, Charles M. Peniston, MD, Anthony C. Ralph-Edwards, MD, Hugh E. Scully, MD, Glen S. Van Arsdell, MD, Richard D. Weisel, MD, and Terrence M. Yau, MD, Toronto General Hospital.

	Appendix 2

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 
Primary study end points
LOS has been previously defined by our group as the need for intra-aortic balloon pump support or prolonged inotropic stimulation (>30 minutes after admission to the intensive care unit) after operation. Patients requiring low-dose dopamine (<5 µg/[kg · min]) for renal perfusion or those requiring vasopressors for low systemic vascular resistance in the setting of high cardiac outputs were not considered to have LOS. A clinical database manager prospectively recorded the prevalence of LOS among all cardiac surgical patients at each institution according to these objective criteria. In the Insulin Cardioplegia Trial, the records of all patients who received intra-aortic balloon pump or postoperative inotropic support were flagged and reviewed by an independent outcomes committee blinded to treatment group. Each record was reviewed by a minimum of three individuals (see Appendix 1 for outcomes committee members), and a determination of LOS was made by majority opinion.

Enzymatic MI was determined from serial measurements of CKMB. Measurements of CKMB were performed at 0, 2, 4, 8, 24, and 48 hours after arrival at the intensive care unit. Integration of the CKMB release over time curve was performed in all patients with at least 4 samples (n = 962, 85%). We previously reported that integrated time values of 645 IU· h are correlated with MI, as assessed by technetium Tc 99m pyrophosphate imaging. An integrated value greater than 1000 IU · h was used as a binary cutoff for the determination of enzymatic MI. To account for survivors with fewer than 4 samples, an analysis was repeated with two different end points for enzymatic MI: peak CKMB greater than 20 and peak CKMB/creatine kinase ratio greater than 5%.

	Appendix: Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 
Dr Edward D. Verrier (Seattle, Wash). How do you reconcile the differences in all the experimental literature that show enhanced protection with the lack of efficacy in this clinical trial?

Dr Rao. That is a good question. I think that all the experimental literature and even our previous studies in low-risk patients, where we looked for very subtle differences, have demonstrated benefit. The purpose of this trial was to see whether the subtle differences that are obtained under highly controlled circumstances would translate into objective clinical benefit in the usual population undergoing high-risk CABG. This study failed to demonstrate that these improvements translated into meaningful clinical benefit for these patients.

	Footnotes

 
Read at the Eighty-first Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif, May 6-9, 2001.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix: Discussion References

 

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8. Burns RJ, Gladstone PJ, Tremblay PC, Feindel CM, Salter DR, Lipton IH, et al. Myocardial infarction determined by technetium-99m pyrophosphate single-photon tomography complicating elective coronary artery bypass grafting for angina pectoris. Am J Cardiol. 1989;63:1429-34.[Medline]
   
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11. Rao V, Cohen G, Weisel RD, et al. The use of glucose and insulin during hypothermic and normothermic CABG. Ann N Y Acad Sci. 1996;793:494-7.
    
12. Cheng DC, Karski J, Peniston C, Raveendran G, Asokumar B, Carroll J, et al. Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use: a prospective, randomized, controlled trial. Anesthesiology. 1996;43:160-8.
    
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