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J Thorac Cardiovasc Surg 2000;119:1176-1184
© 2000 The American Association for Thoracic Surgery

SURGERY FOR ACQUIRED CARDIOVASCULAR DISEASE

INSULIN CARDIOPLEGIA FOR ELECTIVE CORONARY BYPASS SURGERY

From The Toronto General Hospital and Sunnybrook Health Science Centre at The University of Toronto, Toronto, Ontario, Canada.

Supported in part by the Heart and Stroke Foundation of Canada (grants NA3767 and NA4189) and the Medical Research Council of Canada (grant MT13513). V.R., M.A.B., and G.C. are Research Fellows of the Heart and Stroke Foundation of Canada. T.M.Y. is a Research Fellow of the Medical Research Council.

Address for reprints: Richard D. Weisel, MD, Chair, Division of Cardiovascular Surgery, EN 14-215, The Toronto Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4.

	Abstract

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Background: Improved methods of myocardial preservation are required to reduce the morbidity and mortality of coronary bypass surgery for high-risk subgroups. Metabolic stimulation with insulin, glucose solutions, or both has been proposed as a method to preserve the ischemic myocardium. We performed a prospective, double-blind, randomized trial to evaluate the effects of insulin and glucose as cardioplegic additives when used as part of a tepid continuous blood cardioplegic strategy.
Methods: We randomized 56 male patients undergoing elective isolated coronary bypass surgery to 1 of 4 cardioplegic groups containing either 42 or 84 mmol/L glucose with or without 10 IU/L of insulin. Perioperative assessments of myocardial metabolism and left ventricular function were performed.
Results: Insulin-enhanced cardioplegia was associated with beneficial effects on both myocardial metabolic and functional recovery after cardioplegic arrest. Insulin’s effect was independent of the ambient glucose concentration.
Conclusions: Cardioplegic formulations containing a 42 mmol/L concentration of glucose and a 10 IU/L concentration of insulin provide significant benefit to patients undergoing isolated coronary bypass surgery. The clinical effect of these formulations will need to be assessed in high-risk subgroups of patients, such as those with unstable angina, recent myocardial infarction, or poor left ventricular function.

	Introduction

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The contemporary results of coronary artery bypass grafting are excellent with low overall morbidity and mortality. ¹ However, as percutaneous ² and minimally invasive ³ approaches to the surgical treatment of coronary artery disease become more common, the demographic profile of patients requiring conventional surgical revascularization will change. We have already documented an increasing proportion of high-risk patients admitted for coronary bypass surgery, valvular surgery, or both at our institution. ^4,5 These patients often have poor preoperative left ventricular function, ⁶ unstable angina, ⁷ or advanced age ⁸ and pose a challenge for intraoperative myocardial protection. Therefore improved methods of cardioplegic protection are required to lower the risks of surgery for these subgroups of patients.

Glucose-insulin-potassium solutions have been commonly used to treat ischemic myocardium in a variety of medical and surgical settings. ^9,10 Unfortunately, the results of earlier investigations were often conflicting, and interest in metabolic stimulation of the heart waned. One potential confounding factor in the early studies of glucose-insulin-potassium solutions was the routine use of moderate 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 ¹¹ prompted renewed interest in myocardial protection. We believe that a reassessment of myocardial metabolic stimulation is required at normothermic temperatures, which more closely reflect current standards of practice and may provide the most potential benefit.

In an earlier rodent study, Kobayashi and Neely ¹² demonstrated that the activity of a key mitochondrial enzyme, pyruvate dehydrogenase (PDH), was inhibited during early reperfusion after global ischemia. More recent studies have demonstrated that the recovery of postischemic myocardial function is dependent on the recovery of PDH activity. ¹³ We have recently reported that insulin was capable of stimulating mitochondrial PDH activity in isolated human ventricular cardiomyocytes, which led to improved protection against ischemia and reperfusion. ¹⁴ We performed this prospective, randomized, double-blind trial to determine whether insulin-enhanced cardioplegia conferred similar metabolic or functional benefits to patients undergoing coronary bypass surgery.

	Methods

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Patient population
Fifty-six male patients undergoing isolated elective coronary bypass surgery consented to participate in a metabolic evaluation of insulin-enhanced cardioplegia between September 1995 and July 1997. During this interval, the study surgeon (R.D.W.) performed isolated coronary bypass on 533 patients. A total of 477 patients were excluded because of nonelective surgery (n = 303), redo surgery (n = 21), or participation in alternative surgical trials (n = 89). The remaining patients (n = 64) were deemed ineligible to participate because of female sex, diabetes mellitus, recent preoperative infarction, significant left ventricular dysfunction (ejection fraction < 20%), or refusal to participate. All patients signed an informed consent form approved by our institutional ethics committee. The preoperative demographics for the study population are given in Table I.

After institution of cardiopulmonary bypass, all patients received an antegrade induction dose (approximately 1000 mL) of tepid (29°C) high-potassium blood cardioplegic solution. ¹⁵ After cardioplegic arrest, all patients received near-continuous retrograde delivery of cardioplegic solution through the coronary sinus. After completion of each distal anastomosis, the proximal end of the vein graft was attached to a cardioplegic manifold, enabling simultaneous delivery of antegrade and retrograde blood cardioplegic solution. Cardioplegic flow rates were maintained at 200 mL/min unless the coronary sinus pressure rose above 40 mm Hg, whereby the flow rate was adjusted accordingly. ¹⁶ The flow rate remained above 100 mL/min in all patients. ¹⁷ Cardioplegic interruptions were limited to less than 7 minutes, and there were no more than 3 interruptions per patient. During cardiopulmonary bypass, the systemic temperature was allowed to drift to 32°C to 34°C. Rewarming to 37°C was initiated during construction of the last distal vein graft anastomosis.

To minimize contamination by exogenous insulin delivery, a strict protocol was adopted for the treatment of intraoperative hyperkalemia. An additional cardioplegic solution containing identical additives to the randomization group with the exception of potassium chloride was used initially if the serum potassium level rose above 5 mmol/L with no evidence of electrical activity. If the potassium level rose above 5.5 mmol/L, 10 or 20 mg of intravenous furosemide was given to induce diuresis. If the serum potassium concentration rose above 6.0 mmol/L, boluses of human insulin (Humulin; 5-10 IU) were given intravenously. In the event that patients received exogenous insulin or glucose, they remained in their initial randomization group consistent with an intent-to-treat analysis.

After completion of all intraoperative biochemical assessments, the patients were weaned from cardiopulmonary bypass and transferred to the cardiac intensive care unit (ICU). Postoperative ICU care was uniform in all patients and followed an intention to extubate within 6 hours of arrival. ¹⁸ Serial hemodynamic measurements were obtained 2, 4, 8, and 24 hours after aortic crossclamp removal, including heart rate, mean arterial pressure, pulmonary capillary wedge pressure, central venous pressure, and cardiac output. Cardiac index, left ventricular stroke work index, and systemic vascular resistance were calculated by using standard formulas. ^15,16

Perioperative myocardial infarction and low cardiac output syndrome were determined by means of previously established criteria. ¹ In brief, the presence of a new Q wave or left bundle branch block on the postoperative electrocardiogram or a significant elevation of creatine kinase MB isoenzyme in the presence of a pre-existing electrocardiographic abnormality was used to define a myocardial infarction. The requirement for intra-aortic balloon or sustained inotropic support for greater than 30 minutes in the ICU defined the development of low cardiac output syndrome. Patients who were given low-dose dopamine (<5 µg · kg^–1 · min^–1) for renal perfusion were not considered to have low-output syndrome.

Biochemical assessments
Arterial and coronary sinus blood samples were obtained at baseline, during each cardioplegic delivery, and at prespecified intervals during reperfusion. In addition, a coronary sinus catheter was left in situ to obtain postoperative blood samples 2, 4, 8, and 24 hours after aortic crossclamp removal. Blood samples were assayed for oxygen content, acid, pyruvate, and lactate concentrations according to previously described protocols. ^15,16 Differences between arterial and coronary sinus blood samples enabled us to calculate myocardial extraction or release of these substances. During cardioplegic arrest, myocardial consumption, or production was calculated after adjusting extraction-release for coronary flow.

Left ventricular biopsy specimens were obtained in 8 patients (glucose concentration of 84 mmol/L with or without insulin; n = 4 each) for determination of myocardial PDH activity. Full-thickness biopsy specimens were snap-frozen in liquid nitrogen and then homogenized in 250 µL of phosphate-buffered saline solution (PBS). Mitochondrial PDH activity was determined by a modification of a previously described technique. ¹⁴ In brief, 75-µL aliquots were divided into separate Eppendorf tubes containing 75 µL of either PBS or PBS with 5 mmol/L dichloroacetate. After a 10-minute incubation at 37°C, the reaction was stopped with a buffer solution containing 25 mmol/L sodium fluoride to inhibit PDH phosphatase. Next, 50 µL from each Eppendorf tube was exposed to 200 µL of reaction buffer containing ¹⁴C-pyruvate. Protein content was simultaneously determined by using a 100-µL aliquot from each Eppendorf tube assayed by the Lowry method. ¹⁴ The PDH reaction was then terminated by using 100 µL of 10% trichloroacetic acid. Each Eppendorf tube was then inserted into a scintillation vial containing 200 µL of benzothonium hydroxide. After exposure to each tissue sample for 1 hour, the collected ¹⁴CO₂ was then counted in a ß-counter. PDH activity was calculated after correction for protein content and expressed as nanomoles of pyruvate oxidized per milligram of protein per minute.

Statistical analysis
Statistical analysis was performed by using the SAS analytic program (SAS Institute, Cary, NC). Categoric data were analyzed by using the ² or Fisher exact test as appropriate. Continuous data were analyzed by using analysis of variance and are expressed as mean ± SD, unless otherwise specified. Two-way repeated-measures analysis of variance was used to analyze biochemical end points over time. To correct for patient-specific activities of PDH, the percentage recovery of PDH activity was calculated for each patient, and the effects of time and group were assessed with analysis of covariance. Hemodynamic data were analyzed by means of analysis of covariance, examining the main effects of time, group, and preload. Left ventricular preload was estimated from measurements of pulmonary capillary wedge pressure. Exact P values are reported to enable determination of clinical and statistical significance.

	Results

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Operative data
Table II summarizes the perioperative data for all 4 randomization groups. Randomization groups were similar with respect to the number of distal anastomoses performed, the mean aortic crossclamp and cardiopulmonary bypass times, and the volume of cardioplegic solution delivered. There were no differences in the times of cardioplegic interruption expressed as a percentage of the total crossclamp time (P = .6). However, patients exposed to insulin cardioplegia at either ambient glucose concentration had a lower peak serum potassium level than patients in groups 1 and 3 (P < .001). Persistent hyperkalemia required insulin boluses in 6 patients (11%), 5 who received placebo and 1 who received insulin cardioplegia (P = .07). Hypoglycemia requiring supplemental dextrose administration occurred in 5 patients, 3 of whom received insulin and high-glucose cardioplegia. The remaining 2 patients received low-glucose cardioplegia with placebo. Interestingly, there was no observed hypoglycemia in the low-glucose (42 mmol/L) and insulin groups. Fig 1 illustrates arterial glucose levels, which were similar in all 4 study groups during the experimental protocol.

View larger version (25K): [in this window] [in a new window]   Fig. 1. Arterial glucose concentrations in all 4 study groups. The differences in arterial glucose observed during cardioplegic arrest dissipated within 2 hours of arrival into the ICU. There were no overall differences in arterial glucose concentrations between groups. PRE , Prebypass; Xcl , aortic occlusion; Xcl OFF , removal of crossclamp; CPB 10 ’, 10 minutes after discontinuation of cardiopulmonary bypass; 5’, 10’, 2 HR, 4 HR, 8 HR, 24 HR , time after crossclamp removal.

Biochemical outcomes
Fig 2 demonstrates the effects of glucose (upper panel) and insulin (lower panel) on myocardial lactate release during the surgical procedure. There were no significant effects of glucose (P = .8) or insulin (P = .3) over time. During the crossclamp period, there were no differences between groups in myocardial lactate production (corrected for coronary blood flow). However, at crossclamp removal, patients who received insulin-enhanced cardioplegic solution displayed a positive lactate flux (P = .03 by the Student t test) compared with a negative flux in those who received placebo, suggesting better aerobic metabolism.

View larger version (29K): [in this window] [in a new window]   Fig. 2. Intraoperative myocardial lactate flux. Cardioplegic arrest induced significant anaerobic lactate release in all patients. Over time, there were no significant effects of either glucose concentration (upper panel, P = .83) or insulin (lower panel , P = .28) on myocardial lactate flux. However, immediately after crossclamp removal, patients who received insulin cardioplegia demonstrated lactate extraction compared with persistent anaerobic lactate release in the placebo groups (P = .03 by using the Student t test). PRE , Prebypass; XCL , aortic occlusion; OFF , removal of crossclamp; LAST, final cardioplegic dose.

View larger version (36K): [in this window] [in a new window]   Fig. 3. Effects of glucose (upper panel) and insulin (lower panel) on intraoperative myocardial oxygen extraction. During the crossclamp period, there was a significant interactive effect between glucose and insulin (P = .03). During reperfusion, myocardial oxygen extraction returned to baseline in the insulin cardioplegia groups. However, there was increased oxygen extraction in the placebo groups, suggestive of repayment of an oxygen debt. There was no significant effect of glucose concentration (P = .33); however, there was a significant insulin effect over time (insulin·time effect, P = .04). PRE , Prebypass; XCL , aortic occlusion; OFF , removal of crossclamp; LAST, final cardioplegic dose.

View larger version (23K): [in this window] [in a new window]   Fig. 4. Myocardial PDH activity (nanomoles per milligrams per minute) before cardioplegic arrest (PRE) , just before aortic crossclamp removal (XCL) , and after 10 minutes of reperfusion (OFF) . PDH activity increased during cardioplegic arrest but returned to baseline values during early reperfusion (time effect, P = .009). There were no significant effects of either glucose or insulin on PDH activity (group effect, P = .48).

View larger version (24K): [in this window] [in a new window]   Fig. 5. Cardiac index (upper panel) and left ventricular stroke work index (lower panel) at 2 hours after surgery. Patients who received insulin cardioplegia demonstrated enhanced left ventricular performance compared with placebo at similar filling pressures. PCWP , Pulmonary capillary wedge pressure. Circles represent low-glucose cardioplegia, squares represent high-glucose cardioplegia, open symbols represent placebo groups, and closed symbols represent insulin groups.

	Discussion

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Biochemical response to glucose and insulin
Patients in groups 2 and 4 (insulin-enhanced cardioplegia) received approximately 60 U of short-acting human insulin during 1 hour of cardioplegic arrest. Despite this large dose of insulin, there were no significant differences in arterial glucose concentrations in the early postoperative period. This is likely because of the short half-life of insulin in blood combined with our approach of direct myocardial delivery. Adding insulin to the crystalloid component of the cardioplegic solution resulted in a first-pass effect , whereby insulin was directly exposed to myocardial receptors before venous drainage from the right atrium. We believe that this mode of delivery is inherently safer than systemic delivery through a central vein. Only 5 patients required supplemental glucose, and of these, only 2 had severe hypoglycemia (<3 mmol/L). There were no adverse neurologic outcomes in any of the 4 study groups.

Our previous cellular studies indicated that insulin was capable of stimulating myocardial PDH activity. ¹⁴ The theoretic benefit of PDH stimulation involves an earlier transition from anaerobic to aerobic metabolism after an ischemic insult. Weiss and Hiltbrand ²⁰ reported that adenosine triphosphate produced by oxidative phosphorylation was preferentially used for contractile function compared with anaerobically produced adenosine triphosphate, which was used for membrane stability. ²⁰ Furthermore, Lewandowski and White ¹³ demonstrated that postischemic left ventricular function was dependent on the recovery of PDH activity. Unfortunately, we were unable to detect an insulin effect on the activity of myocardial PDH. Although cardioplegic arrest and reperfusion greatly influenced the activity of PDH, our small sample size did not allow us to detect a significant stimulatory effect of insulin. However, myocardial oxygen consumption was higher during cardioplegic arrest in the insulin groups, suggesting enhanced aerobic activity. Although the placebo group demonstrated repayment of an oxygen debt during early reperfusion, myocardial oxygen extraction was similar to baseline in the insulin cardioplegia groups. Although there appeared to be an insulin effect during cardioplegic arrest, the differences in myocardial PDH activity failed to achieve statistical significance, probably because of the small number of patients who had biopsies. Myocardial lactate flux was not affected by cardioplegia group, although at one time point (crossclamp removal) the insulin-enhanced groups demonstrated greater lactate flux, again suggestive of improved aerobic capacity. In previous cell culture studies, we found that insulin resulted in higher PDH activity after 30 minutes of reperfusion. ¹⁴ In this protocol we assessed PDH activity at 10 minutes of reperfusion. Similar to the results obtained from Kobayashi and Neely, ¹² we found an inhibition of PDH activity in the early postischemic period. We hypothesize that the improvements in left ventricular performance observed in the insulin cardioplegia groups are a result of enhanced myocardial PDH activity at 2 hours of reperfusion.

Hemodynamic effects
Although we were unable to detect major biochemical differences between groups, we did demonstrate a significant hemodynamic benefit in the insulin cardioplegia groups. Both cardiac index and stroke work index were higher in the insulin cardioplegia groups at similar filling pressures. This hemodynamic benefit was evident 2 hours after surgery but dissipated by the eighth postoperative hour. There was a marked reduction in systemic vascular resistance in the insulin cardioplegia group, an effect previously reported by other investigators. ²¹ The combination of increased inotropy with decreased afterload may prove to be most efficacious in patients with poor ventricular function. We are presently completing a clinical trial to evaluate the salutatory effects of insulin in this high-risk population.

	Summary

Top Abstract Introduction Methods Results Discussion Summary Appendix References

 
This prospective study was designed to evaluate the effects of insulin and glucose as cardioplegic additives on the recovery of myocardial metabolism and function after elective coronary bypass surgery. Insulin-enhanced cardioplegia demonstrated both metabolic and functional benefit independent of the ambient glucose concentration. Because of the possible deleterious effects of hyperglycemia on postoperative neurologic outcomes, ²² we recommend a low-glucose cardioplegic formulation, even when insulin is used as an additive. The potential clinical benefits of insulin-enhanced cardioplegia will require further investigation in high-risk subgroups of patients undergoing myocardial revascularization.

	Appendix

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Insulin Cardioplegia Trial (ICT) investigators
Steering Committee
George T. Christakis, MD; Joan Ivanov RN, MSc; C. David Naylor, MD, DPhil; Vivek Rao, MD, PhD; Richard D. Weisel, MD.

Trial Coordinators
Michael A. Borger, MD; Susan M. Carson, AHT; Gideon Cohen, MD; Vania DeSouza, MD; Barbara Weller, RN.

Safety and Outcomes Committee
Davey Cheng, MD; Jacek Karski, MD; Keyvan Kartoukian, MD; C. David Mazer, MD; Terry M. Smith, MD; Bill I. Wong, MD; Terrence M. Yau, MD.

Biochemical Support
Frank Merante, PhD; Donald A. G. Mickle, MD; Molly K. Mohabeer; Laura C. Tumiati.

Participating Surgeons
Gopal Bhatnagar, MD; Daniel Bonneau, MD; George T. Christakis, MD; Robert J. Cusimano, MD; Tirone E. David, MD; Lee M. Errett, MD; Christopher M. Feindel, MD; Stephen E. Fremes, MD; Bernard S. Goldman, MD; Lynda L. Mickleborough, MD; Charles M. Peniston, MD; Anthony Ralph-Edwards, MD; Hugh E. Scully, MD; Glen S. Van Arsdell, MD; Richard D. Weisel, MD; Terrence M. Yau, MD.

	Acknowledgments

 
We thank the clinical perfusionists and the nursing staff of the Cardiovascular Intensive Unit of the Toronto General Hospital for their assistance in completing this study.

	Footnotes

 
*For a listing of the Insulin Cardioplegia Trial (ICT) Investigators, see the appendix.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Vivek Rao Michael A. Borger Richard D. Weisel George T. Christakis Gideon Cohen Terrence M. Yau Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rao, V. Articles by Yau, T. M. Search for Related Content PubMed PubMed Citation Articles by Rao, V. Articles by Yau, T. M.