From the Departments of Cardiothoracic Surgery, Biostatistics, and Cardiology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts; and the Division of Endocrinology, Baystate Medical Center, Springfield, Massachusetts Diabetes mellitus is an independent risk factor for increased morbidity and mortality, reduced long-term survival, and decreased freedom from recurrent angina following coronary artery bypass graft (CABG) surgery.1 There is now evidence to suggest that techniques that result in tighter glycemic control may improve survival in diabetic patients during acute coronary syndromes. The Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study showed that mortality could be reduced by 30% in diabetic patients sustaining an acute myocardial infarction (MI) with the infusion of a glucose-insulin solution to achieve serum glucose levels below 200 mg/dL.2 We designed a modified glucose-insulin-potassium (GIK) solution to determine whether tighter perioperative glycemic control in diabetic CABG surgery patients would improve perioperative outcomes.
Patients and methods Following approval from the Boston University Medical Center Institutional Review Board, 141 diabetic patients undergoing primary or
reoperative CABG surgery performed on cardiopulmonary bypass were randomly assigned to a GIK (n = 72) or No-GIK (n = 69) group. The GIK consisted of 500 mL of 5% dextrose in water (D5W) with 80 units of regular insulin and 40 mEq of potassium chloride infused at 30 mL/hr, adjusted using a defined protocol to keep serum glucose at or below 200 mg/dL (table 1). The GIK was started at the time of anesthetic induction and continued for 12 hours after arrival in the intensive care unit (ICU). The No-GIK group received D5W at 30 mL/hr and subcutaneous insulin designed to keep the blood glucose level below 250 mg/dL (table 2). Data are represented as the mean ± standard error of the mean and were considered significant at P values of .05 or lower.
There was no difference in age, sex, ejection fraction, urgency of surgery, or the type of diabetes (insulin versus noninsulin) between the two groups. There was also no difference in the number of vessels bypassed (3.26 ± 0.10 for the GIK group compared with 3.29 ± 0.09 for the No-GIK group) or in the cross clamp time (47.7 ± 1.5 min for the GIK group compared with 44.5 ± 1.4 min for the No-GIK group) and cardiopulmonary bypass time (90.4 ± 2.5 min for the GIK group compared with 87.5 ± 2.4 min for the No-GIK group). All patients received at least one internal mammary artery bypass graft.
Before induction of anesthesia, there was no difference in glucose levels between the two groups (180.4 ± 6.9 mg/dL for the GIK group and 179.0 ± 3.8 mg/dL for the No-GIK group). Just before cardiopulmonary bypass surgery, however, patients treated with GIK had glucose levels that were considerably more favorable compared with the No-GIK group (169.2 ± 4.9 mg/dL and 209.2 ± 5.3 mg/dL, respectively; P < .001). After 18 hours in the ICU, the effect was still evident (170.6 ± 5.3 mg/dL for the GIK group and 257.1 ± 6.0 mg/dL for the No-GIK group; P < .001). Cardiac indices were considerably higher for patients treated with GIK, which was still evident 18 hours after the GIK was stopped (2.91 ± 0.06 L/min/m2 for the GIK group compared with 2.43 ± 0.06 L/min/m2 for the No-GIK group;
P < .001). In addition, serum lactate levels were lower as a result of greater glycemic control. At 6 hours, the serum lactate level for the GIK group was 1.75 ± 0.1 mmol/L compared with 2.33 ± 0.31 mmol/L for the No-GIK group (P = .04). The effect remained and was still evident at 12 hours, with 1.36 ± 0.11 mmol/L for the GIK group compared with 2.24 ± 0.19 mmol/L for the No-GIK group (P < .001). After 6 hours, free fatty acid levels were also lower, with 0.33 ± 0.03 mEq/L for the GIK group and 0.57 ± 0.05 mEq/L for the No-GIK group (P < .001).
The postoperative results are shown in table 3. GIK-treated patients had less need for pacing and inotropic support, gained less weight, spent less time on the ventilator, and had a lower incidence of atrial fibrillation, pneumonia, and wound infection. This contributed to a shorter postoperative hospital length of stay for GIK patients (6.5 ± 0.1 days for the GIK group compared with 9.2 ± 0.3 days for the No-GIK group; P = .003).
Table 4 summarizes the follow-up data obtained over 5 years. Kaplan-Meier estimates of survival showed a significant (P = .04) survival advantage for GIK-treated patients during the initial 2 years following surgery. One GIK patient died of intractable congestive heart failure; six No-GIK patients died, five from cardiac-related causes and one from a cerebrovascular accident. GIK-treated patients developed fewer recurrent wound infections involving the sternum and leg, had decreased episodes of recurrent ischemia, and maintained a lower angina class.
There is growing evidence that hyperglycemia is associated with poorer outcomes in patients with acute coronary syndromes. Several studies have shown that patients with serum glucose levels of 200 mg/dL or above have higher in-hospital and 1-year mortality rates, are at greater risk for reinfarction and congestive heart failure, and have less recovery of contractible function after an acute MI independent of the presence or absence of diabetes mellitus.3-5 Furnary and colleagues found that perioperative mortality was reduced by 50% when CABG surgery patients received a continuous insulin drip compared with intermittent subcutaneous injections of insulin to manage serum glucose levels (2.5% versus 5.3%; P < .001).6
There are several reasons hyperglycemia may be detrimental to the ischemic myocardium. The inflammatory response is augmented, resulting in an increased production
of superoxide radicals, which contributes to endothelial dysfunction. Nicotinamide adenine dinucleotide phosphate levels are decreased, ultimately resulting in less synthesis of endothelial nitric oxidase synthase, a potent vasodilator. Platelet function is impaired due to increased levels of plasminogen activator inhibitor-1 and adhesion molecules.7 This predisposes to coronary thrombosis, which ultimately affects long-term graft patency. Insulin resistance, which occurs during cardiopulmonary bypass, accentuates the detrimental effects of hyperglycemia in the diabetic CABG surgery patient by increasing the serum levels of free fatty acids, which predisposes to arrhythmias and cotributes to depressed myocardial contractility.8
Insulin is beneficial to the ischemic diabetic myocardium by enhancing nitric oxide synthase through the PI3-kinase-Akt pathways.9 It has been shown to decrease free fatty acids and increase myocardial uptake of glucose after CABG surgery.10 It decreases the inflammatory response by lowering levels of oxygen free radicals, adhesion molecules, and C-reactive protein.11 It may also prevent coronary thrombosis by decreasing levels of plasminogen activator inhibitor-1.7
Our study did not provide data to determine the mechanisms for the beneficial effects of GIK in prolonging survival of the diabetic CABG surgery patient. We hypothesize that GIK’s favorable effects on endothelial function and its potential for decreasing vascular inflammation and reducing thrombogenicity contributed to improved early graft patency and enhanced viability of ischemic myocardial tissue. Our future studies will attempt to define these protective mechanisms as we endeavor to develop the optimal concentration of glucose and insulin for maximum cardioprotection in these high-risk patients.
This study has shown that perioperative morbidity can be reduced, and long-term survival enhanced, by tighter glycemic control in the diabetic CABG surgery patient. As the number of diabetic patients requiring CABG surgery increases, these interventions can result in a significant savings of health care dollars in a group of patients known to increase health care costs because of disappointing clinical outcomes. GIK is a safe, effective, and low-cost method of achieving more optimal short- and long-term results in these high-risk patients.