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Ann Thorac Surg 2000;70:145-150
© 2000 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Glucose-insulin-potassium solutions improve outcomes in diabetics who have coronary artery operations

^a Department of Cardiothoracic Surgery, Boston Medical Center and Boston University School of Medicine, Boston, Massachussetts, USA
^b Division of Endocrinology, Boston Medical Center and Boston University School of Medicine, Boston, Massachussetts, USA
^c Division of Cardiology, Boston Medical Center and Boston University School of Medicine, Boston, Massachussetts, USA

Address reprint requests to Dr Lazar, Department of Cardiothoracic Surgery, Boston Medical Center, Suite B404, 88 East Newton St, Boston, MA 02118

	Abstract

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Background. This study was undertaken to determine whether glucose-insulin-potassium (GIK) would improve myocardial performance and limit morbidity after coronary artery bypass grafting in diabetic patients.

Methods. Forty consecutive coronary artery bypass grafting patients with medically treated diabetes mellitus were prospectively randomly assigned to either a GIK group (n = 20; 500 mL D₅W + 80 U regular insulin + 40 mEq KCl 30 mL/hour) or a no-GIK group (n = 20; D₅W at 30 mL/hour). The GIK was begun at anesthetic induction and continued for 12 hours postoperatively.

Results. Patients treated with GIK had higher postoperative cardiac indices (2.88 ± 0.50 versus 2.20 ± 0.39 L/minute per square meter; p < 0.0001), lower inotrope scores (0.40 ± 0.68 versus 1.25 ± 1.44; p = 0.05), less weight gain (5.80 ± 3.76 versus 13.85 ± 6.52 pounds; p < 0.0001), and had shorter times of ventilator support (8.35 ± 2.60 versus 13.45 ± 7.33 hours; p = 0.0128). They had a significantly lower prevalence of atrial fibrillation (15% versus 60%; p = 0.003), and shorter hospital stays (6.70 ± 1.52 versus 10.15 ± 6.62 days; p = 0.02).

Conclusions. Substrate enhancement with GIK in diabetic patients improved myocardial performance and resulted in faster recovery after coronary artery bypass grafting.

	Introduction

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In 1965, Sodi-Pollares and colleagues [1] used glucose-insulin-potassium (GIK) solutions in patients with acutely infarcting myocardium and found that it limited electrocardiographic changes. Early studies using GIK in isolated hearts with regional ischemia found favorable results, including decreased infarct size, increased high-energy phosphate levels, and improved ventricular function [2, 3]. However, under conditions of severe, prolonged ischemia without periods of reperfusion, GIK increased lactate accumulation, resulting in poor ventricular function [4]. Enthusiasm for GIK was further dampened by a British Medical Research Council controlled clinical trial of patients with acute myocardial infarcts that failed to show any survival benefit when GIK was used [5]. After the introduction of cardioplegia, the role of GIK in cardiac operations diminished. Recently, however, the emergence of interventional technologies, such as percutaneous transluminal coronary angioplasty (PTCA), stenting, and thrombolysis, as well as coronary artery bypass grafting (CABG) to treat unstable coronary syndromes, has prompted a renewed interest in GIK for ischemic myocardium [6, 7].

In an experimental study using a porcine model to simulate surgical revascularization of acutely ischemic myocardium, we found that hearts treated with GIK had a significant decrease in the incidence of ventricular arrhythmias, less myocardial tissue acidosis, better preservation of wall motion, and the lowest area of tissue necrosis [8]. Those favorable results prompted us to perform a clinical study in which GIK was given to patients who had emergent and urgent CABG operations [9]. Patients receiving GIK had higher cardiac indices and a decreased need for inotropic support; less weight gain, shorter times on the ventilator, a significantly lower incidence of atrial fibrillation, and shorter intensive care unit and hospital stays.

Patients with diabetes mellitus were excluded from our clinical GIK study. However, there is now evidence that GIK might also have a favorable effect in diabetic patients with acutely ischemic myocardium. The Diabetes Mellitus, Insulin, Glucose infusion in Acute Myocardial Infarction (DIGAMI) study involved 620 patients in Sweden who had an acute myocardial infarction and were prospectively randomly assigned to receive an intravenous GIK infusion followed by multidose subcutaneous insulin injections [10]. The patients treated with GIK had a 30% reduction in mortality rate after 1 year. These favorable effects persisted for a mean of 3.5 years 11]. On the basis of our experimental and clinical data in nondiabetics and the results of the DIGAMI study, we undertook this clinical study to determine whether GIK therapy would also be beneficial to diabetic patients who had CABG.

	Material and methods

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Approval to use GIK solutions in human subjects was obtained from the Boston University Medical Center Institutional Review Board (protocol E3270/A65). Informed consent was obtained from all patients enrolled in the study.

Eligibility and exclusion criteria
Patients with diabetes mellitus (controlled by diet, tablets, or insulin) who had CABG were included in the study. Patients with unstable preoperative insulin requirements resulting in either hyperglycemia or hypoglycemia were excluded. Patients with chronic renal failure (creatinine level 2.0 mg/mL), acute renal failure (urine output < 20 mL/hour three times), hyperkalemia (potassium [K⁺] 5.5 mEq/L), or hepatic insufficiency (total bilirubin 2.5 mg/mL; aspartate aminotransferase and alanine aminotransferase 100 IU) were also excluded, as were patients requiring procedures in combination with CABG (such as valve repair or replacement or aneurysm repair).

Study protocol
Patients who met the eligibility criteria for inclusion into the study were prospectively randomly assigned to a GIK or no-GIK group, based on the last digit of their hospital identification number. All patients had placement of a central intravenous catheter in the holding area, at which time a Swan-Ganz thermodilution catheter (Baxter Healthcare Corp, Irvine, CA) was inserted along with a radial artery catheter. After the central and Swan-Ganz catheters were inserted, patients randomly assigned to the GIK group received an infusion of GIK solution consisting of 500 mL D₅W with 80 U of regular human insulin and 40 mEq of KCl, which was infused at 30 mL/hour. The GIK solution was prepared by a research pharmacist and was continued through the anesthetic induction period and just before the onset of cardiopulmonary bypass. After cardiopulmonary bypass was initiated, the GIK solution was stopped and was restarted immediately after aortic unclamping and continued for 12 hours. The no-GIK group received D₅W infused at 30 mL/hour. Blood glucose and K⁺ were monitored every 2 hours. The scales given in Tables 1 and 2 were used to adjust the GIK and no-GIK infusions, respectively.

Variables measured and data acquisition
Serum glucose and potassium levels were measured before infusion of GIK solution, before the initiation of cardiopulmonary bypass, and every 2 hours after aortic unclamping. Electrocardiograms were obtained preoperatively, immediately after CABG, and on postoperative days 1, 2, 5, and 7. The myocardial fraction of creatine kinase and lactate dehydrogenase isoenzyme levels were measured immediately after CABG and at 6 and 24 hours postoperatively. A perioperative myocardial infarction was diagnosed either by the appearance of new changes on the electrocardiogram (Q waves, ST segment elevation 1 mm, loss of R wave in precordial leads) or by the elevation of creatine kinase MB levels to greater than 50 IU in the immediate 24-hour period postoperatively. Cardiac index was derived from thermodilution cardiac output measurements made hourly for 18 hours postoperatively.

Inotropic agents were used to maintain a cardiac index of at least 2.0 L/m² per minute and a systolic blood pressure at least 90 mm Hg after preload, afterload, and heart rate were maximized. An inotropic score was used to quantify the number of inotropic agents used, the dosage, and length of administration. The score ranged from 0 to 5 where 0 indicated no inotropic agents or dopamine less than 2 µg/kg per minute; 1 indicated inotropic support of at least 2 µg/kg per minute for 24 hours, 2 indicated the use of two inotropic agents, 3 indicated the use of epinephrine, 4 indicated the use of three inotropic agents, and 5 indicated inotropic support for 24 hours or more.

All patients were weighed the evening before the operation and at 5 AM the day after the operation to determine postoperative weight gain in pounds. The time spent on the ventilator was recorded in hours from the time of admission to the intensive care unit to the time of extubation. Standardized weaning protocols were used in all patients. Criteria for extubation included an inspiratory force of at least 20 cm, a respiratory rate of 30 breaths per minute or fewer, oxygen saturation of at least 90%; pH 7.35 to 7.45, and partial pressure of carbon dioxide less than 50 mm Hg. The prevalence of atrial fibrillation was recorded for all patients. Administration of ß-blockers was instituted preoperatively and on the first postoperative day in all patients with a heart rate of at least 60 beats per minute and a systolic blood pressure at least 100 mm Hg. Length of hospital stay was recorded for all patients and was defined as the time in the hospital from day of the operation to the day of discharge. Criteria for discharge included a stable rhythm, temperature less than 99°F for 24 hours, well-healed incisions, and a resting oxygen saturation of at least 90% on room air.

Statistical analyses
The data presented are the actual number of occurrences in a group and the mean plus or minus the standard deviations. We used ² analysis and Fisher exact two-sided test to compare occurrences between the GIK and no-GIK groups. Nonpaired Student t tests and Wilcoxon-Mann Whitney tests were used to compare measured data between the groups. Analyses of variance were used to measure changes in serum K⁺ and glucose, and cardiac indices over different periods of time. Data were considered significant at a p value of less than 0.05.

	Results

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During the study period, 40 patients were eligible for the study, all of whom were enrolled in the study and completed the protocol, with 20 in each group. None of the patients had hypoglycemic complications. All 40 patients received insulin. In the no-GIK group, 16 patients received only subcutaneous doses of insulin, whereas 4 patients received both subcutaneous and intravenous doses of insulin. All 20 GIK patients received only intravenous doses of insulin.

Patient profiles and cardiac risk factors
Table 3 summarizes the patient profiles and cardiac risk factors for both groups. Mean age, the ratio of men to women, angina class, and ejection fraction were similar in the GIK and no-GIK groups. Most patients in both groups required preoperative intravenous heparin, had a recent or remote myocardial infarction, and had hypertension. There was no difference between groups in the need for preoperative intra-aortic balloon pump support, the use of intravenous nitroglycerin, and the incidence of congestive heart failure. Nearly half the patients in both groups had insulin-dependent diabetes.

Serum K⁺ and glucose levels
Levels of serum K⁺ remained constant in both the GIK and no-GIK patients and there were no differences in mean values between the groups (Fig 1). There was no difference in serum glucose levels before the infusion of GIK (GIK, 185 ± 25 mg/dL versus no-GIK, 195 ± 18 mg/dL; p = 0.43; Fig 2). After initiation of GIK therapy, serum glucose levels were significantly lower in the GIK-treated patients immediately before cardiopulmonary bypass (GIK, 169 ± 48 mg/dL versus no-GIK, 210 ± 31 mg/dL; p = 0.0028; 95% confidence interval [CI] -67.57 to -15.12), after aortic unclamping (GIK, 146 ± 40 mg/dL versus no-GIK, 230 ± 32 mg/dL; p < 0.0001; 95% CI -107.78 to -60.51), at 6 hours (GIK, 138 ± 42 mg/dL versus no-GIK, 246 ± 36 mg/dL; p < 0.0001; 95% CI -132.70 to -82.19), and at 12 hours of reperfusion (GIK, 135 ± 36 mg/dL versus no-GIK, 258 ± 43 mg/dL; p < 0.0001; 95% CI -147.93 to -96.56). Serum glucose levels remained lower in the GIK-treated patients even after the GIK infusion was discontinued (GIK, 188 ± 42 mg/dL versus no-GIK, 244 ± 40 mg/dL; p = 0.0002; 95% CI -81.91 to -28.19).

View larger version (9K): [in this window] [in a new window]   Fig 1. Serum K+ levels. All values represent the mean plus or minus the standard deviation. Serum K+ remained constant in both the GIK and no-GIK patients during prebypass and reperfusion.

View larger version (12K): [in this window] [in a new window]   Fig 2. Serum glucose levels. All values represent the mean plus or minus the standard deviation. *p less than 0.001. p less than 0.0003. There was no difference in serum glucose levels before the infusion of GIK. After initiation of GIK therapy, glucose levels were significantly lower in the GIK-treated patients and remained lower even after the GIK infusion was discontinued.

The cardiac indices in both groups are summarized in Figure 3. Both groups had similar cardiac indices before induction (GIK, 2.01 ± 0.15 L/m² per minute versus no-GIK, 2.05 ± 0.30 L/m² per minute; p = 0.56; 95% CI -0.20 to 0.11) and cardiopulmonary bypass (GIK, 2.23 ± 0.31 L/m² per minute versus no-GIK, 2.10 ± 0.29 L/m² per minute; p = 0.18; 95% CI -0.06 to 0.32). However, the GIK-treated patients had significantly higher cardiac indices during reperfusion at 0 hours (GIK, 2.52 ± 0.31 L/m² per minute versus no-GIK, 2.10 ± 0.32 L/m² per minute; p = 0.003; 95% CI 0.14 to 0.70), 6 hours (GIK, 2.66 ± 0.53 L/m² per minute versus no-GIK, 2.14 ± 0.47 L/m² per minute; p = 0.002; 95%CI 0.20 to 0.84), and 12 hours (GIK 2.86 ± 0.52 L/m² per minute versus no-GIK, 2.19 ± 0.41 L/m² per minute; p < 0.0001; 95% CI 0.36 to 0.97). The higher cardiac indices persisted in the GIK group even after the infusion was discontinued at 18 hours of the reperfusion period (GIK, 2.88 ± 0.50 L/m² per minute versus no-GIK, 2.20 ± 0.39 L/m² per minute; p < 0.0001; 95% CI 0.38 to 0.97).

View larger version (11K): [in this window] [in a new window]   Fig 3. Cardiac index (CI). All values represent the mean plus or minus the standard deviation. *p less than 0.004. p less than 0.0001. Both groups started out with similar cardiac indices before cardiopulmonary bypass. Patients treated with GIK had significantly higher cardiac indices during reperfusion, which persisted even after the GIK infusion was discontinued.

	Comment

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The primary energy substrate for the nonischemic myocardium is free fatty acids, which account for 60% to 70% of all myocardial oxygen needs [12]. However, during periods of ischemia, free fatty acids are detrimental to the myocardium because they increase oxygen consumption, inhibit glucose utilization, decrease contractility, predispose to arrhythmias, and increase oxygen free radicals [13]. Exogenous glucose is a more favorable substrate during periods of myocardial ischemia [12]. Adenosine triphosphate derived from glycolysis has an important effect in membrane ion transport, which is crucial to the cellular integrity of myocytes, endothelium, and vascular smooth muscle cells. Furthermore, glucose esterifies intracellular free fatty acids by increasing the supply of -glycerophosphate, thereby decreasing the toxic metabolic end-products of free fatty acids, including oxygen free radicals [14]. Glucose might also be beneficial to the postischemic myocardium by replenishing depleted citric acid cycle substrates. Glucose is a direct precursor of pyruvate, which is carboxylated to malate and oxaloacetate [15]. Pyruvate-derived oxaloacetate replenishes the citric acid cycle and promotes the transfer of reducing equivalents to the respiratory chain. Experimental studies have shown that glucose converted to pyruvate can restore contractile function through the replenishment of depleted citric acid cycle substrates [15].

In addition to enhancing glucose uptake by the myocardium, insulin might also benefit the postischemic myocardium by stimulating pyruvate dehydrogenase activity, which may improve aerobic metabolism upon reperfusion [16]. Insulin resistance, which is mediated by high levels of neuroendocrine hormones and which has been reported during cardioplegic arrest and subsequent reperfusion during cardiac operations, is thought to contribute to increased concentrations of serum free fatty acids and decreased glucose after reperfusion [17]. In a randomized study of CABG patients, Svensson and coworkers [17] showed that infusions of intravenous insulin during the reperfusion period decreased the levels of free fatty acids and increased myocardial uptake of glucose, lactate, and free fatty acids. In a prospective, double blind study in CABG patients, Rao and coworkers [18] showed that insulin added to antegrade/retrograde tepid (29^oC) blood cardioplegia stimulated the transition from anaerobic to aerobic metabolism during reperfusion, prevented lactate release, and improved left ventricular stroke work index.

The benefits of using GIK to treat the ischemic myocardium is based on the rationale that during ischemia, exogenous glucose can provide increased adenosine triphosphate through glycolysis and lower circulating free fatty acids, which maintains cell viability. Upon reperfusion, glucose and insulin replenish citric acid cycle substrates thus promoting high-energy phosphorylation.

There are several mechanisms by which GIK therapy may be especially helpful to diabetic patients with acute coronary ischemia. Diabetics are characterized by impaired glucose uptake during ischemia and markedly increased plasma levels of free fatty acids, which predispose them to arrhythmias and further depression in myocardial performance. Several studies have shown a strong relationship between higher levels of free fatty acids and a higher incidence of complications in patients who had an acute myocardial infarction [19]. The enhanced utilization of glucose provided by GIK therapy might help to decrease serum free fatty acid levels in these patients. Vessels in diabetic patients tend to be prone to vasoconstriction because of insulin resistance, which results in decreased prostacyclin and nitric oxide production and higher levels of endothelin-1 [20]. Insulin has been shown to upregulate the L-arginine–nitric-oxide pathway, resulting in vasodilation and decreased vascular resistance [21]. This improved endothelial function could contribute to decreased coronary and peripheral vascular resistance, which contributes to improved myocardial performance during reperfusion in diabetic patients. Diabetic patients have also been shown to have impaired platelet function [22]. Thromboxane A production and platelet aggregability are decreased, which predisposes diabetic patients to coronary thrombosis. Supplemental insulin therapy might improve platelet function and decrease plasma activity of plasminogen activator inhibitor, which is increased in diabetic patients [22].

Our data in CABG patients and the results of the DIGAMI study in patients with acute myocardial infarctions strongly suggests that substrate enhancement with GIK is beneficial to diabetic patients with ischemic myocardium. Diabetic CABG patients treated with GIK had a significant increase in postoperative cardiac index and a decrease in the need for inotropic support. Postoperative weight gain was significantly decreased, resulting in shorter time on the ventilator. As in our previous study in nondiabetics, GIK-treated patients had a significantly lower prevalence of postoperative atrial arrhythmias. Possible mechanisms for the decreased incidence of atrial fibrillation include the ability of GIK to increase atrial levels of glycogen during cardioplegia, thus minimizing atrial ischemia [23], and its ability to prevent diastolic dysfunction during ischemia, thus decreasing atrial dilatation resulting from impaired ventricular compliance [24]. Hence, GIK therapy may not only improve myocardial performance, but it could also lead to decreased medical costs for CABG patients. It is inexpensive, readily available from the hospital pharmacy, easy to administer by the nursing staff, and resulted in no adverse reactions.

The small sample size and short-term follow-up in this study limited our ability to determine whether GIK therapy will decrease morbidity, especially wound infections, and prolong survival. In future studies, we plan to increase the sample size, extend the follow- up period, and measure metabolic substrates to determine the mechanisms for GIK’s favorable actions. We hope to determine whether the beneficial short-term actions of GIK therapy will result in increased long-term survival and a decreased incidence of ischemic events in diabetic patients who have CABG operations.

	References

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