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Clinical Science (2001) 101, 37–43 (Printed in Great Britain) Effects of high-dose glucose–insulin–potassium on myocardial metabolism after coronary surgery in patients with Type II diabetes Zolta! n SZABO! *, Hans ARNQVIST†, Erik HA/ KANSON*, Lennart JORFELDT‡ and Rolf SVEDJEHOLM§ *Department of Cardiothoracic Anaesthesia, Linko$ ping Heart Centre, University Hospital, S-581 85 Linko$ ping, Sweden, †Department of Medical Endocrinology, Linko$ ping Heart Centre, University Hospital, S-581 85 Linko$ ping, Sweden, ‡Department of Thoracic Physiology, Karolinska Hospital, 104 01 Stockholm, Sweden, and §Department of Cardiothoracic Surgery, Linko$ ping Heart Centre, University Hospital, S-581 85 Linko$ ping, Sweden A B S T R A C T The effects of glucose–insulin–potassium (GIK) on cardiac metabolism have been studied previously in non-diabetic patients after cardiac surgery. Although patients with diabetes mellitus can be expected to benefit most from such treatment, the impact of GIK in diabetic patients undergoing cardiac surgery remains unexplored. Therefore the present study investigates the effects of high-dose GIK on myocardial substrate utilization after coronary surgery in patients with Type II diabetes. A total of 20 patients with Type II diabetes undergoing elective coronary surgery were randomly allocated to either post-operative high-dose GIK or standard post-operative care, including insulin infusion if necessary to keep blood glucose below 10 mmol/l. Myocardial substrate utilization was studied using the coronary sinus catheter technique. Haemodynamic state was assessed with the aid of Swan–Ganz catheters. High-dose GIK caused a shift towards carbohydrate utilization, with significant lactate uptake throughout the study period and significant uptake of glucose after 4 h. Arterial levels of non-esterified fatty acids and β-hydroxybutyric acid decreased, and after 1 h no significant uptake of these substrates was found. Increases in the cardiac index and stroke volume index were found in patients treated with high-dose GIK. A decrease in systemic vascular resistance was found both in the control group and in the high-dose GIK group. We conclude that high-dose GIK can be used in diabetic patients after cardiac surgery to promote carbohydrate uptake at the expense of non-esterified fatty acids and β-hydroxybutyric acid. This could have implications for treatment of the diabetic heart in association with surgery and ischaemia. INTRODUCTION Glucose–insulin–potassium (GIK) has been re-appraised in recent years for the treatment of the heart in association with myocardial infarction and cardiac surgery [1–7]. The optimum doses of insulin in treatment of myocardial infarction and of cardiac surgery appear to differ markedly. Due to neuroendocrine stress, high doses of insulin are required to achieve maximal metabolic effects after cardiac surgery in non-diabetic patients [8–10]. Although patients with diabetes mellitus can be expected to benefit most from such treatment, the impact of GIK on cardiac Key words : coronary surgery, diabetes, glucose, β-hydroxybutyric acid, insulin, lactate, myocardial metabolism, non-esterified fatty acids, potassium. Abbreviations : BW, body weight ; GIK, glucose–insulin–potassium ; NEFA, non-esterified fatty acids. Correspondence : Dr Zolta! n Szabo! (e-mail Zoltan.Szabo!lio.se). # 2001 The Biochemical Society and the Medical Research Society 37 38 Z. Szabo! and others metabolism in diabetic subjects remains unexplored. Therefore the effects of high-dose GIK on myocardial substrate utilization after elective coronary artery bypass graft surgery in patients with Type II diabetes have been investigated. METHODS Patients A total of 20 patients with Type II diabetes undergoing elective coronary surgery for stable angina pectoris were studied. Exclusion criteria were a left ventricular ejection fraction of 0.40, age 80 years, serious late complications of diabetes, liver disease, poorly controlled diabetes or metabolic disturbance other than diabetes. Demographic data are given in Table 1. Clinical management All patients were operated on before 12.00 hours. After an overnight fast, β-blockers and calcium antagonists were administered orally, but ACE (angiotensin-converting enzyme) inhibitors, oral anti-diabetic treatment and insulin were withheld. The patients were premedicated intramuscularly with 8–10 mg of oxicodone and 0.4–0.5 mg of scopolamine. Anaesthesia was induced with thiopentone at a dose of 2–3 mg\kg body weight (BW) and fentanyl at a dose of 30 µg\kg BW. Pancuronium bromide was used for neuromuscular blockade. Anaesthesia was maintained with fentanyl and isoflurane. After sternotomy, 3 mg of heparin\kg BW was given. Cardiopulmonary bypass was conducted with a membrane oxygenator and a roller pump generating pulsatile flow. The extracorporeal circuit was primed with crystalloid fluid containing no glucose or lactate (Ringer’s acetate ; Braun2) and mannitol. Moderate haemodilution (haematocrit 20–25 %) and moderate hypothermia (32– Table 1 34 mC) were employed. A combination of antegrade and retrograde delivery of St Thomas’ cold crystalloid cardioplegic solution was used for myocardial protection. After the distal anastomoses were completed, the ascending aorta was unclamped and the proximal vein anastomoses were performed during partial aortic occlusion. Weaning from cardiopulmonary bypass was started at a rectal temperature of 36 mC. Heparin was neutralized with protamine sulphate (3 mg\kg BW), with additional doses given if the activated clotting time (measured with an Automated Coagulation Timer ACT II ; Medtronic Hemo Tec, Parker, CO, U.S.A.) exceeded 125 s. Immediately before closure of the sternum, 4 mg of pancuronium was given intravenously, and this was repeated during the study period to prevent shivering. To minimize the influence of post-operative events such as extubation, pain, shivering and emotional stress during the study period, the patients were ventilated normally and sedated with a continuous infusion of midazolam (2– 6 mg\h). Analgesia during the study period was achieved by ketobemidone infusion (1–4 mg\h) supplemented with intermittent doses of fentanyl. Nitroglycerine or nitroprusside was added if necessary to prevent post-operative hypertension to a pressure greater than 150 mmHg. Ringer’s acetate was used for volume substitution. Tachycardia exceeding 90\min unrelated to hypovolaemia was treated with intravenous boluses of 1–5 mg of metoprolol (Seloken2). Post-operative rewarming in the intensive care unit was facilitated by radiant heat provided by a thermal ceiling. Shed mediastinal blood was routinely re-transfused after surgery. Study protocol The study was performed in accordance with the Helsinki Declaration of Human Rights, and approved by the ethics committee for medical research at Linko$ ping University. Informed consent was obtained from each patient. Patient characteristics and intra-operative data Values are meanspS.E.M. BMI, body mass index ; HbA1c, glycosylated haemoglobin Parameter Control (n l 10) GIK (n l 10) Age (years) Weight (kg) Length (cm) BMI (kg/m2) Female gender (%) Hypertension (%) Pre-operative long-term insulin treatment (%) Pre-operative HbA1c (%) Number of distal anastomoses Cardiopulmonary bypass time (min) Aortic cross-clamp time (min) 56p3 92p6 172p2 30.3p1.07 30 30 60 6.7p0.3 3.5p0.2 84p7 46p5 58p2 87p4 174p3 28.7p1.0 10 60 60 7.2p0.2 3.7p0.3 77p8 45p7 # 2001 The Biochemical Society and the Medical Research Society Glucose–insulin–potassium and the diabetic heart The patients were randomly allocated to groups receiving either post-operative high-dose GIK treatment (n l 10) or standard post-operative glucose control (n l 10). The study was not blinded because of the insulin doses used. Originally three arms of the study were considered, with one arm investigating the effect of a GIK regime employing an insulin dose of 0.08 i.u.:h−":kg−" BW [11]. However, this arm was abandoned after the first patient, because of unacceptable blood glucose control. The high-dose GIK treatment has been described previously [7]. Briefly fast-acting insulin (Actrapid Novo2) was infused at a rate of 1 i.u.:h−":kg−" BW for 6 h. A bolus of 25 i.u. was also injected after 5 min. A 30 % (w\v) glucose solution supplemented with 10 mmol\l magnesium and 40 mmol\l phosphate was also infused, with the aim of keeping blood glucose between 7 and 10 mmol\l. The average infusion rate was 83 ml\h during the study period. After stopping insulin infusion, the glucose infusion was decreased gradually. Potassium was infused separately. During the study period, three of the control patients required insulin infusion ranging from 1 to 10 i.u.\h to keep blood glucose levels at 10 mmol\l. Post-operatively, a coronary sinus catheter (Wilton Webster Labs Inc., Altadena, CA, U.S.A.) was inserted through the right internal jugular vein. The final midcoronary sinus position was confirmed by fluoroscopy and measurement of oxygen saturation. Coronary sinus blood flow (CF 300A Flowmeter ; Webster Labs Inc.) was measured using the retrograde thermodilution technique. The mean of three measurements was used. The study was started on average 3 h after release of the aortic cross-clamp. Blood sampling from the coronary sinus and radial artery was done in the basal state (before starting GIK) and after 30 min and 1, 2 and 4 h. Haemodynamic state and coronary sinus blood flow were measured at the same time points. Samples for glucose, lactate, glycerol, β-hydroxybutyric acid, glutamate and alanine were analysed in whole blood. Samples for non-esterified fatty acids (NEFA) were analysed in plasma. Details of biochemical analyses have been presented previously [12]. Myocardial fluxes of substrates were calculated as the product of arterial–coronary-sinus blood or plasma concentration differences and coronary sinus blood or plasma flow, as appropriate [12]. A release of substrates was defined as a myocardial flux value significantly less than zero (P 0.05), whereas uptake of substrates was defined as a myocardial flux significantly greater than zero (P 0.05). The oxygen consumption of the heart was estimated as the product of the arterial–coronary-sinus blood oxygen content difference and coronary sinus blood flow. Oxygen content was given by [B-HbiSO i(6.2i10−%)] # j(PO i0.01), where B-Hb represents blood level of # haemoglobin (in g\l), SO is oxygen saturation expressed # as a percentage, and PO is oxygen tension (in kPa). # Statistical methods Statistical analyses were performed with a computerized statistical package (Statistica 5.1 ; StatSoft, Inc., Tulsa, OK, U.S.A.). ANOVA for repeated measures employing the Tukey honest significant difference test was used to analyse inter-group differences (between the GIK and control groups) after the basal state and to analyse changes occurring over time. The Mann–Whitney U-test adjusted for repeated measures with the Bonferroni correction was used to determine statistical differences from zero. Statistical significance was defined as P 0.05. Data are presented as meanspS.E.M. RESULTS Clinical outcome Pre-operative and intra-operative data are presented in Table 1. There was no mortality. The median stay in the intensive care unit was 1 day for both groups. Haemodynamic results Haemodynamic state was stable in both groups during the study period (Table 2). In the high-dose GIK group an increase in cardiac index occurred, from 2.1p0.1 litres:min−":m−# in the basal state to 2.9p0.2 litres:min−":m−# after 4 h (P 0.05). The stroke volume index increased in the high-dose GIK group, and a reduction in systemic vascular resistance during the study period was observed in both groups. No significant change in left ventricular stroke work index occurred in either group. Inter-group differences (effect of GIK) reached statistical significance only for the cardiac index, but a borderline P value was found for the stroke volume index. Metabolic findings Arterial levels of NEFA, β-hydroxybutyric acid and glycerol were significantly lower in the group receiving high-dose GIK treatment than in the control group (Table 3). In the control group, the heart extracted NEFA and β-hydroxybutyric acid, but no uptake of carbohydrate substrates was observed (Table 4). In the highdose GIK group, uptake of lactate occurred throughout the study period, and at 4 h significant uptake of glucose was also observed (Table 4). No uptake of NEFA was found during high-dose GIK treatment, and uptake of βhydroxybutyric acid was observed only during the first 1 h of the study period. Inter-group differences caused by GIK reached statistical significance only for the higher uptake of lactate and the lower uptake of βhydroxybutyric acid (Table 4). The difference in lactate # 2001 The Biochemical Society and the Medical Research Society 39 40 Z. Szabo! and others Table 2 Haemodynamic results Values are meanspS.E.M. HR, heart rate ; CI, cardiac index ; BSA, body surface area ; MAP, mean arterial pressure ; CVP, central venous pressure ; PCWP, pulmonary capillary wedge pressure ; SVRI, systemic vascular resistance index ; LVSWI, left ventricular stroke work index ; SI, stroke index ; S VO2, mixed venous oxygen saturation. Statistically significant inter-group differences due to GIK (ANOVA repeated-measures design) are indicated in the right-hand column ; ns, not significant. Post hoc differences are indicated as follows : **P 0.01, ***P 0.001 denote significant differences compared with the basal state (0 h) ; †P 0.05, ††P 0.01, †††P 0.001 denote significant inter-group differences. Variable Group Basal 30 min 1h 2h 4h HR (beats/min) Control GIK Control GIK Control GIK Control GIK Control GIK Control GIK Control GIK Control GIK Control GIK 88p5 77p4 2.1p0.1 2.1p0.1 79p4 88p5 6p1 6p1 10p2 10p1 2907p238 3086p210 27.0p2.6 33.4p2.1 24.9p1.4 28.4p2.0 63.8p1.8 68.5p2.2 87p5 83p5 2.1p0.1 2.3p0.1 81p4 80p4 6p1 6p1 10p2 10p1 2832p254 2621p149 27.6p2.1 30.5p2.3 25.6p1.3 28.2p2.1 64.5p1.6 67.3p1.6 89p5 83p5 2.1p0.1 2.5p0.2 75p4 74p4** 8p1 7p1 9p1 11p2 2521p229 2247p178*** 25.5p2.0 31.3p3.4 25.3p1.4 31.0p3.0†† 59.2p2.2 67.2p1.6†† 89p4 83p5 2.1p0.1 2.4p0.1 73p3 71p3*** 7p1 7p1 9p1 11p1 2512p141 2137p126*** 25.3p2.3 29.2p2 25.0p1.7 30.2p1.8† 60.7p2.5 67.7p1.5††† 84p4 82p4 2.3p0.1 2.9p0.2*** 72p3 68p3*** 8p1 7p1 9p1 11p1 2260p174** 1667p112*** 27.6p1.7 33.5p2.2 28.0p1.7 36.6p2.1***††† 61.1p2.2 70.0p1.5††† CI (litres:min−1:m−2 BSA) MAP (mmHg) CVP (mmHg) PCWP (mmHg) SVRI (dyne:s:cm−5:m−2 BSA) LVSWI (g:beat−1:m−2 BSA) SI (ml:beat−1:m−2 BSA) S VO2 (%) Table 3 P (ANOVA) ns 0.017 ns ns ns ns ns ns (0.06) ns Arterial concentrations of substrates and insulin Values are meanspS.E.M. Statistically significant inter-group differences due to GIK (ANOVA repeated-measures design) are indicated in the right-hand column ; ns, not significant. Post hoc differences are indicated as follows : **P 0.01, ***P 0.001 denote significant differences compared with the basal state (0 h) ; ††P 0.01, †††P 0.001 denote significant inter-group differences. Metabolite Glucose (mmol/l) Group Control GIK Lactate (mmol/l) Control GIK NEFA (mmol/l) Control GIK Glycerol (µmol/l) Control GIK β-Hydroxybutyric acid (µmol/l) Control GIK Glutamate (µmol/l) Control GIK Alanine (µmol/l) Control GIK Insulin (pmol/l) Control GIK Basal 30 min 7.16p1.32 7.01p1.43 6.14p0.47 8.52p0.53*** 1.15p0.40 1.01p0.38 1.22p0.22 1.33p0.18 0.67p0.17 0.81p0.25 0.63p0.84 0.49p0.67††† 91p44 136p58 63p10 42p6††† 150p58 229p63 100p57 79p52 168p9 174p7 154p11 160p15 243p21 224p22 306p41 304p50 94p53 32p13 84p28 12088p2559***††† 1h 2h 7.48p1.60 7.54p1.36 8.16p0.70** 7.37p0.70 1.15p0.47 1.08p0.44 1.65p0.11** 1.42p0.10 0.77p0.25 – 0.34p0.59**††† – 134p75 121p77 40p4††† 40p3††† 321p79 450p84 28p14 11p3†† 165p6 159p7 141p7 133p9 234p21 215p14 285p35 265p21 34p15 44p12 10301p782***††† 11125p1464***††† uptake was explained by a markedly higher rate of extraction during high-dose GIK treatment (P l 0.008). In the high-dose GIK group, the average fractional extraction of lactate increased from 15.9 % in the basal # 2001 The Biochemical Society and the Medical Research Society 4h 7.95p1.21 6.97p0.43 1.12p0.51 1.36p0.65 0.69p0.24 0.27p0.70***††† 79p32 37p3 395p117 14p3†† 154p7 135p10 234p25 251p20 62p15 14007p1509***††† P (ANOVA) ns ns 0.0007 0.007 0.005 ns ns 0.0001 state to 33.8 % at 1 h (P 0.05), and thereafter ranged between 25 % and 32 %. In the control group, the average fractional extraction rate of lactate ranged from a peak of 4.9 % in the basal state to 0.6 % after 4 h. Myocardial Glucose–insulin–potassium and the diabetic heart Table 4 Myocardial flux of substrates and oxygen consumption Values are meanspS.E.M. CS, coronary sinus ; MV O2, myocardial oxygen consumption. Statistically significant inter-group differences due to GIK (ANOVA repeatedmeasures design) are indicated in the right-hand column ; ns, not significant. Post hoc differences are indicated as follows : *P 0.05, **P 0.01 denote significant differences compared with the basal state (0 h) ; ††P 0.01 denotes significant inter-group differences. Statistically significant uptake or release of substrates is indicated by : ‡P 0.05. Parameter Flux ( µmol/min) Glucose Lactate NEFA Glycerol β-Hydroxybutyric acid Glutamate Alanine CS blood flow (ml/min) MV O2 ( µmol/min) Group Basal state Control GIK Control GIK Control GIK Control GIK Control GIK Control GIK Control GIK 35p23 23p11 16p13 k6p16 k10p5 20p36 23.9p13.5 11.4p8.6 9.2p6.7 23.4p7.2‡ 31.9p12‡ 74.0p12**††‡ 11.8p3.6‡ 6.7p1.4‡ 4.3p1.3‡ 8.5p1.7‡ 3.9p1.8 3.4p2.5 2.4p2.4 0.8p0.6 0.4p0.3 k2.0p2.6 0.8p0.3‡ k1.3p0.5‡ 2.4p5.8 5.9p3.7‡ 11.1p4.0‡ 3.7p1.5‡ 3.9p3.1 2.1p1.7‡ 1.9p2.4‡ 2.3p1.2‡ 2.5p0.9‡ 3.3p1.3 4.3p2.4‡ 2.8p0.4‡ 1.2p5.8 0.4p1.5 k4.1p1.1 k2.0p3.0 k1.2p3.0 k6.1p3.1 Control GIK Control GIK 141p38 122p19 485p147‡ 519p95‡ 30 min 92p11 126p27 337p47‡ 449p82‡ uptake of glutamate was observed in both groups, but significant release of alanine was only recorded once in the control group. Plasma insulin levels in the high-dose GIK and control groups are given in Table 3. The average glucose infusion rate in the high-dose GIK group ranged between 4.7p0.2 and 5.1p0.6 mg:min−":kg−" BW. DISCUSSION To our knowledge, this is the first study to investigate the effects of GIK on cardiac metabolism in patients with diabetes. The main finding was that high-dose GIK promoted the myocardial uptake of carbohydrate substrates at the expense of NEFA and β-hydroxybutyric acid early after coronary surgery in patients with Type II diabetes. Myocardial substrate utilization after cardiac surgery has been studied previously in non-diabetic patients [10,12,13]. The metabolic state in these patients was characterized by elevated blood glucose and plasma NEFA, reliance on NEFA for myocardial energy uptake and restricted uptake of carbohydrates. It was also demonstrated that GIK could enhance the myocardial uptake of carbohydrate substrates ; however, due to neuroendocrine stress, insulin doses of up to 1 i.u.:h−":kg−" BW were required to achieve maximal 1h 111p21 149p27 381p69‡ 518p61‡ 2h 4h k19p28 27p14 0.2p6.0 38.9p19‡ – – 0.5p0.6 k0.0p0.2 13.9p5.7‡ 0.5p0.3 1.9p0.8‡ 1.4p1.0‡ k5.7p2.6‡ k0.4p1.3 5p20 62p18‡ 3.7p6 50.5p10.5‡ 7.9p2.7 2.0p1.2* 0.6p0.6 0.3p0.3 9.0p3.4‡ 0.6p0.3 2.8p0.5‡ 2.7p0.7‡ k6.7p1.7 k1.5p2.7 100p12 112p25 388p60‡ 424p82‡ 122p15 115p22 386p46‡ 415p72‡ P (ANOVA) ns 0.003 ns ns 0.004 ns ns ns ns metabolic effects [8–10,13]. This dosage was used in the present study, leading to an approximate 150-fold increase in plasma insulin. Insulin levels of this magnitude are known to be associated with vasodilatation [14]. Our haemodynamic results are in keeping with this, and consequently an increased cardiac index was found in the high-dose GIK group. In the basal state, satisfactory haemodynamic and metabolic recovery had occurred in both groups. The control patients were treated with insulin, if necessary, to keep blood glucose below 10 mmol\l. In spite of this, no uptake of carbohydrate substrates was observed, and NEFA and β-hydroxybutyric acid were the major substrates taken up by the heart. In contrast, high-dose GIK enhanced the myocardial uptake of carbohydrate substrates, in particular lactate, at the expense of NEFA and β-hydroxybutyric acid. The effect of high-dose GIK on myocardial glucose uptake was not as evident as that on myocardial lactate uptake. Insufficient statistical power due to study size and the relationship between analytical precision and fractional extraction rate could partly explain this discrepancy. Also, the possibilities of an attenuated effect of GIK on myocardial glucose uptake in diabetic patients, or a predominant direct or indirect activation of pyruvate dehydrogenase underlying the action of insulin (discussed below), under these circumstances have to be considered. However, despite conservative statistical assessment, significant uptake of # 2001 The Biochemical Society and the Medical Research Society 41 42 Z. Szabo! and others glucose was observed at the end of the study period in the high-dose GIK group, and the uptake of glucose and lactate would have sufficed to explain the entire oxygen consumption, assuming that all substrates taken up by the heart were metabolized. These metabolic findings could have clinical implications, as energy derived from carbohydrates has been claimed to be important for the preservation of mechanical function, structure and ionic balance in association with myocardial ischaemia [8,15]. Furthermore, during high-dose GIK treatment, plasma levels of NEFA decreased and no myocardial uptake of NEFA was observed. Although NEFA normally constitute the major source of energy for the heart, a state with elevated NEFA levels and myocardial substrate uptake restricted to predominantly NEFA represents an unfavourable metabolic situation for the ischaemic and post-ischaemic heart, because of increased oxygen expenditure and the accumulation of toxic metabolites [8,15]. Thus the present study shows that myocardial substrate utilization can be modified in the desired direction even in diabetic patients after cardiac surgery. Also, the results of the present study concerning systemic glucose uptake could have implications for critically ill diabetic patients in settings other than cardiac surgery. By use of high-dose GIK, substantial amounts of energy in the form of glucose could be provided coincident with the maintenance of acceptable blood glucose control. The need for large doses of insulin to achieve this effect was illustrated by the fact that one arm of our study originally designed to investigate the impact of a GIK regime employing an insulin dose of 0.08 i.u.:h−":kg−" BW [11] was abandoned because of unacceptable blood glucose control. The methods employed here do not elucidate the precise mechanisms behind the action of high-dose GIK on myocardial substrate uptake. Normally, myocardial uptake of carbohydrate substrates is not insulindependent. In our study high-dose GIK caused marked decreases in arterial levels of NEFA and β-hydroxybutyric acid, which may have indirectly enhanced the uptake of carbohydrates and the activity of pyruvate dehydrogenase [8,15]. Certainly, the observed impact on myocardial lactate uptake in the absence of a concomitant increase in alanine release is compatible with enhanced pyruvate dehydrogenase activity. Furthermore, insulin can enhance the uptake of carbohydrates directly by stimulating glucose transporters, and possibly by intracellular stimulation of pyruvate dehydrogenase [15,16]. Despite encouraging early results with GIK for treatment of acute myocardial infarction in the 1960s and 1970s, it was abandoned due to inconclusive trials. In retrospect, this was done without sufficient statistical power [3]. A meta-analysis including all properly randomized placebo-controlled trials on GIK demonstrated a significant decrease in mortality in acute # 2001 The Biochemical Society and the Medical Research Society myocardial infarction [3], and this was later supported by the ECLA study [2]. With regard to diabetic subjects, two clinical studies have demonstrated encouraging results with GIK for the treatment of myocardial infarction and in association with cardiac surgery [5,6]. These studies employed substantially lower doses of insulin than in the present study, and the metabolic impact was not investigated. Although it is appreciated that effects other than purely metabolic ones may play a role, it is conceivable that insulin doses sufficient to achieve maximal metabolic effects could enhance the efficacy of this treatment. Further studies are warranted in order to clarify these issues, and to investigate potential clinical benefits or hazards associated with high-dose GIK in clinical practice. ACKNOWLEDGMENTS We thank Mats Fredriksson (Department of Occupational and Environmental Medicine, Linko$ ping University) for expert statistical advice. This study was supported by grants from The Swedish Heart Lung Foundation, The Swedish Medical Research Council (Project no 04139), Stina och Birger Johanssons stiftelse, Svenska Diabetes Fo$ rbundets Forskningsfond, O$ stergo$ tlands La$ ns Landsting and the Linko$ ping Heart Centre. REFERENCES 1 Apstein, C. 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E., Berglin, W.-O. E., Ekroth, R., Milocco, I., Nilsson, F. and William-Olsson, G. (1984) Haemodynamic effects of a single large dose of insulin in open heart surgery. Cardiovasc. Res. 18, 697–701 15 Stanley, W. C., Lopaschuk, G. D., Hall, J. L. and McCormack, J. G. (1997) Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions. Cardiovasc. Res. 33, 243–257 16 Rao, V., Merante, F., Weisel, R. D. et al. (1998) Insulin stimulates pyruvate dehydrogenase and protects human ventricular cardiomyocytes from simulated ischemia. J. Thorac. Cardiovasc. Surg. 116, 485–494 Received 2 January 2001/12 February 2001; accepted 28 March 2001 # 2001 The Biochemical Society and the Medical Research Society 43