BJA Advance Access originally published online on February 27, 2008
British Journal of Anaesthesia 2008 100(4):442-450; doi:10.1093/bja/aen018
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Perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery
1 Department of Anaesthesiology
2 Department of Cardiac Surgery
3 Department of Intensive Care Medicine
4 Department of Vascular Medicine
5 Laboratory of Clinical Chemistry
6 Laboratory of Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
* Corresponding author. E-mail: c.j.zuurbier{at}amc.uva.nl
Accepted for publication November 26, 2007.
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Abstract |
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Background: Glucose–insulin–potassium (GIK) administration is advocated on the premise of preventing hyperglycaemia and hyperlipidaemia during reperfusion after cardiac interventions. Current research has focused on hyperglycaemia, largely ignoring lipids, or other substrates. The present study examines lipids and other substrates during and after on-pump coronary artery bypass grafting and how they are affected by a hyperinsulinaemic normoglycaemic clamp.
Methods: Forty-four patients were randomized to a control group (n=21) or to a GIK group (n=23) receiving a hyperinsulinaemic normoglycaemic clamp during 26 h. Plasma levels of free fatty acid (FFA), total and lipoprotein (VLDL, HDL, and LDL)-triglycerides (TG), ketone bodies, and lactate were determined.
Results: In the control group, mean FFA peaked at 0.76 (SEM 0.05) mmol litre–1 at early reperfusion and decreased to 0.3–0.5 mmol litre–1 during the remaining part of the study. GIK decreased FFA levels to 0.38 (0.05) mmol litre–1 at early reperfusion, and to low concentrations of 0.10 (0.01) mmol litre–1 during the hyperinsulinaemic clamp. GIK reduced the area under the curve (AUC) for FFA by 75% and for TG by 53%. The reduction in total TG was reflected by a reduction in the VLDL (–54% AUC) and HDL (–42% AUC) fraction, but not in the LDL fraction. GIK prevented the increase in ketone bodies after reperfusion (–44 to –47% AUC), but was without effect on lactate levels.
Conclusions: Mild hyperlipidaemia was only observed during early reperfusion (before heparin reversal) and the hyperinsulinaemic normoglycaemic clamp actually resulted in hypolipidaemia during the largest part of reperfusion after cardiac surgery.
Keywords: metabolism, insulin; metabolism, lipid; surgery, cardiovascular; surgery, metabolic response
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Introduction |
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Metabolic modulation as a therapeutic approach for cardiac dysfunction during episodes of ischaemia and reperfusion has been an active field of research for more than 40 yr.1 Glucose–insulin–potassium (GIK) therapy remains the mainstay of this field, based on the assumption that GIK lowers circulating free fatty acid (FFA) levels, which are assumed to be elevated and therefore detrimental during cardiac reperfusion.2 3 Furthermore, GIK increases cardiac glucose metabolism with a concomitant decrease in hyperglycaemia, both assumed to be cardioprotective.4–6
That insulin therapy is effective at preventing hyperglycaemia has been shown by many studies.7–10 Surprisingly, the effect of insulin administration on plasma levels of FFA and triglycerides (TG) has largely been ignored.11 This may be especially important in relation to recent information indicating that acute FFA depletion may actually decrease cardiac performance in patients with heart failure.12 In addition, uncertainty exists concerning the reliability of reports of FFA concentrations during reperfusion. Although older literature reports FFA>1 mmol litre–1 during reperfusion, this is not always observed in recent studies.8 13 One difficulty in the accurate determination of FFA in blood samples is the ongoing lipolysis in the test tube, especially after the in vivo administration of heparin.14 Without special precautions, for example, inhibition of ex vivo lipolysis with a potent lipoprotein lipase (LPL) inhibitor,14 plasma fatty acid levels may be substantially overestimated.
Although it is generally believed that the heart derives its energy mainly from fatty acids, current literature indicates that lactate is also an important substrate for the heart.15 16 Finally, especially in the presence of insulin resistance, which may occur during cardiac reperfusion, ketone bodies derived from fatty acids become an important substrate for brain and also possibly for heart.17 To our knowledge, little information exists concerning plasma ketone body levels during coronary artery bypass grafting (CABG) and how these and lactate levels are affected by GIK administration. GIK was applied as a hyperinsulinaemic normoglycaemic clamp, resulting in supraphysiological plasma insulin concentrations.10 18 With this technique, the insulin infusion rate of 0.1 IU kg–1 min–1 is in the high range of insulin rates commonly used in GIK administrations.
The present study was designed to determine how a perioperative hyperinsulinaemic normoglycaemic clamp10 18 for 26 h in non-diabetic patients undergoing CABG affects important substrates of the myocardium other than glucose. These include FFA, total and lipoprotein TG, lactate and the ketone bodies acetoacetate, and β-hydroxybutyrate. Special care was given to prevent ex vivo lipolysis of TG.
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Methods |
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After approval by the local Medical Ethics Committee and after obtaining written informed consent, 44 patients with normal left ventricular (LV) function undergoing elective CABG were enrolled in this study. Thirty-six patients also participated in our previously reported neurohumoural stress study.18 Excluded were patients with the following characteristics: LV ejection fraction <45%, unstable angina pectoris, atrioventricular conduction defects, and diabetes mellitus. The last were excluded on the basis of a known diagnosis of diabetes mellitus or fasting plasma glucose levels of at least 7.0 mmol litre–1. Patients taking corticosteroids or non-steroidal anti-inflammatory drugs and patients undergoing additional surgical procedures, for example, valve replacement or aneurysmectomy, were also excluded. All patients were randomly allocated to the control group or to the hyperinsulinaemic normoglycaemic clamp (clamp) group. Patients in the control group received standard institutional perioperative care. Patients allocated to the clamp group received additional infusions of insulin and glucose.
Insulin and glucose infusions
After baseline blood sampling and the insertion of a pulmonary artery catheter (Edwards Lifesciences, Irvine, CA, USA) into the right internal jugular vein providing a central venous access port for insulin and glucose infusion, hyperinsulinaemic normoglycaemic clamping was started and continued throughout the period of cardiopulmonary bypass (CPB) until 24 h after release of the aortic cross-clamp. Sobule insulin (Actrapid, NovoNordisk, Copenhagen, Denmark) was infused continuously at a fixed rate of 0.1 IU kg–1 h–1. A separate mixture of glucose 30% (Baxter-Clintec Benelux SA, Bruxelles, Belgium), potassium chloride 80 mmol litre–1, and phosphate 60 mmol litre–1 was infused at a variable rate adjusted to maintain blood glucose levels within a target range of 4.0–5.5 mmol litre–1. The adjustments to the glucose infusion rate follow similar procedures as previously published.10 18
Intraoperative management
Anaesthesia was induced with sufentanil 3 µg kg–1 (Sufenta®, Janssen-Cilag, Tilburg, The Netherlands) and propofol 50–100 mg (Fresenius Kabi, Den Bosch, The Netherlands). Pancuronium bromide 0.1 mg kg–1 (Pavulon®, Organon, Oss, The Netherlands) was given for muscle relaxation. Morphine 20 mg was given as a slow bolus injection before start of surgery. Anaesthesia was maintained with a continuous infusion of propofol 2–5 mg kg–1 h–1. CPB procedures and postoperative intensive care management are identical to those previously reported.10 18 After systemic heparinization (300 U kg–1, Leo Pharmaceutical Products, Weesp, The Netherlands), CPB was initiated with cannulae placed in the ascending aorta and right atrium. After termination of CPB, heparin was antagonized with protamine hydrochloride or protamine sulphate (ICN Pharmaceuticals Holland B.V.). Throughout the ICU stay, a continuous infusion of glucose 5% was given at a rate of 30 ml h–1 (1.5 g h–1) to all patients through a central venous line.
Blood samples and measurement points
Samples in the operating room and ICU were taken from the radial artery catheter. On the ward, blood samples were collected through venapuncture of the anticubital vein (contralateral to the arm used for glucose administration). At the following time points, blood samples were collected for the measurement of glucose, insulin, lactate, FFA, total TG, VLDL-TG, LDL-TG, HDL-TG, acetoacetate and β-hydroxybutyrate: (1) after induction of anaesthesia and the insertion of the pulmonary artery catheter, but before the start of clamping (‘baseline’); (2) 45 min after start of hyperinsulinaemic normoglycaemic clamping, but before CPB, and before heparinization (‘before CPB’); (3) immediately after release of the aortic cross-clamp, that is, during heparinization (‘reperfusion’); (4) 2 h after release of the aortic cross-clamp (‘2 h reperfusion’); (5) 6 h after release of the aortic cross-clamp (‘6 h reperfusion’); and (6–9) on the first and second postoperative day, both in the morning between 6 and 8 a.m. and in the evening between 6 and 8 p.m. (respectively, POD1 morning, POD1 evening, POD2 morning, POD2 evening). Cardiac enzymes (CK-MB and TnT) were sampled on arrival in the ICU and every 3 h thereafter, until it was clear that levels were past the peak level.
Insulin was determined by a luminescence enzyme immunoassay (Immulite, Diagnostic Products Corporation, Los Angeles, CA, USA). The intra- and inter-assay coefficients of variation were 3–5% and 6–9%, respectively. The detection limit was 2 mU litre–1.
Plasma glucose measurements were performed with a Chiron Rapidlab 865 blood-gas analyzer (GMI, Ramsey, MN, USA).
FFAs were measured using a enzymatic colorimetric method (Wako Chemicals). The intra- and inter-assay coefficients of variation were 1.80% and 2.37%, respectively. Blood (5 ml) was collected in a tube containing 100 µl (1 mg ml–1 ethanol) tetrahydrolipstatin (THL, Roche, Basel, Switzerland). In a separate pilot study, we determined to what extent in vitro test tube lipolysis contributed to elevated FFA levels in blood obtained during CABG procedures. To this end, FFA levels were measured in five patients in the presence and absence of THL in the test tube, before and after administration of heparin (these patients did not participate in the actual study). The presence of THL reduced FFA from 0.67 to 0.56 mmol litre–1 (P<0.05, paired t-test) before heparin administration, and from 1.62 to 0.67 mmol litre–1 (P<0.05, paired t-test) after heparin administration. These results emphasize the requirement of an LPL inhibitor in the test tube for appropriate determination of FFA, especially during heparin treatment. Confirmation of the effect of THL on FFA determination without the presence of heparin should ideally be provided by another study of a larger size.
TG analysis was performed by the GPO-PAP method on the Modular P 800 analyzer (Roche Diagnostics). The intra- and inter-assay coefficients of variation were 1.70% and 1.07%, respectively. Analysis of lipoprotein-TG was performed for samples of the last 12 patients included in each of the two study groups. For lipoprotein TG levels, plasma samples were chromatographed by fast protein liquid chromatography on a Superose 6 column (HR10/30, Pharmacia) and eluted with (in w/v) NaCl 0.9%, Tris 0.01%, EDTA 0.01%, sodium azide 0.02%, pH 7.6 to collect the VLDL, LDL, and HDL fractions. TG concentration was assayed by standard enzymatic assay using quinoneimine compound as end product which is measured colorimetrically at 505 nm. The intra- and inter-assay coefficients of variation were <5% and <10%, respectively, for the TG measurement in each lipoprotein fraction.
Blood for ketone bodies and lactate was immediately deproteinized in 0.5 mol litre–1 perchloric acid, centrifuged, stored at –20°, and analysed within 10 days (ketone bodies and lactate are stable within this period). The intra- and inter-assay coefficients of variation were 1.1% and 5.7% for lactate, respectively, and 0.7% and 6.4% for the ketone bodies, respectively. Ketones and lactate were measured using standard enzymatic methods applied sequentially on an automated spectrophotometric centrifugal analyser (Roche COBAS FARA). Either reduction of the cofactor nicotinamide-adenine-dinucleotide (NAD) to NADH or oxidation of NADH to NAD was measured at 340 nm.
Statistical analysis
Randomization was performed by a person not involved in the trial and a randomization program (supplied by the statistics department) which was installed on a stand-alone computer. Consenting patients were randomly assigned to control treatment or clamp treatment. A block randomization was performed where the size of the blocks varied randomly. The present study is a preplanned analysis of our previously published study examining effects of a hyperinsulinaemic normoglycaemic clamp on the neurohumoral stress response during coronary artery surgery.18 The primary variable in that study was cortisol, for which the required sample size was calculated. In this respect, the metabolic variables reported in the current study are secondary variables. This approach actually resulted in a very high power for the current main variables FFA (power 100%) and TG data (power 99.9%).
Patient characteristics data were reported as mean (SD) for continuous variables in the case of approximately normal distribution and as counts (proportions) for categorical variables. Outcome variables (glucose and metabolite concentrations) were reported as mean (SD) or median (range). A standard t-test was performed to analyse differences at baseline.
One-way analysis for repeated measurements within-group for time effects was performed on outcome variables. When a significant time effect was found (P<0.05), means at different time points were compared with baseline value (with Bonferroni correction).
A standard t-test was performed to analyse differences in areas under the curve (AUCs) between the control group and the hyperinsulinaemic normoglycaemic clamp group during and after the period of clamping for the different outcome variables. For the use of AUC, also following the clamp period, it is assumed that alterations in the variables between time points are linear. P-values of <0.05 were considered statistically significant. Data analyses were performed with SPSS 11.5.
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Patients
Patient and surgical characteristics and in-hospital outcome variables are summarized in Table 1. No differences were observed for any of these variables between the two groups.
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Insulin and glucose
Data are reported as mean (SD). The mean infusion rate of insulin throughout the clamping period was 7.7 (1.1) IU h–1. In the clamp group, the total glucose load was 314 (91) g during the 26 h clamping period. The mean (SD) glucose infusion rate was 105 (22) mg kg–1 h–1 before CPB and peaked at 177 (78) mg kg–1 h–1 at 6 h after reperfusion and was 150 (62) mg kg–1 h–1 at the end of the insulin clamp.
Insulin and glucose levels at selected time points are shown in Table 2. The hyperinsulinaemic clamp resulted in 4–10 times higher insulin levels when compared with the control group. After clamping was discontinued, plasma insulin returned to values similar to those found in the control group. At baseline, plasma glucose levels were similar between the groups. In the control group, glucose levels increased significantly compared with the clamp group at 6 h of reperfusion, demonstrating the development of hyperglycaemia in this group. Normoglycaemia was maintained in the hyperinsulinaemic clamp group. After discontinuation of the clamp, hyperglycaemia also developed in the clamp group, with glucose levels similar to the control group.
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Free fatty acids
FFA levels are shown in Figure 1A. At baseline, there were no differences in plasma FFA levels. In the control group, mean (SD) FFA levels significantly rose to values above baseline to a maximum of 0.76 (0.25) mmol litre–1 at the start of reperfusion, that is, in the presence of heparin. After the antagonizing of heparin with protamine, FFA returned to baseline levels (
0.4 mmol litre–1) for the remaining time of the protocol. In the hyperinsulinaemic clamp group, FFA levels remained at baseline values at early reperfusion, but decreased to levels below baseline thereafter to very low levels of 0.1 mmol litre–1 during the remaining of the clamp period. After discontinuation of the hyperinsulinaemic normoglycaemic clamp, an initial mean (SD) overshoot to 0.67 (0.33) mmol litre–1 was observed in the clamp group, although the AUC during this post-clamp period was not significantly different between the groups. During the clamp period, the AUC of FFA levels was 75% less in the clamp group when compared with the control group (P<0.001).
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Triglycerides
There were no significant differences in plasma TG concentrations between the two groups at baseline (Fig. 1B; n=21 for control group and n=23 for GIK group). During the clamp period, TG decreased upon early reperfusion in both groups, although all values remained in the normal range for TG (0.5–2.0 mmol litre–1). TG remained depressed during the clamp period for the clamp group, but were partially restored in the control group. The hyperinsulinaemic normoglycaemic clamp resulted in a 53% smaller AUC of plasma TG when compared with the control group (P<0.01). The AUC following the clamp period was not different between the groups.
Lipoprotein TG
The TG contained in the separate lipoprotein fractions were similar between the control and the clamp group at baseline (Fig. 2; n=12 patients per group). At early reperfusion, in the presence of heparin, TG were dramatically reduced in all lipoprotein fractions. After the inhibition of heparin during the subsequent reperfusion period, TG recovered in the control group. However, in the clamp group, TG recovery during the clamp period was inhibited. The hyperinsulinaemic normoglycaemic clamp reduced the AUC of lipoprotein-TG during the clamp period by 54% (VLDL-TG; P=0.034) and 42% (HDL-TG; P<0.001), when compared with the control group. No chances in the AUC for the LDL-TG were observed with the clamp between both groups.
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Ketone bodies
No differences at baseline for the ketone bodies acetoacetate and β-hydroxybutyrate were observed between the two groups (Fig. 3A and B). During the first 6 h of reperfusion in the control group, both acetoacetate and β-hydroxybutyrate rose two- to three-fold when compared with baseline values. However, the hyperinsulinaemic normoglycaemic clamp prevented this increase in ketone bodies during reperfusion and reduced the AUC for the ketone bodies when compared with the control group with 47% (P=0.012) and 44% (P=0.011) for acetoacetate and β-hydroxybutyrate, respectively. Discontinuation of the clamp resulted in similar AUCs for both groups for each ketone body.
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Lactate
The mean (SD) plasma lactate concentration (Fig. 4) at baseline was 0.70 (0.29) mmol litre–1 for the control group and 0.79 (0.29) mmol litre–1 for the clamp group (not significant). After the by-pass operation, lactate levels were significantly elevated compared with baseline for both groups throughout the remainder of the observation period. Although there was a trend towards higher lactate levels at early reperfusion for the clamp group, the AUC for lactate during and after the clamp period was not different between both groups.
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Discussion |
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The use of GIK infusion strategies has been controversial since the introduction of the classical GIK cocktail by Sodi-Pallares and colleagues19 in 1962. Reported results associated with the use of this technique in patients with acute myocardial infarction and critical illness (including CABG) range from improvement of clinical outcome in some studies8 20 21 to the absence of detectable benefit22 23 and even adverse events (mostly hypoglycaemia) in other studies.24 25 At the present time, there is no uniform explanation for the absence of a consistent effect of GIK strategies on outcome. The mechanism involved in the positive effects of GIK on post-ischaemic myocardial function has been mainly attributed to prevention or normalization of hyperglycaemia and reduction of presumably highly elevated plasma FFA levels (>1 mmol litre–1) and accelerated myocardial beta oxidation in the reperfusion period. In this context, the major findings of the present study may be summarized as follows: (i) mild hyperlipidaemia only occurred at the start of reperfusion (before heparin reversal), (ii) mild hyperglycaemia (
8 mmol litre–1) developed after the CABG procedure, (iii) a hyperinsulinaemic normoglycaemic clamp effectively prevented hyperglycaemia during, but not after the clamp, and (iv) the hyperinsulinaemic normoglycaemic clamp is associated with hypolipidaemia after the CABG procedure. We found only significant short-lived increases in FFA to 0.76 mmol litre–1 after the start of reperfusion in the control group. This is in contrast with other, mostly older, studies reporting FFA levels >>1 mmol litre–1 upon reperfusion after CABG or acute myocardial infarction.2 3 8 26 27 This discrepancy is most likely limited to FFA determinations in the presence of heparin. When no heparin is present or heparin activity is inhibited by protamine, most studies report FFA levels after CABG in the normal range of 0.4–0.7 mmol litre–1, 8 13 28 as was also found in the present study. Heparin releases LPL from the glycocalyx of the vessel wall into the lumen of the vessel. As a consequence, LPL will be present in every blood sample, resulting in ongoing lipolysis in the test tube.14 Our own pilot experiments clearly demonstrated high FFA levels of 1.6 mmol litre–1, similar to values obtained by Lazar and colleagues8 when lipolysis in the test tube was not inhibited by the use of an LPL blocker like THL.14 The increased levels (0.76 mmol litre–1) were slightly above the normal physiological range of fasting FFA levels.29 It seems therefore reasonable to conclude that long-lasting hyperlipidaemia does not occur with current clinical treatment of CABG patients, taking away one of the arguments for the use of GIK during the major part of the reperfusion period after CABG procedures. The hyperlipidaemia found during the initial period of reperfusion may argue for a restricted use of GIK therapy during this initial phase of reperfusion only.
One of the well-known adverse side-effects of the use of insulin therapy relates to the increased risk of developing temporarily periods of hypoglycaemia.30 In our previous studies, we demonstrated that severe hypoglycaemia can be prevented by separate infusions of insulin and a 30% glucose solution at variable speed.10 18 The present study demonstrates that insulin therapy results in a large reduction in the plasma FFA concentration, that is, hypolipidaemia develops. This hypolipidaemia is probably due to insulin-mediated inhibition of the hormone-sensitive lipase in adipose tissue, the determining enzyme for whole-body lipid fuel availability.31 Thus, besides the sporadic occurrence of hypoglycaemia, hypolipidaemia will almost certainly occur with hyperinsulinaemic therapy. Interestingly, the plasma FFA concentration of 0.1 mmol litre–1 found with insulin therapy in the present study is below the threshold at which there is still a net uptake of fatty acids by the heart.32 Because the concentration of substrate is a major determinant of the rate of cellular metabolism of that substrate,32 33 the 75% decrease in AUC for FFA will most likely be associated with a reduction in ATP production derived from fat metabolism.33 In addition, the 53% decrease in AUC for TG will result in further decreases in fat metabolism as TG stored in chylomicrons and VLDL also contributes significantly to fat metabolism of the heart.34 Few studies have examined the consequences of hypolipidaemia. Two recent animal studies in lipase-deficient mouse models demonstrate altered energy metabolism and cardiac dysfunction.35 36 Interestingly, Tuunanen and colleagues12 recently demonstrated in patients with chronic heart failure and in healthy controls that acute depletion of plasma FFA by the lipase inhibitor acipimox, to levels similar to those obtained in the insulin group of the present study, was associated with decreased cardiac stroke volume. Moreover, the acute depletion of FFA decreased cardiac energy efficiency (defined as LV work divided by oxidative metabolism) in the heart failure patients. These data indicate that too low levels of fat fuels in the blood may have detrimental effects on glucose and lipid homeostasis and cardiac function.
Our hyperinsulinaemic normoglycaemic clamp resulted in supraphysiological plasma insulin concentrations of 700 pmol litre–1, which is line with our previous studies.10 18 The insulin infusion rate of 0.1 IU kg–1h–1 is in the high range of rates used in other GIK studies examining acute cardiac interventions, including CABG and acute myocardial infarction. These rates range from (in U kg–1h–1) 0.05,37 0.07,8 0.08,21 to 0.126 and finally 0.15.23 38 None of these studies actually reported plasma insulin concentrations. Assuming a linear relationship between the infusion rate and the plasma concentration of insulin, all patients in these studies must have had insulin concentrations >300 pmol litre–1. This insulin concentration has been reported to result in almost total blockade of local output of FFA from adipose tissue31 and thus very low plasma FFA. It is possible that the reported diverse effects of insulin therapy on clinical outcome in these studies can partly be attributed to hypolipidaemia, when insulin administration is higher than 0.05 U kg–1h–1.
Ketone bodies were moderately increased after CABG in control patients, probably indicating insulin insensitivity and mild glucose deprivation within hepatocytes, whereas fat supply is still plentiful. The increase in ketone bodies after CABG is consistent with other reports.39 Mild ketosis is suggested to have therapeutic potential17 and the strong decrease in the concentrations of circulating ketone bodies during the hyperinsulinaemic normoglycaemic clamp may be more harmful than beneficial.
Circulating lactate levels almost doubled in the control group during prolonged reperfusion after CABG when compared with baseline, confirming data obtained by Lazar and colleagues8 in diabetic patients. However, the hyperinsulinaemic normoglycaemic clamp was not associated with altered lactate levels in the present study, opposite to the lactate-lowering effects of GIK in diabetic CABG patients.8 The prevention of decreased lactate levels in the present GIK group may be due to the fact that we examined non-diabetic patients, in whom glycolytic activity can be increased through the use of insulin with concomitant glucose administration.
In conclusion, the use of a hyperinsulinaemic normoglycaemic clamp is associated with significant changes in the plasma concentrations of a number of substrates other than glucose. Further studies are required to determine the importance of these changes.
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Netherlands Heart Foundation (2001B107 to H.B. Van W.).
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This article is accompanied by Editorial I. 
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