Departments of 1 Anaesthesia, 2 Clinical Chemistry, 3 Epidemiology and Biostatistics, 4 Intensive Care and 5 Cardiothoracic Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
* Corresponding author. E-mail: H.B.vanWezel{at}amc.uva.nl
Accepted for publication July 11, 2005.
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Abstract |
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Methods. Data obtained in 21 non-diabetic patients with normal left ventricular function scheduled for elective coronary artery surgery, who were randomly allocated to a control or GIK group, were analysed. In GIK patients, regular insulin was infused at a fixed rate of 0.1 IU kg1 h1. The infusion rate of glucose (30%) was adjusted to maintain blood glucose levels within a target range of 4.05.5 mmol litre1. Plasma concentrations of interleukins 6, 8 and 10, C-reactive protein (CRP) and serum amyloid A (SAA) were measured on the day of surgery and on the first and second postoperative days (POD1 and POD2).
Results. In the GIK group hypoglycaemia (glucose <2.2 mmol litre1) did not occur, whereas hyperglycemia (glucose >6.1 mmol litre1) developed in 15% of all measurements. In control patients, hyperglycaemia developed in >80% of all measurements in the presence of low endogenous insulin levels. CRP and SAA levels increased in both groups, with maximum levels measured on POD2. GIK treatment significantly reduced CRP and SAA levels. Interleukin levels increased significantly in both groups following cardiopulmonary bypass, but no differences were found between the groups.
Conclusion. Hyperinsulinaemic normoglycaemic clamp is an effective method of maintaining tight glycaemic control in patients undergoing CABG and it attenuates the systemic inflammatory response in these patients. This effect may partly contribute to the reported beneficial effect of glycaemic control in patients undergoing CABG.
Keywords: complications, systemic inflammatory response syndrome ; metabolism, glucose ; metabolism, hyperglycaemia ; metabolism, insulin ; surgery, cardiovascular
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Introduction |
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Recent evidence from animal studies suggests that GIK has the potential to reduce the inflammatory response.11 12 Chaudhuri and colleagues13 were the first to demonstrate the anti-inflammatory effects of insulin in patients with AMI, as reflected by a reduction in the absolute increase in post-infarct levels of C-reactive protein (CRP) and serum amyloid A (SAA). To date, anti-inflammatory effects of insulin have not been described in the setting of CABG, although these patients may theoretically benefit particularly from such an effect since CABG is known to be accompanied by a substantial systemic inflammatory response.14
Furthermore, acute hyperglycaemia frequently develops in patients undergoing CABG, usually following cardiopulmonary bypass (CPB),15 and it has been demonstrated in both rats and humans that pro-inflammatory cytokine concentrations are increased by acute hyperglycemia.16 17 We hypothesize that maintaining tight glycaemic control with insulin attenuates the systemic inflammatory response in patients undergoing CABG.
The first aim of the present study was to describe the use of a perioperative (>25 h) hyperinsulinaemic normoglycaemic clamp technique as proposed by Svedjeholm18 in 1995 and recently applied intraoperatively (<4 h) by Carvalho.19 The second goal was to quantify its effect on markers of systemic inflammation in patients with normal left ventricular function scheduled for elective CABG.
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Methods |
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A locally designed randomization programme was used to allocate patients to a control group or a GIK group. Patients in the control group received standard institutional perioperative care. Patients allocated to the GIK group received additional infusions of insulin and glucose.
Insulin and glucose infusions
After insertion of a central venous catheter and baseline blood sampling, hyperinsulinaemic normoglycaemic clamping was started and continued throughout the period of CPB until 24 h after release of the aortic cross-clamp. Soluble insulin (Actrapid, NovoNordisk, Copenhagen, Denmark) was infused continuously at a fixed rate of 0.1 IU·kg1·h1.
A separate mixture of glucose 30% (Baxter-Clintec Benelux SA, Brussels, Belgium), potassium chloride 80 mmol litre1 and phosphate 60 mmol litre1 was infused at a variable rate adjusted to maintain blood glucose levels within a target range of 4.05.5 mmol litre1. This rather narrow range was used to create a buffer in case of unexpected overshoot hypoglycaemia or hyperglycaemia during the clamping period. A wider range of blood glucose levels between 2.2 and 6.1 mmol litre1 was considered normoglycaemic as described by Van den Berghe and colleagues.2
The infusion of glucose was started at a rate of 0.5 ml·kg1·h1. In all patients the first glucose samples were taken 15 and 30 min after the start of the glucose and insulin infusions in order to obtain the initial direction and degree of change of plasma glucose levels under hyperinsulinaemic conditions. Adjustments to the glucose 30% infusion rate were made as follows.
When plasma glucose was <3.0 mmol litre1 the infusion rate of glucose 30% was increased by 10 ml h1 and one or more additional 10 ml boluses of glucose 30% were administered, depending on the absolute value of plasma glucose. Plasma glucose levels were checked 515 min later. If required, the infusion rate of glucose 30% was increased again by 510 ml h1.
When plasma glucose was between 3.0 and 4.0 mmol litre1, the infusion rate of glucose 30% was increased by 510 ml h1. The plasma glucose concentration was checked 1530 min later.
When plasma glucose was within the target range of 4.05.5 mmol litre1 the infusion rate of glucose 30% remained unchanged, unless there was a difference of >0.5 mmol litre1 in the plasma glucose level compared with the previous measurement. In such a situation the glucose infusion rate was increased or decreased by 510 ml h1. Plasma glucose levels were checked 60120 min later.
When plasma glucose was >5.5 mmol litre1 the infusion rate of glucose 30% was reduced by 510 ml h1. Plasma glucose levels were checked 60120 min later.
Anaesthetic management
Calcium-channel blockers and long-acting nitrates were given until the evening before surgery, and ß-adrenoceptor blocking agents were continued until the morning of surgery. Lorazepam 23 mg was given as premedication 2 h before surgery.
Anaesthesia was induced with sufentanil 3 µg kg1 (Sufenta®, Janssen-Cilag, Tilburg, The Netherlands) and propofol 50100 mg (Fresenius Kabi, Den Bosch, The Netherlands). Pancuronium bromide 0.1 mg kg1 (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 25 mg·kg1·h1. The lungs were ventilated with airoxygen (). Dexamethasone and
2-adrenoceptor agonists were not used in any of the participating patients. After induction of anaesthesia, a flow-directed pulmonary artery catheter (Edwards Lifesciences, Irvine, CA, USA) was inserted into the right internal jugular vein.
Cardiopulmonary bypass
The CPB system was primed with 1850 ml of priming liquid consisting of Haemaccel 1000 ml (Behring, Malburg, Germany), Ringer's lactate 500 ml, aprotinin 200 ml (Bayer, Leverkusen, Germany), mannitol 20% solution 100 ml and sodium bicarbonate 8.4%, 50 ml. After systemic heparinization (300 U kg1) (Leo Pharmaceutical Products, Weesp, The Netherlands), CPB was initiated with cannulas placed in the ascending aorta and right atrium. Activated clotting time was kept >480 s. The non-pulsatile flow rate was maintained at 2.4 litre min1 m2 during the cooling and rewarming phases. At a temperature of 3032°C flow rate was kept at 2.2 litre min1 m2. For myocardial protection, patients received high-potassium cold crystalloid cardioplegia (1000 ml) (St Thomas type II containing potassium 20 mmol, calcium 2 mmol, magnesium 16 mmol, chloride 203 mmol and procaine hydrochloride 273 mg, given at a temperature of 4°C) during aortic cross-clamping. The haematocrit during CPB was maintained >20%. After termination of CPB, heparin was antagonized with protamine hydrochloride (ICN Pharmaceuticals Holland B.V.) at a ratio of 1:1. Residual volume from the extracorporeal circuit was infused into the patient after a cell-saving process.
After surgery, patients were admitted to the intensive care unit (ICU) and treated according to a standardized clinical protocol. Fluid administration consisted of NaCl 0.9% and hydroxyethyl starch 6% of molecular weight 200 kDa (Haes-Steril, Fresenius Kabi, Den Bosch, The Netherlands). Throughout the ICU stay, a continuous infusion of glucose 5% was given at a rate of 30 ml h1 (1.5 g h1) to all patients through a central venous line. All patients in both groups stayed for a relatively long period in the ICU as a result of the study design, i.e. continuation of hyperinsulinaemic normoglycaemic clamping for 24 h in the reperfusion period.
Blood samples and measurement points
Samples in the operating room and ICU were taken from the radial artery catheter. Blood samples taken on the ward were collected by venipuncture. Insulin and glucose samples were collected at the following predetermined time points: (1) before induction of anaesthesia (awake); (2) after insertion of the pulmonary artery catheter, but before the start of clamping (baseline); (3) 15 min before CPB, before heparinization (before CPB); (4) immediately after release of the aortic cross-clamp ( reperfusion); (5) 2 h after release of the aortic cross-clamp (2 h reperfusion); (6) on the day of surgery (DOS) between 6 and 8 pm; (710) on the first and second postoperative days (POD1 and POD2) in the morning between 6 and 8 a.m. and in the evening between 6 and 8 p.m. (POD1 68 a.m., POD1 68 p.m., POD2 68 a.m. and POD2 68 p.m., respectively). Blood for CRP and SAA measurements was collected at baseline and at time points 410. Cytokines were measured at baseline and at 2 h after reperfusion, on the DOS between 6 and 8 p.m. and on POD1 between 6 and 8 a.m.
Cardiac enzymes (CK-MB) were sampled on arrival in the ICU and every 3 h thereafter until it was clear that levels were past the peak level.
CRP levels were measured using an immunoturbidimetric assay. The detection limit of the assay was 0.1 mg litre1. SAA levels were measured using an N-latex-SAA testkit (DADE Behring, Leusden, The Netherlands) and a ProSpec nephelometer (DADE Behring, Leusden, The Netherlands). The detection level of the assay was 0.695 mg litre1. Blood samples for interleukin (IL) measurements were centrifuged at 1500 rpm for 15 min and then stored in aliquots at 80°C until required for further analysis. IL-6, IL-8 and IL-10 were measured by sandwich ELISA using a commercially available kit (BD Biosciences, The Netherlands).
Insulin was determined by a luminescence enzyme immunoassay (Immulite, Diagnostic Products Corporation, Los Angeles, CA). The intra- and interassay coefficients of variation were 35% and 69%, respectively. The detection limit was 2 mU litre1.
The following postoperative data were obtained to estimate the presence and degree of a systemic inflammatory response syndrome (SIRS): leucocyte count measured once daily, starting preoperatively until POD5; heart rate measured from the start of reperfusion until POD5; body temperature measured from the start of reperfusion until POD5; ventilatory frequency measured hourly starting before extubation until 5 h after extubation.
Statistical analysis
Demographic data were reported as mean (SD) for continuous variables in the case of an approximately normal distribution, median (IQR) for non-normal distributed variables and as counts (proportions) for categorical variables. Two-way analyses of variance (ANOVA), by treatment group and time, for repeated measurements were performed on the outcome parameters. The main model assumption (homogeneity of error variances) was tested by Levene's test, and the same analysis was performed on rank-order-transformed variables if necessary. When a significant main effect between treatment groups was found (P<0.05), means at subsequent time points (with Bonferroni correction) were compared between treatment groups. A t-test was performed to analyse differences in areas under the curve (AUCs) for CRP and SAA. Data analyses were performed with SPSS 11.5. P-values <0.05 were considered statistically significant.
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Results |
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The characteristics of the remaining 21 patients are summarized in Table 1. Patients were comparable with respect to age, weight and BMI, extent of coronary artery disease and preoperative medication. An overview of perioperative characteristics is given in Table 2. Table 3 gives an overview of fluid administration, output and balance in the operating room and in the ICU on the DOS and in the ICU on POD1.
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In the GIK group, normoglycaemia was achieved at all predetermined measurement points during the clamp period, except for levels taken before CPB (i.e. after the start of the clamp procedure). After discontinuation of the hyperinsulinaemic normoglycaemic clamp, glucose concentrations increased significantly above baseline to levels in the range of 8 mmol litre1, which was similar to those found in the control group (Fig. 1B).
The scattergram shown in Figure 2 gives an overview of all glucose measurements in both groups. Hypoglycaemia (<2.2 mmol litre1) did not occur at any time in either group. Hyperglycaemia (>6.1 mmol litre1) occurred in 15% of all measurements in the GIK group and in >80% of all measurements in the control group.
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In the GIK group, mean serum potassium levels also remained within the normokalaemic range before and during GIK infusion. However, after discontinuation of the GIK infusions, hyperkalaemia developed in the GIK group on POD1 in the evening (mean serum potassium 4.6 mmol litre1, range 4.15.9 mmol litre1) and on POD2 in the morning (mean serum potassium 4.6 mmol litre1, range 4.15.2 mmol litre1). This was not associated with cardiac arrhythmias.
Cytokines
Table 4 summarizes the data obtained from the cytokine measurements. CABG was associated with significantly increased levels of both IL-6 and IL-8 after cardiopulmonary bypass compared with baseline. Although a trend towards lower IL-6 and IL-8 levels in the GIK compared with the control group was observed, this did not reach statistical significance.
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Serum amyloid A
Figure 4 shows data for SAA. Baseline levels of SAA were 1.8 (1.0) mg litre1 and 1.4 (1.2) mg litre1 for the control and GIK groups, respectively. In both groups, SAA levels started to rise following reperfusion and maximum levels were measured on the evening of the POD2. Compared with control patients, overall SAA levels were lower in GIK patients (P=0.028). In the morning of POD 1 the mean (SEM) SAA values were significantly (P<0.05) reduced in the insulin group compared with the control group (179 (7) mg litre1 compared with 295 (18) mg litre1, respectively). In the evening of POD1 the mean (SEM) SAA levels were also significantly (P<0.05) reduced in the insulin group compared with the control group (431 (39) mg litre1 versus 675 (36) mg litre1, respectively).
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Clinical parameters reflecting the presence and degree of SIRS
Of the parameters analysed to estimate the potential presence and degree of SIRS, only the leucocyte count was significantly lower (P=0.01) in the GIK group on the evening of the day of surgery (5.2 (0.3) leucocytes ml1 compared with 12.1 (4.4) leucocytes ml1 in the GIK group and the control group, respectively).
There were no additional significant differences in leucocyte count or in any of the other analysed indicators of the presence and degree of SIRS (heart rate, body temperature or ventilatory frequency) between the groups at any time during the study.
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Discussion |
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Although GIK infusions have been applied in the setting of cardiac surgery and AMI for several decades, there is still no standardized protocol available. In contrast with the widely used GIK cocktail technique, where GIK is administered as one mixture with a fixed composition and infused at a set rate, hyperinsulinaemic normoglycaemic clamping allows for adjustments in the infusion rate of glucose in response to changes in perioperative systemic insulin sensitivity and endogenous insulin and glucose production. Studies where GIK is infused as a cocktail have been hampered by hyperglycaemic and/or hypoglycaemic episodes.20 21 In the recently published CREATE-ECLA trial it was observed that GIK administered as a cocktail resulted in higher blood glucose levels than in control patients, which may have blunted the potential benefits of insulin.22
Using a different approach, i.e. intensive insulin therapy in combination with fixed high infusion rates of glucose as partial nutritional support, Van den Berghe and colleagues2 23 reported 5.2% hypoglycemia, defined as glucose levels <2.2 mmol litre1. This seems a very low glucose value to use as the lower limit of normoglycemia (especially during routine clinical use of GIK), but it was apparently not associated with complications in the controlled study situation described.2 23 Using the criteria of van den Berghe's study we detected no hypoglycaemia in our patients receiving GIK, while hyperglycaemia (>6.1 mmol litre1) occurred in 15% of all measurements taken during the clamp period (Fig. 2). In our control group, hypoglycaemic events were not seen either, but hyperglycaemia occurred in >80% of all measurements. Possible explanations for the high incidence of hyperglycaemia (mean peak value 8.5 mmol litre1; see Fig. 1) in our control patients include the surprisingly low endogenous insulin concentrations in that group (in the presence of hyperglycaemia) and intolerance to the 5% glucose infusion (1.5 g of glucose per hour) which was started after arrival in the intensive care unit in all our patients. The latter suggestion is supported by the higher glucose levels (12 mmol litre1) found in Van den Berghe's study in ICU patients, where glucose was infused at a rate of 8 g h1, i.e. five times higher than in our study. As indicated by Mazuski and colleagues,24 this emphasizes the potential risks of parenteral nutrition with glucose without concomitant control of blood glucose levels. The importance and potential effect on outcome of this iatrogenic hyperglycaemia should be further investigated.
Several other factors may contribute to the occurrence of hyperglycaemia, such as increased hepatic glucose production due to elevated concentrations of cortisol, hepatic insulin resistance, catecholaminergic stimulation of glucose production, inhibition of insulin release by catecholamine stimulation of pancreatic receptors and inhibition of insulin release through morphine-induced opening of pancreatic K+-ATP channels, analogous to inhibition of insulin secretion by diazoxide.2527 Finally, hypothalamic insulin resistance may also play a role.2830
With regard to the systemic inflammatory responses, our data demonstrate an attenuation of inflammation with hyperinsulinaemic normoglycaemic clamping in patients undergoing CABG. The release pattern of both CRP and SAA in our control patients has been observed by others.3136 The increase in CRP and SAA over time was significantly reduced in patients receiving GIK.
The production of the acute phase proteins CRP and SAA in the liver may be partly induced by IL-6 and occurs in response to tissue injury, infection and trauma.3739 We observed no GIK effect on IL-6, whereas CRP and SAA levels were significantly depressed by GIK. Mechanistically, the observed reduction in CRP and SAA levels may result from a suppressed transcriptional induction of the IL-6 responsive acute phase plasma protein genes with insulin.40 41 Although we observed an overall reduction in inflammation parameters with GIK, this reduction was mostly demonstrated during the clamp period only. Shortly after discontinuation of the hyperinsulinaemic clamp, acute phase protein levels became indistinguishable between the two groups. This rebound pattern coincides with our reported data on glucose, and may suggest that insulin treatment should be prolonged beyond 24 h in the reperfusion period.
CRP and SAA levels are elevated following AMI.42 43 It has been found that following AMI, peak CRP levels predict infarct size and outcome44 45 and the magnitude of peak levels correlates with the occurrence of heart failure.42 However, the nature of the ischaemic challenge and the amount and extent of tissue injury are not comparable between AMI and CABG, and therefore results of studies in one patient group may not apply to the other. AMI is characterized by mild local inflammation (peak CRP levels in the range of 10 mg litre1) with a high degree of necrosis (mean top CK-MB levels in the range of 100300 µg litre1).13 In contrast, CABG is characterized by more severe systemic inflammation (peak CRP levels in the range of 200 mg litre1 (Fig. 3)) with little necrosis (mean maximum CK-MB levels in the range of 30 µg litre1). Therefore it is anticipated that the anti-inflammatory action of insulin is especially beneficial in patients with a high grade of systemic inflammation, i.e. CABG patients and patients suffering large complicated AMIs.
Studies relating acute phase protein concentrations to outcome have not been performed in patients undergoing CABG. However, it has recently been demonstrated by Bisoendial and colleagues46 that infusion of recombinant human CRP in humans leads to acute activation of inflammation as reflected by subsequent increases in IL-6, IL-8 and SAA. They concluded that CRP is not just a non-specific acute phase respondent, but rather a mediator in the inflammatory cascade and atherothrombotic disease. Therefore a reduction of CRP levels may have the potential to affect clinical outcome in AMI and CABG. In addition, the reported significant reduction in leucocyte count on the evening of surgery by GIK in the present study offers a potential indication that GIK affects leucocyte activation and the cascade of events ultimately leading to (some degree of) SIRS, which is a condition associated with severe effects on outcome.47 However, the present study was underpowered for detecting such significant effects on clinical outcome because of the small size of the groups and the selection of low-risk patients with good left ventricular function and no comorbidity who generally do not develop postoperative complications. This type of patient was deliberately selected to reduce the possible influence of confounding factors on glucose metabolism and inflammatory response, such as the prolonged postoperative use of inotropic agents and/or vasoactive compounds including norepinephrine and differences in fluid balance between the groups (dilution).
Future studies of high-risk cardiac surgical patients (who may suffer postoperative complications as a result of their inability to control the perioperative systemic inflammatory response14) should be performed to assess the effect of hyperinsulinaemic normoglycaemic clamping on perioperative inflammatory control and its hypothetical association with reduced perioperative morbidity and mortality. This is especially important as, with increasing numbers of elderly and diabetic patients, the cohort of high-risk patients will grow during the next decades. Other fields of interest that may be beneficially affected by perioperative GIK infusion include the coagulation cascade, complement activation, neurohumoral stress responses, parameters reflecting insulin resistance (ketone bodies and lactate), the lipid profile and leucocyte function.
In conclusion, this study demonstrates that in patients undergoing CABG, GIK applied as a perioperative hyperinsulinaemic normoglycaemic clamp is an effective method of maintaining tight glycaemic control, which is associated with a reduction in the increase in systemic inflammation. We hypothesize that these effects contribute to the reported beneficial influence on outcome of tight glycaemic control with insulin in the setting of CABG, AMI and critical illness.
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Acknowledgments |
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References |
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