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Eur J Cardiothorac Surg 2001;20:923-929
© 2001 Elsevier Science NL
a Department of Clinical Chemistry, Sint Antonius Hospital, Nieuwegein, The Netherlands
b Department of Cardiothoracic Surgery, Sint Antonius Hospital, Nieuwegein, The Netherlands
c Department of Anesthesiology, Sint Antonius Hospital, Nieuwegein, The Netherlands
Received 19 April 2001; received in revised form 17 July 2001; accepted 20 July 2001.
Corresponding author. Tel.: +31-30-6099111; fax: +31-30-6092528
e-mail: w.gerritsen{at}kcl-azn.demon.nl
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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Key Words: Oxidative stress • Ischemia/reperfusion injury • Cardiopulmonary bypass • Purines • Malondialdehyde • Renal function
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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Patients nowadays undergo off-pump CABG, a revival of a less adverse technique? It is well known that temporary occlusion of the coronary arteries can induce regional ischemia depending on the off-pump CABG technique that has been used. The extent of this ischemia depends on the collateral circulation [13–17].
The aim of this study was to investigate the difference in oxidative stress and the effect on renal function in off-pump versus on-pump CABG before, during and after the intervention.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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No exclusion criteria other than redo CABG and a minimum of three anastomoses had to be performed.
2.1. Anticoagulation protocol
The administration of coumarines and Ascal® were stopped 6 days preoperatively. The anticoagulation protocol was started postoperatively with 100 mg Ascal® and subcutaneous Fraxiparin® daily. Coumarines were administered for off- and on-pump CABG groups until the international normalized ratio (INR) value was between 2.5 and 3.5, after which Fraxiparin® was stopped.
2.2. Anesthetic technique
Pre-medication consisted of morphine (10 mg) and haloperidol (5 mg), given intramuscularly 1 h before arrival on the operation area. General anesthesia was induced with diazepam (0.4 mg/kg) or etomidate (0.3 mg/kg), pancuronium (0.1 mg/kg) and fentanyl (7 µg/kg). Anesthesia was maintained with nitrous oxide in oxygen and additional doses of diazepam (0.2–0.4 mg/kg per h), fentanyl (total dose, 50–100 µg/kg per h) and pancuronium (0.05–0.1 mg/kg per h). Hypertension was treated with vasodilators (nitroglycerine and nitroprusside). A mean arterial pressure of 60 mmHg or higher and a heart rate of less than 70 beats/min was maintained. Heparin was administered after median sternotomy and internal mammary dissection at 300 IE/kg for the on-pump CABG group and 150 IE/kg for the off-pump CABG group. After all anastomoses were completed, heparin was neutralized with protamine sulfate at 120 IE/150 IE heparin.
2.3. Surgical procedure
In both groups, median sternotomy and harvesting of the internal mammary artery were followed by full exposure of the coronary artery branches to be revascularized. All patients in both groups were placed in the Trendelenburg position with less than a 20° tilt. The revascularization in the off-pump CABG group was performed on the beating heart using the Medtronic Octopus device (Medtronic®, Minneapolis, MN) [5]. Temporary coronary occlusion was achieved using Acland clamps (S&T Marketing Limited, Neuhausen am Rheinfal, Switzerland), while no shunts were used. A standard CPB technique was used for the on-pump CABG group. The CPB circuit was composed of a roller pump (Sarns, USA), a hollow fiber polypropylene oxygenator with an incorporated cardiotomy reservoir (Cobe® Optima® XPTM, Cobe Cardiovascular, Inc.®, Arvada, CO) and plasticized polyvinyl chloride tubing. The pump was primed with 1.5–2 l of 50% homemade primer solution (90 mmol/l sodium chloride, 5 mmol/l potassium chloride, 1.5 mmol/l magnesium chloride, 27 mmol/l sodium acetate, 23 mmol/l sodium gluconate) and 50% Haemaccel® solution (Hoechst Marion Rousel, Switzerland). The flow rate was 2.4 l/min per m2 body surface area, and a normothermic temperature was maintained at the start of CPB. After a few minutes, the temperature was lowered to 32°C with a flow rate of 2 l/min per m2 until nearly the end of CPB, after which the temperature and flow rate were restored to the starting values. The mean blood pressure was regulated between 60 and 80 mmHg. The CO2 tension was kept, non-temperature corrected, at normal values with a pH ranging from 7.35 to 7.45 at 37°C (
-stat). The heart was protected with topical cooling, together with 1000 ml of cold cardioplegic solution based on hydroxylethyl starch (60 g/l; Fresenius AG) and containing 2 mmol/l D,L-magnesium aspartate, 4 mmol/l procain hydrochloride, 0.5 mmol/l calcium hydrochloride, 25 mmol/l sodium chloride, 5 mmol/l potassium chloride, 10 mmol/l glucose, and 200 mmol/l mannitol. The osmolarity was 320 mosm/l and the pH 7.4.
Postoperatively, patients were weaned from the ventilator as soon as possible (between 0 and 4 h for the off-pump CABG group, between 4 and 8 h for the on-pump CABG group).
2.4. Sample collection and analyses
Blood samples were obtained from a catheter in the radial artery and collected in tubes containing K3.EDTA or lithium heparin before and after coronary bypass grafting at the following moments:
2.4.1. Hypoxanthine, xanthine and malondialdehyde assay
Aliquots of urine specimens, filtered through a 0.2 µm sterile acrodisc filter (Gelman Sciences, Ann Arbor, MI), were analyzed with LKB-HPLC (Pharmacia Biotech AB, Uppsala, Sweden). The separation happens in one run on a 150x4.6 mm octadecyl silyl silica column (Supelco, Inc., Bellafonte, PA) using a gradient elution according to the method of Lazzarino [18] and modified by Gerritsen [6].
2.4.2. Other assays
Hemoglobin, hematocrit, platelets and leukocytes were determined on a Coulter STKS® (Beckman Coulter Nederland B.V., Mijdrecht, the Netherlands). Uric acid, creatinine, creatinine kinase, creatinine kinase MB-iso-enzyme, aspartate amino transferase, sodium and potassium were determined according to the manufacturer's instructions on a Cobas Integra 700 analyzer (Roche, Kayseraugst, Switzerland). The urinary indices, hypoxanthine, xanthine and malondialdehyde, are expressed as a ratio of the urinary creatinine and all urinary indices are in this way corrected for alterations in renal function
2.5. Data analysis and statistical considerations
All data for continuous variables with a normal distribution are presented as means±standard deviations (SD). Significant changes within groups (P<0.05) were determined by the Wilcoxon signed rank test. Comparisons between groups were carried out using the Mann–Whitney test or Fisher's Exact test where appropriate. All analyses were performed with SPSS software version 9.0.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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In the two study groups, no hospital mortality, no neurological accidents, incidences of myocardial infarction or acute renal failure occurred.
3.2. Measurements in blood
3.2.1. Creatinine
The mean creatinine plasma concentrations as markers of renal function are shown in Table 3. Preoperatively, there was a significant difference in the mean creatinine concentration between the off-pump CABG group and on-pump CABG group (P=0.017). Even without the data of the two patients who suffered renal dysfunction, there was still a significant difference in the mean creatinine concentration between the off-pump CABG group and on-pump CABG group (P=0.047). For both groups of patients, the mean creatinine concentrations differed significantly from the mean preoperative concentration during the entire study period, except for the concentrations measured at time-points T4 and T6 for the on-pump CABG group which remained constant compared with preoperative values.
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3.3. Urine output/period
The mean urine output over the total collecting time was 3844±1144 ml/48 h for the off-pump CABG group which was nearly identical to 4073±993 ml/48 h for the on-pump group. For the off-pump CABG group, the mean urine output of 1457±476 ml/24 h before surgery was significantly lower than the mean urine output during and after the surgery of 2261±805 ml/24 h (P<0.001). The mean 24 h urine output for the on-pump CABG group was significantly lower before surgery at 1569±502 ml than the mean 24 h output during and after surgery at 2473±837 ml (P<0.001). The mean urine output/period shown in Table 3 of the on-pump CABG group during surgery increased significantly compared with the mean urine output/period of the off-pump group during surgery (P=0.007).
3.4. Measurements in urine
3.4.1. Creatinine
The mean urinary creatinine concentrations shown in Table 3 were significantly decreased for the on-pump CABG group during the operation room time (P<0.001), followed by a gradual significant increase 9 h postoperatively (P<0.001), after which the mean creatinine concentration slightly decreased to just below the mean preoperative concentration. The mean urinary creatinine concentration of the off-pump CABG group had small, non-significant fluctuation during surgery compared with the mean preoperative concentration. At time-point T4, the urinary creatinine concentration decreased significantly (P=0.002), after which it remained constant during the next time-point T6 (P=0.050).
The mean total urinary creatinine concentration over the total collecting time for the off-pump CABG group (23.38±6.68 mmol/48 h) was comparable with that of the on-pump CABG group (21.34±6.29 mmol/48 h). The mean urinary creatinine for the off-pump CABG group increased from 10.61±1.17 before surgery to 12.49±4.32 mmol/24 h during and after surgery. The increase of the mean total urinary creatinine concentration for the on-pump CABG group was also slight from 10.32±0.81 to 11.15±3.91 mmol/24 h during and after surgery. The mean total urinary creatinine concentration shown in Table 3 of the on-pump CABG group during surgery decreased significantly compared with the mean total urinary creatinine concentration of the off-pump group during surgery (P=0.019).
3.4.2. Uric acid
As shown in Table 3, the profile of the mean urinary uric acid concentrations for both groups were identical compared with the profile of the mean urinary creatinine concentrations.
3.4.3. Hypoxanthine
The mean preoperative hypoxanthine-creatinine ratios were similar for both groups. At arrival to the ICU, the mean hypoxanthine-creatinine ratio (11.9±5.8 mmol/mol creatinine) was significantly higher in the on-pump CABG group with respect to the off-pump CABG group (4.7±3.2 mmol/mol creatinine; P<0.001). During the next period, the mean hypoxanthine-creatinine ratios for the on-pump CABG group decreased to 10.4±6.7 mmol/mol creatinine after a 9 h stay at the ICU and to 9.2±7.6 mmol/mol creatinine after 20 h at ICU. However, both time-points still remained significantly elevated with respect to the mean preoperative ratio (P<0.001 for both time-points). On the contrary, the mean hypoxanthine-creatinine ratio in the off-pump CABG group still increased significantly during the first 9 h of stay at the ICU to 7.0±5.8 mmol/mol creatinine (P<0.001), after which the ratio decreased significantly to 6.0±5.4 mmol/mol creatinine at 20 h in the ICU (P=0.003). Nevertheless, all mean hypoxanthine-creatinine ratios in the on-pump CABG group were much more increased than the mean hypoxanthine-creatinine ratios from the off-pump CABG group (Fig. 1a).
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3.4.5. Malondialdehyde
During the operation room time, the mean malondialdehyde-creatinine ratio was significantly elevated in the on-pump CABG group from 0.21±0.09 preoperatively to 0.57±0.31 mmol/mol creatinine at arrival to the ICU (P<0.001). This strong significant increase was prolonged until 9 h of ICU stay (0.61±0.49 mmol/mol creatinine), after which the malondialdehyde-creatinine ratio significantly decreased to 0.32±0.13 mmol/mol creatinine at 20 h of stay at the ICU (P=0.040). In the off-pump CABG group, the mean malondialdehyde-creatinine ratio increased significantly and reached the highest level 9 h postoperatively at 0.29±0.26 mmol/mol creatinine (P=0.011). During the following period, the mean malondialdehyde-creatinine ratio decreased to 0.24±0.13 mmol/mol creatinine, however, the ratio still remained significantly higher than the preoperative value (P=0.014). During all time-points, the mean malondialdehyde-creatinine ratio was lower, with significance for time-points T2 and T4, for the off-pump CABG group compared with the on-pump CABG group (P<0.001 and P=0.004, respectively; Fig. 1c).
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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In this study, we tried to demonstrate differences in ischemia/reperfusion, oxidative stress and renal function parameters between the two patient groups undergoing off- and on-pump CABG.
In a previous study, we demonstrated that hypoxanthine, xanthine, uric acid and malondialdehyde in urine are good parameters for ischemia–reperfusion and oxidative stress damage in patients undergoing on-pump CABG surgery [6]. That study was based on the assumption that the clearance of small molecules, such as creatinine and malondialdehyde, is comparable because they are filtered only by the glomerulus (passive filtration), whereas for uric acid and probably purine filtration, tubular reabsorption and tubular secretion are evident. In order to correct and normalize the indices for renal function, hypoxanthine, xanthine and malondialdehyde are expressed as a ratio of the urinary creatinine [6].
As a result of ischemia, we found a significant increase of hypoxanthine and xanthine ratios in both groups. Although there is a trend for lower ratios of ischemia markers in the off-pump group, a certain level of ischemia was still present during and after surgery. This ischemia can be explained by several factors. First, in our series, in the off-pump CABG, we used temporary occlusion of coronary branches in order to create a dry field which is needed to perform an adequate anastomoses. During coronary occlusion, regional myocardial ischemia can occur. Second, there still remains some extent of embolic load generated by clamping of the aorta and infusions. Third, the effect of the Trendelenburg position on distal perfusion to abdominal organs is unknown, but can be of importance. Finally, tilting of the heart can induce hemodynamic deterioration and subsequent hypoperfusion.
Concerning renal function for the on-pump CABG group, as was also found in previous studies, there was a decrease in renal function during surgery, as measured by the creatinine concentration [3]. The total urine output over the collecting periods before and after surgery was identical for the on- and off-pump CABG groups. For the off-pump CABG group, we found an undisturbed constant renal function during off-pump CABG. These findings confirmed an expected better renal function under more physiological circumstances. The constant renal function in patients with preexisting renal dysfunction operated off-pump is an especially encouraging result. Normally, we expect a deterioration of renal function in these patients when operated on-pump. As described above, inflammatory response and embolic load might be two important factors that differ very clearly between both operation techniques. Moreover, each of these two factors can give rise to ischemia and oxidative stress independently [5,20]. When these differences are significant in both techniques, one would expect that we could measure this using our routine markers for ischemia and oxidative stress. Moreover, when differences between techniques are considerable, this might also have some impact on perioperative renal function.
For the lipid peroxidation parameter, malondialdehyde, as a result of oxidative stress, we found a significant difference in the extent comparing off-pump versus on-pump CABG. The maximum increase of the malondialdehyde-creatinine ratio for both groups was reached 5 h postoperatively, after which the mean malondialdehyde-creatinine ratio decreased but still remained significantly elevated with respect to the preoperative ratio. At all sampling time-points, the malondialdehyde-creatinine ratio was lower for the off-pump CABG group compared with the on-pump CABG group.
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5. Conclusions |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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Acknowledgments |
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Footnotes |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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