Malondialdehyde in plasma, a biomarker of global oxidative stress during mini-CABG compared to on- and off-pump CABG surgery: a pilot study
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《血管的通路杂志》
a Department of Clinical Chemistry, Sint Antonius Hospital, Koekoekslaan 1, P.O. Box 2500, 3430 EM Nieuwegein, The Netherlands
b Cardiothoracic Surgery, Sint Antonius Hospital, Nieuwegein, The Netherlands
c Anesthesiology, Sint Antonius Hospital, Nieuwegein, The Netherlands
d Department of Anaesthesia, University Medical Center Groningen, Groningen, The Netherlands
Abstract
In contrast to conventional on-pump coronary artery bypass grafting only mild increase of parameters of oxidative stress is reported during and after off-pump coronary artery bypass grafting. In an attempt to reduce the side effects of extra corporeal circulation the mini- extra corporeal circulation concept was introduced. In this study peroperative oxidative stress biomarkers were compared using three different techniques for CABG (conventional, mini and off-pump). It concerns a prospective randomized pilot study of 60 aged patients (70+ years) divided over 3 study groups. During the peroperative time points there was a significant increase in the mean concentration of uric acid for the CCABG group. On arrival at the intensive care unit the mean concentrations decreased significantly. During the per-operative period all groups showed significant increase in the concentration of malondialdehyde, however, this increase was the steepest for the CCABG group. On arrival at the intensive care unit the mean concentration decreased significantly for all groups. We found only mild organ ischemia/reperfusion injury and oxidative stress in the OPCAB group and the MCABG group with respect to the CCABG group.
Key Words: Off-pump; CABG, Mini-CABG; Oxidative stress; Malondialdehyde; Uric acid
1. Introduction
Despite improvements in surgical techniques, anaesthesia and postoperative care, cardiac surgery with the use of extra corporeal circulation (ECC) is associated with oxidative stress [1,2].
Insufficient per and postoperative circulation resulting from systemic inflammatory response and emboli are mentioned as significant causes of this phenomenon [3]. Furthermore, the use of cardioplegic arrest can also result in myocardial dysfunction resulting in hypoperfusion [4]. Morbidity associated with these mechanisms may involve multiple organs, such as the heart, brain, lung, kidney, or gastro-intestinal tract [5].
Measurements of parameters for oxidative stress are a well-accepted technique to express the extent of cell damage [1]. Their involvement is known to be substantial when the on-pump technique is used [1,5]. Although the heart is protected against ischemia during on-pump CABG, a certain level of ischemia still occurs.
Off-pump coronary artery bypass grafting has become a well-accepted and safe technique [6]. Short-term and mid-term angiography follow-up studies show comparable results to the conventional technique [6]. Oxidative stress studies show a significant reduction of MDA-levels during off-pump surgery compared to the conventional technique [1,2].
There are only few data showing oxidative stress in elective on- and off-pump CABG in a prospective set-up [1,3].
The aim of this pilot study was to compare the per-operative component of ischemia/reperfusion injury by means of uric acid and oxidative stress by means of lipid peroxidation e.g. malondialdehyde, during on- and off-pump CABG techniques.
2. Materials and methods
Sixty patients aged 70 years and older, 38 men and 22 women undergoing elective coronary bypass surgery were consecutively enrolled in a prospective observational setting. In this study, 20 patients were operated off-pump (OPCAB group), 20 patients using the Mini-ECC (MCABG group) and 20 patients using conventional CABG (CCABG group). No exclusion criteria other than redo of CABG and a minimum of three anastomoses were defined.
The Medical Ethical Committee of the Sint Antonius Hospital approved the protocol.
2.1. Anticoagulation protocol
The administration of coumarines and carbasalate calcium were stopped 6 days preoperatively. The anticoagulation protocol started per-operatively with subcutaneous low molecular heparins (LMWHs) daily. Eight hundred mg of acetyl salicylic acid was administered at the end of the procedure. Coumarines and LMWHs 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 LMWHs were stopped.
2.2. Anaesthetic technique
Pre-medication consisted of temazepam (10 mg), given orally 2–3 h before the procedure started. Anaesthesia consisted of a balanced opiate-based general anaesthesia technique. Induction took place by means of infusion of propofol (1.5–2 mg kg–1), pancuronium (0.1 mg kg–1) and fentanyl (7 μg kg–1). Anaesthesia was maintained with nitrous oxide in oxygen and continuous propofol infusion (10–20 ml h–1), remifentanyl (0.25–1 μg kg–1) and pancuronium as required. Hypertension was treated with vasodilators (nitro-glycerine and nitroprusside). A mean arterial pressure of 60 mmHg or higher and a heart rate less than 70 beats per minute was maintained. Heparin was administered at 300 IU kg–1 for the on-pump CABG group and 150 IU kg–1 for the off-pump CABG group. After all anastomoses were completed, heparin was neutralised with protamine chloride 120 IU/150 IU.
All patients received standardized post-operative care. Propofol was stopped and tracheal extubation is accomplished when the patient was hemodynamic stable, responsive and cooperative, FiO2, 50%, PaO2>11 kPa, pH>7.3, core temperature >36 °C and without excessive chest tube drainage. Postoperative pain relief was achieved with intravenous morphine (0.5 mg kg–1 h–1) and paracetamol, 1000 mg administered rectally three times daily.
2.3. Perfusion technique CCABG
The ECC circuit was composed of a roller pump (Sarns, USA), a hollow fibre polypropylene oxygenator with an incorporated cardiotomy reservoir (Cobe Optima XP TM, Cobe Cardiovascular Inc, Arvada, USA) and plasticized polyvinyl chloride tubing. The pump was primed with 1.5–2 l of 50% homemade primer solution. The heart was protected with topical cooling, together with 1000 ml of cold cardioplegic solution based on hydroxy-ethyl starch (HES: 60 g/l; Fresenius AG) and containing 2 mmol/l D, L-magnesium aspartate, 4 mmol l–1 procaine hydrochloride, 0.5 mmol l–1 calcium hydrochloride, 25 mmol l–1 sodium chloride, 5 mmol l–1 potassium chloride, 10 mmol l–1 glucose and 200 mmol l–1 mannitol with an osmolarity of 320 mOsm l–1, pH 7.4.
2.4. Perfusion technique MCABG
The MECC system consisted of a closed system, containing a Rotaflow centrifugal pump (Jostra, Germany) and a Quadrox membrane oxygenator (Jostra, Germany). Via short tubings, the venous line was directly connected to a centrifugal pump, which passes the oxygenator and, via the arterial line, returned to the patient. All components were from tip to tip Bioline coated (Jostra, Germany). Priming volume of the system was 500 ml of sodium chloride 0.9% (this solution contents 14.4% HES). Depending on the patient's hemostability the amount of prime will be returned to zero by starting MECC. When MECC starts, the nasopharyngeal temperature will be maintained at 33–34 °C. Acid-base management during mild hypothermia was monitored with alpha-stat and the cardiac index was kept between 2.0 and 2.4 l min–1 m–2. Blood from the surgical field was collected in a cell-saving device (Cobe BRAT 2).
Preservation of the heart was performed with a modified Calafiore-technique (warm blood cardioplegia with 30 ml potassium chloride 2 mol l–1 and 6 ml magnesium sulfoxide 1 mol l–1).
2.5. Surgical procedure
In the groups, median sternotomy and harvesting of the internal mammary artery were followed by full exposure of the coronary artery branches to be revascularised. All patients in the groups were placed in the Trendelenburg position less than 20° tilt. The revascularisation in the OPCAB group was performed on the beating heart using the Medtronic Octopus device (Medtronic, Minneapolis, USA) [7]. Temporary coronary occlusion was achieved using Acland clamps (S&T Marketing Limited, Neuhausen am Rheinfal, Swiss), while no shunts were used. For the MCABG and CCABG groups standard cannulation with a DLP (Medtronic, Minneapolis, USA) arterial canula in the ascending aorta and a DLP two stage canula in the right atrium. Postoperatively, patients were weaned from the ventilator as soon as possible (between 0 and 4 h for the OPCAB group, and between 4 and 8 h for the MCABG and CCABG groups).
2.6. Sample collection
Samples were obtained from the radial artery (RA) before, during and after coronary artery bypass grafting for patients undergoing MCABG, CCABG group/OPCAB group at the following time points: just after induction of anaesthesia, just before start of ECC/just before clamping of the first grafted artery, 10 min after removal of the cross clamp on the aorta/of the last grafted artery, and at arrival at ICU.
3. Assays
3.1. Uric acid and malondialdehyde
The separation is in one run on a 150x4.6 mm octadecyl silyl silica column (Supelco Inc, Bellafonte, PA, USA) using a gradient elution according to the method of Gerritsen [1]. All results were corrected for hemodilution according to the method described by Beaumont [8].
3.2. Data analysis and statistical considerations
Data analyses were performed using SPSS software version 12.0. Results were reported as mean±standard deviation (S.D.). Comparisons between groups (pre-operative and surgical data) were carried out using the Fisher's Exact tests or chi-square test, if appropriate. An outlier test was used to determine outliers. Comparisons within groups were made using repeated measures using ANOVA or the Student's t-test for the same time points between groups. A P-value less than 0.05 was considered as significant.
4. Results
4.1. Patients
The preoperative clinical and surgical data are presented in Tables 1 and 2, respectively. The preoperative clinical data showed no significance between the groups with respect to gender, age, severity of coronary disease, diabetes mellitus, New York Heart Association functional class, left ventricle function and extent of vessel disease. There was significance for COPD (P<0.05). Preoperative laboratory analysis revealed no patients with renal dysfunction (defined as having plasma levels of 120 μmol/l). For the surgical data, there was a significant difference in the amount of grafts per patient (P=0.003). In the study groups, no hospital mortality, no neurological accidents, incidences of myocardial infarction or acute renal failure occurred.
4.2. Uric acid
After induction of anaesthesia until 10 min after reperfusion in all groups the mean concentration of uric acid increased. On arrival at the intensive care unit the mean concentrations decreased for all groups. The mean concentration of the CCABG group at the time point ‘10 min after reperfusion’ was significantly higher (P=0.005) with respect to the OPCAB group.
Between all consecutive time points in the CCABG group, there was significance (P=0.023, 0.005 and 0.002; Fig. 1, Table 3). All values of the MCABG group were slightly increased compared to the OPCAB group.
4.3. Malondialdehyde
In the CCABG group two outliers were removed. The mean concentration of malondialdehyde increased significantly for all groups after induction of anaesthesia until 10 min after reperfusion. On arrival at the intensive care unit, the mean concentrations decreased significantly for all groups (Fig. 2, Table 3). The time points before clamping of the first artery/start ECC and 10 min after reperfusion were significantly higher for the CCABG group compared to the OPCAB group (P=0.011 and P=0.021).
At all time points, the mean values were slightly increased in the MECC group compared to the OPCAB group.
5. Discussion
In this study, we showed significant differences in the lipid peroxidation parameter MDA between the groups investigated in favour of OPCAB surgery. As we found in a previous study, parameters of oxidative stress are significantly increased during and after CABG with the use of ECC [1]. Recent studies concerning patients operated off-pump have reported a reduction in inflammatory reaction [9]. Furthermore, it was found by our group, as well as by others, that avoiding the use of ECC significantly reduces oxidative stress [1]. In the present study, we evaluated global oxidative stress by means of MDA and ischemia/reperfusion injury by means of uric acid in peripheral blood before, during and after surgery in patients who underwent on- and off-pump surgery in a prospective observational setting.
Uric acid is produced during the xanthine oxido-reductase pathway. Its concentration will increase during ischemia/reperfusion injury [10,11]. In a recent study uric acid appeared to be an independent predictor of mortality in patients with angiographically proven coronary artery disease [10]. Increased levels of uric acid have been found in a variety of diseases, from myocardial ischemia [12] to meningitis [13]. Uric acid acts as an anti-oxidant and is well known as a contributive factor in measuring the anti-oxidant capacity of body fluids like plasma and cerebrospinal fluid [11]. In this study, in all groups, there was a peroperative increase for uric acid. However, for the CCABG group this increase was significant. We can conclude that the intensity of oxidative stress is most outspoken in this group.
As a consequence of oxidative stress lipid peroxidation can occur. One of the end products of lipid peroxidation, malondialdehyde (MDA), was increased in all groups compared to baseline levels. Concentrations of MDA were significantly lower in the OPCAB group at all time points. This difference indicates that organs are more extensively exposed to lipid peroxidation when the on-pump technique is applied. We found that malondialdehyde significantly increases peri-operatively for all groups. This significant increase in concentration was the mildest for the OPCAB and the MCABG group, compared to the CCABG group.
Despite this difference in lipid peroxidation there was no difference in clinical outcome observed between the patient groups because our patient group was too small. Recently, Sellke et al. confirmed our findings that to definitely answer the remaining question of whether either strategy is superior, and in which patients, a large-scale prospective randomized trial is required [14].
Because of the organ protective effect of the mini-CABG we expect a growing importance in the near future.
6. Conclusion
Despite the fact that this pilot study only concerns a small patient group comparison, oxidative stress parameters showed a consistent pattern. The results indicate significant differences in organ production of the lipid peroxidation product malondialdehyde in favour of the OPCAB group. We found only mild oxidative stress and ischemia/reperfusion injury in the OPCAB group and the MCABG group compared to the CCABG group.
References
Gerritsen WB, van Boven WJ, Driessen AH, Haas FJ, Aarts LP. Off-pump vs. on-pump coronary artery bypass grafting: oxidative stress and renal function. Eur J Cardiothorac Surg 2001; 20:5923–939.
Matata BM, Sosnowski AW, Galinanes M. Off-pump bypass graft operation significantly reduces oxidative stress and inflammation. Ann Thorac Surg 2000; 69:3785–791.
Wan S, Izzat MB, Lee TW, Wan IY, Tang NL, Yim AP. Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999; 68:152–56.
Buckberg GD. Update on current techniques of myocardial protection. Ann Thorac Surg 1995; 60:3805–814.
Ascione R, Lloyd CT, Underwood MJ, Gomes WJ, Angelini GD. On-pump vs. off-pump coronary revascularization: evaluation of renal function. Ann Thorac Surg 1999; 68:2493–498.
Puskas JD, Thourani VH, Marshall JJ, Dempsey SJ, Steiner MA, Sammons BH, Brown WM, Gott JP, Weintraub WS, Guyton RA. Clinical outcomes, angiographic patency, and resource utilization in 200 consecutive off-pump coronary bypass patients. Ann Thorac Surg 2001; 71:51477–1483.
Jansen EW, Lahpor JR, Borst C, Grundeman PF, Bredee JJ. Off-pump coronary bypass grafting: how to use the Octopus tissue stabilizer. Ann Thorac Surg 1998; 66:2576–579.
Beaumont van W. Evaluation of hemoconcentration from hematocrit measurements. J Appl Physiol 1972; 32:5712–713.
Czerny M, Baumer H, Kilo J, Lassnigg A, Hamwi A, Vukovich T, Wolner E, Grimm M. Inflammatory response and myocardial injury following coronary artery bypass grafting with or without cardiopulmonary bypass. Eur J Cardiothorac Surg 2000; 17:6737–742.
Bickel C, Rupprecht HJ, Blankenberg S, Rippin G, Hafner G, Daunhauer A, Hofmann KP, Meyer J. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 2002; 89:112–17.
Benzie IF, Chung W, Tomlinson B. Simultaneous measurement of allantoin and urate in plasma: analytical evaluation and potential clinical application in oxidant: antioxidant balance studies. Clin Chem 1999; 45:6 Pt 1901–904.
Miller NJ, Johnston JD, Collis CS, Rice-Evans C. Serum total antioxidant activity after myocardial infarction. Ann Clin Biochem 1997; 34:Pt 185–90.
Kastenbauer S, Koedel U, Becker BF, Pfister HW. Oxidative stress in bacterial meningitis in humans. Neurology 2002; 58:2186–191.
Sellke FW, DiMaio JM, Caplan LR, Ferguson TB, Gardner TJ, Hiratzka LF, Isselbacher EM, Lytle BW, Mack MJ, Murkin JM, Robbins RC. Comparing on-pump and off-pump coronary artery bypass grafting: numerous studies but few conclusions: a scientific statement from the American Heart Association council on cardiovascular surgery and anesthesia in collaboration with the interdisciplinary working group on quality of care and outcomes research. Circulation 2005; 111:212858–2864.(Wim B. Gerritsen, Wim-Jan)
b Cardiothoracic Surgery, Sint Antonius Hospital, Nieuwegein, The Netherlands
c Anesthesiology, Sint Antonius Hospital, Nieuwegein, The Netherlands
d Department of Anaesthesia, University Medical Center Groningen, Groningen, The Netherlands
Abstract
In contrast to conventional on-pump coronary artery bypass grafting only mild increase of parameters of oxidative stress is reported during and after off-pump coronary artery bypass grafting. In an attempt to reduce the side effects of extra corporeal circulation the mini- extra corporeal circulation concept was introduced. In this study peroperative oxidative stress biomarkers were compared using three different techniques for CABG (conventional, mini and off-pump). It concerns a prospective randomized pilot study of 60 aged patients (70+ years) divided over 3 study groups. During the peroperative time points there was a significant increase in the mean concentration of uric acid for the CCABG group. On arrival at the intensive care unit the mean concentrations decreased significantly. During the per-operative period all groups showed significant increase in the concentration of malondialdehyde, however, this increase was the steepest for the CCABG group. On arrival at the intensive care unit the mean concentration decreased significantly for all groups. We found only mild organ ischemia/reperfusion injury and oxidative stress in the OPCAB group and the MCABG group with respect to the CCABG group.
Key Words: Off-pump; CABG, Mini-CABG; Oxidative stress; Malondialdehyde; Uric acid
1. Introduction
Despite improvements in surgical techniques, anaesthesia and postoperative care, cardiac surgery with the use of extra corporeal circulation (ECC) is associated with oxidative stress [1,2].
Insufficient per and postoperative circulation resulting from systemic inflammatory response and emboli are mentioned as significant causes of this phenomenon [3]. Furthermore, the use of cardioplegic arrest can also result in myocardial dysfunction resulting in hypoperfusion [4]. Morbidity associated with these mechanisms may involve multiple organs, such as the heart, brain, lung, kidney, or gastro-intestinal tract [5].
Measurements of parameters for oxidative stress are a well-accepted technique to express the extent of cell damage [1]. Their involvement is known to be substantial when the on-pump technique is used [1,5]. Although the heart is protected against ischemia during on-pump CABG, a certain level of ischemia still occurs.
Off-pump coronary artery bypass grafting has become a well-accepted and safe technique [6]. Short-term and mid-term angiography follow-up studies show comparable results to the conventional technique [6]. Oxidative stress studies show a significant reduction of MDA-levels during off-pump surgery compared to the conventional technique [1,2].
There are only few data showing oxidative stress in elective on- and off-pump CABG in a prospective set-up [1,3].
The aim of this pilot study was to compare the per-operative component of ischemia/reperfusion injury by means of uric acid and oxidative stress by means of lipid peroxidation e.g. malondialdehyde, during on- and off-pump CABG techniques.
2. Materials and methods
Sixty patients aged 70 years and older, 38 men and 22 women undergoing elective coronary bypass surgery were consecutively enrolled in a prospective observational setting. In this study, 20 patients were operated off-pump (OPCAB group), 20 patients using the Mini-ECC (MCABG group) and 20 patients using conventional CABG (CCABG group). No exclusion criteria other than redo of CABG and a minimum of three anastomoses were defined.
The Medical Ethical Committee of the Sint Antonius Hospital approved the protocol.
2.1. Anticoagulation protocol
The administration of coumarines and carbasalate calcium were stopped 6 days preoperatively. The anticoagulation protocol started per-operatively with subcutaneous low molecular heparins (LMWHs) daily. Eight hundred mg of acetyl salicylic acid was administered at the end of the procedure. Coumarines and LMWHs 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 LMWHs were stopped.
2.2. Anaesthetic technique
Pre-medication consisted of temazepam (10 mg), given orally 2–3 h before the procedure started. Anaesthesia consisted of a balanced opiate-based general anaesthesia technique. Induction took place by means of infusion of propofol (1.5–2 mg kg–1), pancuronium (0.1 mg kg–1) and fentanyl (7 μg kg–1). Anaesthesia was maintained with nitrous oxide in oxygen and continuous propofol infusion (10–20 ml h–1), remifentanyl (0.25–1 μg kg–1) and pancuronium as required. Hypertension was treated with vasodilators (nitro-glycerine and nitroprusside). A mean arterial pressure of 60 mmHg or higher and a heart rate less than 70 beats per minute was maintained. Heparin was administered at 300 IU kg–1 for the on-pump CABG group and 150 IU kg–1 for the off-pump CABG group. After all anastomoses were completed, heparin was neutralised with protamine chloride 120 IU/150 IU.
All patients received standardized post-operative care. Propofol was stopped and tracheal extubation is accomplished when the patient was hemodynamic stable, responsive and cooperative, FiO2, 50%, PaO2>11 kPa, pH>7.3, core temperature >36 °C and without excessive chest tube drainage. Postoperative pain relief was achieved with intravenous morphine (0.5 mg kg–1 h–1) and paracetamol, 1000 mg administered rectally three times daily.
2.3. Perfusion technique CCABG
The ECC circuit was composed of a roller pump (Sarns, USA), a hollow fibre polypropylene oxygenator with an incorporated cardiotomy reservoir (Cobe Optima XP TM, Cobe Cardiovascular Inc, Arvada, USA) and plasticized polyvinyl chloride tubing. The pump was primed with 1.5–2 l of 50% homemade primer solution. The heart was protected with topical cooling, together with 1000 ml of cold cardioplegic solution based on hydroxy-ethyl starch (HES: 60 g/l; Fresenius AG) and containing 2 mmol/l D, L-magnesium aspartate, 4 mmol l–1 procaine hydrochloride, 0.5 mmol l–1 calcium hydrochloride, 25 mmol l–1 sodium chloride, 5 mmol l–1 potassium chloride, 10 mmol l–1 glucose and 200 mmol l–1 mannitol with an osmolarity of 320 mOsm l–1, pH 7.4.
2.4. Perfusion technique MCABG
The MECC system consisted of a closed system, containing a Rotaflow centrifugal pump (Jostra, Germany) and a Quadrox membrane oxygenator (Jostra, Germany). Via short tubings, the venous line was directly connected to a centrifugal pump, which passes the oxygenator and, via the arterial line, returned to the patient. All components were from tip to tip Bioline coated (Jostra, Germany). Priming volume of the system was 500 ml of sodium chloride 0.9% (this solution contents 14.4% HES). Depending on the patient's hemostability the amount of prime will be returned to zero by starting MECC. When MECC starts, the nasopharyngeal temperature will be maintained at 33–34 °C. Acid-base management during mild hypothermia was monitored with alpha-stat and the cardiac index was kept between 2.0 and 2.4 l min–1 m–2. Blood from the surgical field was collected in a cell-saving device (Cobe BRAT 2).
Preservation of the heart was performed with a modified Calafiore-technique (warm blood cardioplegia with 30 ml potassium chloride 2 mol l–1 and 6 ml magnesium sulfoxide 1 mol l–1).
2.5. Surgical procedure
In the groups, median sternotomy and harvesting of the internal mammary artery were followed by full exposure of the coronary artery branches to be revascularised. All patients in the groups were placed in the Trendelenburg position less than 20° tilt. The revascularisation in the OPCAB group was performed on the beating heart using the Medtronic Octopus device (Medtronic, Minneapolis, USA) [7]. Temporary coronary occlusion was achieved using Acland clamps (S&T Marketing Limited, Neuhausen am Rheinfal, Swiss), while no shunts were used. For the MCABG and CCABG groups standard cannulation with a DLP (Medtronic, Minneapolis, USA) arterial canula in the ascending aorta and a DLP two stage canula in the right atrium. Postoperatively, patients were weaned from the ventilator as soon as possible (between 0 and 4 h for the OPCAB group, and between 4 and 8 h for the MCABG and CCABG groups).
2.6. Sample collection
Samples were obtained from the radial artery (RA) before, during and after coronary artery bypass grafting for patients undergoing MCABG, CCABG group/OPCAB group at the following time points: just after induction of anaesthesia, just before start of ECC/just before clamping of the first grafted artery, 10 min after removal of the cross clamp on the aorta/of the last grafted artery, and at arrival at ICU.
3. Assays
3.1. Uric acid and malondialdehyde
The separation is in one run on a 150x4.6 mm octadecyl silyl silica column (Supelco Inc, Bellafonte, PA, USA) using a gradient elution according to the method of Gerritsen [1]. All results were corrected for hemodilution according to the method described by Beaumont [8].
3.2. Data analysis and statistical considerations
Data analyses were performed using SPSS software version 12.0. Results were reported as mean±standard deviation (S.D.). Comparisons between groups (pre-operative and surgical data) were carried out using the Fisher's Exact tests or chi-square test, if appropriate. An outlier test was used to determine outliers. Comparisons within groups were made using repeated measures using ANOVA or the Student's t-test for the same time points between groups. A P-value less than 0.05 was considered as significant.
4. Results
4.1. Patients
The preoperative clinical and surgical data are presented in Tables 1 and 2, respectively. The preoperative clinical data showed no significance between the groups with respect to gender, age, severity of coronary disease, diabetes mellitus, New York Heart Association functional class, left ventricle function and extent of vessel disease. There was significance for COPD (P<0.05). Preoperative laboratory analysis revealed no patients with renal dysfunction (defined as having plasma levels of 120 μmol/l). For the surgical data, there was a significant difference in the amount of grafts per patient (P=0.003). In the study groups, no hospital mortality, no neurological accidents, incidences of myocardial infarction or acute renal failure occurred.
4.2. Uric acid
After induction of anaesthesia until 10 min after reperfusion in all groups the mean concentration of uric acid increased. On arrival at the intensive care unit the mean concentrations decreased for all groups. The mean concentration of the CCABG group at the time point ‘10 min after reperfusion’ was significantly higher (P=0.005) with respect to the OPCAB group.
Between all consecutive time points in the CCABG group, there was significance (P=0.023, 0.005 and 0.002; Fig. 1, Table 3). All values of the MCABG group were slightly increased compared to the OPCAB group.
4.3. Malondialdehyde
In the CCABG group two outliers were removed. The mean concentration of malondialdehyde increased significantly for all groups after induction of anaesthesia until 10 min after reperfusion. On arrival at the intensive care unit, the mean concentrations decreased significantly for all groups (Fig. 2, Table 3). The time points before clamping of the first artery/start ECC and 10 min after reperfusion were significantly higher for the CCABG group compared to the OPCAB group (P=0.011 and P=0.021).
At all time points, the mean values were slightly increased in the MECC group compared to the OPCAB group.
5. Discussion
In this study, we showed significant differences in the lipid peroxidation parameter MDA between the groups investigated in favour of OPCAB surgery. As we found in a previous study, parameters of oxidative stress are significantly increased during and after CABG with the use of ECC [1]. Recent studies concerning patients operated off-pump have reported a reduction in inflammatory reaction [9]. Furthermore, it was found by our group, as well as by others, that avoiding the use of ECC significantly reduces oxidative stress [1]. In the present study, we evaluated global oxidative stress by means of MDA and ischemia/reperfusion injury by means of uric acid in peripheral blood before, during and after surgery in patients who underwent on- and off-pump surgery in a prospective observational setting.
Uric acid is produced during the xanthine oxido-reductase pathway. Its concentration will increase during ischemia/reperfusion injury [10,11]. In a recent study uric acid appeared to be an independent predictor of mortality in patients with angiographically proven coronary artery disease [10]. Increased levels of uric acid have been found in a variety of diseases, from myocardial ischemia [12] to meningitis [13]. Uric acid acts as an anti-oxidant and is well known as a contributive factor in measuring the anti-oxidant capacity of body fluids like plasma and cerebrospinal fluid [11]. In this study, in all groups, there was a peroperative increase for uric acid. However, for the CCABG group this increase was significant. We can conclude that the intensity of oxidative stress is most outspoken in this group.
As a consequence of oxidative stress lipid peroxidation can occur. One of the end products of lipid peroxidation, malondialdehyde (MDA), was increased in all groups compared to baseline levels. Concentrations of MDA were significantly lower in the OPCAB group at all time points. This difference indicates that organs are more extensively exposed to lipid peroxidation when the on-pump technique is applied. We found that malondialdehyde significantly increases peri-operatively for all groups. This significant increase in concentration was the mildest for the OPCAB and the MCABG group, compared to the CCABG group.
Despite this difference in lipid peroxidation there was no difference in clinical outcome observed between the patient groups because our patient group was too small. Recently, Sellke et al. confirmed our findings that to definitely answer the remaining question of whether either strategy is superior, and in which patients, a large-scale prospective randomized trial is required [14].
Because of the organ protective effect of the mini-CABG we expect a growing importance in the near future.
6. Conclusion
Despite the fact that this pilot study only concerns a small patient group comparison, oxidative stress parameters showed a consistent pattern. The results indicate significant differences in organ production of the lipid peroxidation product malondialdehyde in favour of the OPCAB group. We found only mild oxidative stress and ischemia/reperfusion injury in the OPCAB group and the MCABG group compared to the CCABG group.
References
Gerritsen WB, van Boven WJ, Driessen AH, Haas FJ, Aarts LP. Off-pump vs. on-pump coronary artery bypass grafting: oxidative stress and renal function. Eur J Cardiothorac Surg 2001; 20:5923–939.
Matata BM, Sosnowski AW, Galinanes M. Off-pump bypass graft operation significantly reduces oxidative stress and inflammation. Ann Thorac Surg 2000; 69:3785–791.
Wan S, Izzat MB, Lee TW, Wan IY, Tang NL, Yim AP. Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac Surg 1999; 68:152–56.
Buckberg GD. Update on current techniques of myocardial protection. Ann Thorac Surg 1995; 60:3805–814.
Ascione R, Lloyd CT, Underwood MJ, Gomes WJ, Angelini GD. On-pump vs. off-pump coronary revascularization: evaluation of renal function. Ann Thorac Surg 1999; 68:2493–498.
Puskas JD, Thourani VH, Marshall JJ, Dempsey SJ, Steiner MA, Sammons BH, Brown WM, Gott JP, Weintraub WS, Guyton RA. Clinical outcomes, angiographic patency, and resource utilization in 200 consecutive off-pump coronary bypass patients. Ann Thorac Surg 2001; 71:51477–1483.
Jansen EW, Lahpor JR, Borst C, Grundeman PF, Bredee JJ. Off-pump coronary bypass grafting: how to use the Octopus tissue stabilizer. Ann Thorac Surg 1998; 66:2576–579.
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