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Ann Thorac Surg 2002;74:2088-2095
© 2002 The Society of Thoracic Surgeons
a Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom
Accepted for publication July 15, 2002.
* Address reprint requests to Dr Angelini, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
e-mail: g.d.angelini{at}bristol.ac.uk
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Abstract |
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METHODS: Sixty patients were prospectively randomized to conventional surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest, beating heart surgery (off-pump), or beating heart surgery with the RVAD. Serial blood samples were collected postoperatively, for analysis of inflammatory markers, troponin I, protein S100, and free hemoglobin. Renal tubular function was assessed by measuring urine N-acetyl-glucosaminidase activity.
RESULTS: No hospital deaths or major postoperative complications occurred in the study population. Interleukin-6, interleukin-8, C3a, and troponin I levels after surgery were significantly higher in the CPB group compared with the off-pump and RVAD groups. Free hemoglobin levels immediately after the operation, peak and total S100 levels, and N-acetyl-glucosaminidase activity were also significantly higher in the CPB group.
CONCLUSIONS: Off-pump coronary revascularization, with or without RVAD, reduces inflammatory response, myocardial, neurologic, and renal injury, and decreases hemolysis when compared with conventional surgery with CPB and cardioplegic arrest.
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Introduction |
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Myocardial revascularization on the beating heart has been shown to be associated with a significant reduction in the systemic inflammatory response commonly seen in patients undergoing conventional on pump coronary artery bypass grafting (CABG) [1–4]. This decreased inflammatory response might contribute in part to the reduced postoperative morbidity reported with off-pump coronary surgery [5, 6]. Interest in the use of off-pump CABG for multivessel disease is therefore increasing. However, off-pump grafting of the circumflex and posterior descending coronary arteries, is still associated with hemodynamic impairment [7]. Right ventricular assist devices (RVADs) have been proposed during off-pump coronary surgery as a method for improving visualization and safety of the procedure, by off-loading the right ventricle and preventing right ventricular dysfunction as a result of mechanical interference with diastolic expansion [8]. Nevertheless, no data are available on the effects of RVADs on inflammatory reaction and perioperative organ dysfunction in patients undergoing coronary revascularization.
The present study was designed to investigate the impact of the A-Med RVAD (Edwards Life Science, Irvine, CA) on the inflammatory response and organ functions in patients randomized to undergo CABG with cardiopulmonary bypass (CPB) or on the beating heart with or without the use of an RVAD.
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Material and methods |
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Anesthetic technique
Anesthetic technique was standardized for all patients as previously reported [1, 7]. In the CPB and RVAD group heparin was given at a dose of 300 IU/kg to achieve a target activated clotting time of at least 480 seconds. In the off-pump group, a heparin dose of 100 IU/kg was given soon after mammary artery harvesting, and the target activated clotting time was maintained between 250 and 350 seconds. Protamine was administered to reverse heparin action.
Surgical technique
Cardiopulmonary bypass group
Cardiopulmonary bypass was instituted using ascending aortic cannulation, a two-stage venous cannulation in the right atrium and a standard circuit as previously reported [1]. Systemic temperatures was kept between 34° and 36°C. Myocardial protection was achieved using intermittent, anterograde, hyperkalemic warm-blood cardioplegia [9]. Corticosteroids or aprotinin were not used, as these agents have been reported to reduce the inflammatory response during CPB [10].
Off-pump group
The method of exposure and stabilization to perform the coronary anastomosis has been described previously [7]. Briefly, a half-folded swab (12 cm wide and 70 cm long) is snared to the posterior pericardium (using a single stitch 0-silk suture), halfway between the inferior vena cava and the left inferior pulmonary vein. Traction is applied on the two limbs of the swab and the snare. These are then fixed to the surgical drapes to facilitate exposure of the target coronary vessels, which are then stabilized with a reusable stainless steel stabilizer. In both the off-pump and RVAD groups, anastomoses were performed with an intracoronary shunt to ensure distal perfusion, and a cell-saving system (Dideco Compact, Mirandola, Italy) was used during the procedure.
Right ventricular assist device group
The methods of exposure and stabilization were the same as in the off-pump group. The A-Med right heart support (A-Med Miniature Centrifugal Pump System; A-Med Systems, Inc, West Sacramento, CA) is a mini-support system, consisting of a control console, a microcentrifugal pump and a non–heparin-coated coaxial cannula. The centrifugal pump is a miniature pump which requires a very low priming volume (7 mL). The RVAD catheter is inserted through the right atrium and the tip advanced just beyond the pulmonary valve. On completion of the left internal mammary artery to left anterior descending coronary artery graft, support was started for the revascularization of the circumflex and right coronary systems. The A-Med RVAD works on the principle that blood is drained from the right atrium, passes through the miniature centrifugal pump, and is then delivered through the cannula’s inner reinfusion lumen into the pulmonary artery. The centrifugal pump is capable of delivering blood flow at rates of 1 to 6 L/min. Pump flow was adjusted between 2 and 4 L/min to maintain a mean blood pressure more than 65 mm Hg, with the right side of the heart decompressed to allow an easy exposure of the circumflex and posterior descending coronary arteries. The entire circuit volume is approximately 30 mL.
Intensive therapy unit management
At the end of surgery, patients were transferred to the intensive care unit and managed according to unit protocol [11]. Fluid management postoperatively consisted of 5% dextrose infused at 1 mL·kg-1·h-1, with additional succinylated gelatin or blood to maintain normovolemia and hematocrit greater than 24%.
Clinical outcome
Patient clinical characteristics, intraoperative and postoperative variables were prospectively recorded, as previously reported [11]. Clinical diagnostic criteria for perioperative myocardial infarction were new Q waves of longer than 0.04 ms, or a reduction in R waves of more than 25% in at least two leads. Inotropic support was considered as either modest (between 3 and 6 µgkg-1min-1 dopamine), or significant (6 to 10 µgkg-1min-1 dopamine with or without other inotropic agents such as adrenaline, noradrenaline, or enoximone).
Pulmonary complications included pneumothorax and lobar lung collapse (on chest roentgenogram as assessed by an intensivist unaware of the group allocation), chest infection (persistence of pyrexia requiring antibiotic therapy according to positive sputum culture), and acute respiratory distress syndrome. Total blood loss, red blood cell transfusion requirements, daily red cell and white cell count, hemoglobin and hematocrit levels, duration of tracheal intubation, and length of intensive care unit and hospital stay were also recorded [11].
Biochemical measurements
Blood samples were collected at seven time points as explained in Table 1.
Samples were immediately cooled to 4°C and centrifuged (3,000g for 10 minutes at 4°C). Plasma was stored at -70°C until being assayed. The inflammatory response was assessed by examining the degree of activation of the common complement pathway that leads to the production of C3a and C5a and by measuring the plasma levels of the proinflammatory cytokines interleukin (IL)-6 and IL-8 (radioimmunoassay, and ELISA assays, Biotrak; Amersham, Buckinghamshire, UK). Cardiac troponin I (TnI) was measured using with ACCESS system (Beckman, Inc, UK).
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Statistical analysis
A sample size of 20 subjects in each group was chosen for the study to have approximately 90% power to detect a target difference between groups of 1 standard deviation or greater at a significance level of 5% (two-tailed).
Base line, operative, postoperative, and biochemical data were compared between groups using 
2 tests or analyses of variance. Base line data were compared with check for possible chance imbalances between groups arising from randomization. All other comparisons, including operative data, represented tests of differences in "outcome" because it was considered possible that operative technique would affect operative data. Whenever these analyses indicated that outcomes differed between groups (p < 0.05), differences between pairs of groups were tested by unpaired t tests or 2 x 2 2 tests, ie, CPB versus off-pump, CPB versus RVAD, and off-pump versus RVAD. All analyses were carried out using STATA 7.0 (Stata Corporation, College Station, Texas).
Areas under the curves (level of variable by time) for each biochemical variable and patient were calculated using the trapezium rule. The time points assumed for these calculations are shown in Table 1. Areas were transformed by taking natural logarithms because the distributions of areas were positively skewed. Mean logged areas were the standardized (transformed into SD units) to aid interpretation; 1.0 SD is conventionally considered to represent a "large" difference and 0.5 SD a moderate difference. These steps were taken because there was no prior hypothesis about differences in the time course of indicators of myocardial damage between groups. Descriptive data in natural units (means) are nevertheless presented graphically as a function of time to depict the time courses of response. Error bars in Figures 1 to 5 represent 1 standard error. However, the raw data for each group and time point were often highly skewed and the samples were of modest size (about 20); the central limits theorem therefore may not completely justify the use of standard errors in some cases, and the error bars should be interpreted as approximate.
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Results |
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Interleukin-6 and interleukin-8
Figures 1A and 1B show the time courses of plasma levels of IL-6 and IL-8 in the three groups. The logged area under the curve for IL-6 differed significantly between the three groups (p = 0.007), with the area being significantly greater for the CPB group than either the off-pump group (difference in area = 0.80 SD, 95% CI 0.21 to 1.39, p = 0.009) or the RVAD group (difference = 0.91 SD, 95% CI 0.30 to 1.52, p = 0.004). No significant difference in the area under the curve was found between the off-pump and RVAD groups (difference = 0.11 SD, 95% CI -0.50 to 0.71, p = 0.72).
The logged area under the curve for IL-8 also differed significantly between the three groups (p = 0.0004). Again, the area was significantly greater for the CPB group than either the off-pump (difference = 0.99 SD, 95% CI 0.41 to 1.57, p = 0.001) or the RVAD group (difference = 1.13 SD, 95% CI 0.55 to 1.71, p < 0.001). There was no significant difference in area between the off-pump and RVAD groups (difference = 0.14 SD, 95% CI -0.43 to 0.71, p = 0.62).
C3a, C5a
Figures 2A and 2B
show the time courses of plasma levels of C3a and C5a in the three groups. The logged area under the curve for C3a differed significantly between the three groups (p = 0.002), with the area being significantly greater for the CPB group than either the off-pump (difference in area = 1.12 SD, 95% CI 0.52 to 1.73, p < 0.001) or the RVAD group (difference = 0.62 SD, 95% CI 0.01 to 1.22, p = 0.05). There was no significant difference in area between the off-pump and RVAD groups (difference = -0.50 SD, 95% CI –1.11 to 0.10, p = 0.10). The logged area under the curve for C5a did not differ significantly between the three groups (p = 0.15).
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Protein S100
In all groups S100 levels rose soon after the operation when compared with base line values. Figure 4
shows the time courses of plasma levels of protein S100 in the three groups. The area under the curve for protein S100 differed significantly between the three groups (p = 0.002), with the area being significantly greater for the CPB group than either the off-pump (difference in area = 0.97 SD, 95% CI 0.38 to 1.55, p = 0.002) or the RVAD group (difference = 0.96 SD, 95% CI 0.37 to 1.55, p = 0.002). There was no significant difference in area between the off-pump and RVAD groups (difference = -0.01 SD, 95% CI –0.59 to 0.57, p = 0.97). Total IL-8 was also found to be a strong predictor of total S100 protein (regression coefficient 0.38, 95% CI 0.12 to 0.64, p = 0.004).
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Our study demonstrated the safety and effectiveness of the A-Med RVAD in the clinical setting of off-pump coronary surgery. Use of the device did not prolong the operation and was associated with a significant central venous pressure reduction during the construction of the posterior and lateral wall coronary artery anastomosis when compared with patients undergoing beating heart coronary surgery without an RVAD. The use of an RVAD might therefore be particularly advantageous in patients with dilated hearts when the exposure of these coronary arteries is difficult and often associated with significant hemodynamic impairment.
The use of CPB was associated with increased inotropic support and red blood cell transfusion compared with the off-pump and RVAD groups, in accordance with previous studies comparing beating versus conventional coronary surgery [21, 22]. The tendency for increased postoperative blood loss in the RVAD group could be explained by the higher cell-saving blood collection, which is known to have a negative impact on red cell and platelet function, and protein levels [23]. This increase in cell-saving blood collection during the operation might be explained as a result of the initial learning curve of the RVAD cannulation technique.
Our randomized study analyzed the effects of RVAD on inflammatory response and organ function in patients undergoing myocardial revascularization. These analyses required interpolation of missing data, potentially increasing the chance of finding significant differences between groups when, in fact, none existed. However, the strength and consistency of the findings, across different biochemical markers, suggests that the relatively small amount of missing data (5% to 10% for different variables) is unlikely to have caused type 1 errors of this kind.
The results indicate that, compared with conventional CABG, off-pump surgery with or without RVAD is associated with reduced cytokine reactions. In a previous randomized study [1] we showed significantly higher levels of IL-8 soon after the end of CPB in patients undergoing conventional CABG compared with those undergoing beating heart revascularization. Similar results were obtained by Wan and colleagues [2], who also showed a significant correlation between IL-8 production and TnI release. The present study demonstrated that the use of RVAD in off-pump coronary surgery did not induce significant IL-8 and TnI release.
The increase in IL-6 observed in all three groups compared with base line might be related to the surgical trauma [24]. However, the use of CPB was associated with a significantly greater increase in postoperative IL-6 levels compared with the off-pump and RVAD groups, indicating that CPB-related factors are triggering IL-6 release. Dreyer and colleagues [25] have recently demonstrated that CPB with cardioplegic arrest is a sufficient stimulus to induce IL-6 synthesis in cardiac myocytes and that the local production of IL-6 plays a pivotal role in the regulation of myocardial function postoperatively.
Complement activation during CPB leads to the formation of the anaphylatoxins C3a and C5a that contribute to the inflammatory response by increasing capillary permeability, altering vasomotor tone, impairing cardiac function, and activating neutrophils and mast cells [26]. C3a usually peaks at the end of CPB [27], and this peak is known to be related to the duration of CPB [26]. Levels then return to pre-CPB values 24 to 48 hours postoperatively [27]. In accordance with other reports [1, 27], our study also showed a peak of complement activation soon after CPB that was higher than the peak seen at the same time point in the off-pump or RVAD groups. Overall, levels of C3a, but not C5a, were significantly higher in the CPB group than the off-pump and RVAD groups. The mild elevation of C3a observed in the off-pump and RVAD groups could be related to the surgical manipulations, as suggested by Hahn-Pederson and associates [28]. However, the fact that total C3a was significantly more elevated in the CPB group suggests an overall higher production of this potent anaphylatoxin due to the CPB. These results were obtained despite the effect of hemodilution of the CPB prime, which is known to lower the concentrations of the inflammatory mediators [29].
Postoperative TnI release was also shown to be significantly greater in the CPB groups compared with the off-pump and RVAD groups. These findings are consistent with previous data [21] indicating a decreased level of myocardial injury in off-pump coronary surgery, and the use of an RVAD did not induce any significant increase in TnI release.
A certain degree of hemolysis always occurs during CPB [30] and CPB patients consequently have a transient elevation of plasma free hemoglobin that peaks several hours postoperatively [13]. Furthermore, it is known that reperfusion after ischemic arrest causes an increase in free hemoglobin concentrations, simultaneously releasing free iron and generating hydroxyl radicals [14]. Recent animal work has shown that free hemoglobin directly impaired left ventricular function and coronary blood flow in neonatal rabbit hearts, especially when ischemia and reperfusion were involved [15]. The significantly raised free hemoglobin levels could directly cause coronary endothelial damage and amplify the deleterious effects of ischemia-reperfusion on left ventricular function.
Urinary NAG has emerged as the most widely assayed urinary enzyme for detection of renal damage, and potential deleterious effects of CPB on renal function previously reported [31] were confirmed in the current study. The increase in NAG activity levels in the CPB group was significantly higher than when myocardial revascularization was performed off-pump, with or without an RVAD.
Serum S-100 protein has been used as a biochemical marker of neural injury [32, 33]. We have previously demonstrated a bigger rise of protein S100 immediately after the operation in patients undergoing on-pump compared with those undergoing off-pump revascularization [34], and our present results confirmed this difference. Recently, some studies have questioned the validity of S100 as a marker of neurologic injury, postulating that mechanisms other than CPB may determine or prevent the release of S100, including the absence or presence of line filters, the use of a cardiotomy suction during the period of CPB, or postoperative autotransfusion [35]. On the other hand, Westaby and associates [33] speculated that the elevation of S100 reflects diffuse microembolic cerebral injury together with increased permeability of the blood–brain barrier. In this study we found that the postoperative level of IL-8 (logged area under the curve) was a strong predictor of total S100, indicating a possible role of the inflammatory response in damaging the blood–brain barrier and enhancing protein S100 release.
Conclusions
This study shows that off-pump coronary revascularization with or without the use of an RVAD reduces the inflammatory response, myocardial, neurologic and renal injury, and decreases hemolysis when compared with conventional surgery with CPB and cardioplegic arrest.
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), off-pump (
), and RVAD (
) groups. Thebarsrepresent mean levels of interleukin 6/8 at each time point for each group.Error barsrepresent 1 standard error. The logged areas under the curves for the CPB group were larger than for either the off-pump group (p= 0.009 andp= 0.001 for interleukin-6 and -8, respectively) or the RVAD group (p= 0.004 andp< 0.001, respectively). There was no significant difference in area between the off-pump and RVAD groups (p= 0.72 andp= 0.62, respectively). (CPB = cardiopulmonary bypass; RVAD = right ventricular assist device.)
