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Ann Thorac Surg 1999;67:1721-1725
© 1999 The Society of Thoracic Surgeons
a Departments of Department of Cardiothoracic Anaesthetics and Intensive Care, Karolinska Hospital, Stockholm, Sweden
b Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden
c Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden
Accepted for publication December 30, 1998.
Address reprint requests to Dr Anderson, Department Cardiothoracic Anaesthetics and Intensive Care, Karolinska Hospital, S-171 76 Stockholm, Sweden
e-mail: russell.anderson{at}kirurgi.ki.se
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Abstract |
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Methods. Fourteen patients with off-pump operations and 18 patients with CPB were compared. Seven patients in the off-pump group underwent a minithoracotomy and received only an arterial graft, whereas 7 patients underwent sternotomy and received both an arterial and one or two vein grafts. S100B was measured in arterial plasma using an immunoassay with enhanced sensitivity.
Results. S100B before the operation was 0.03 µg/L. At wound closure, S100B in patients of the off-pump and CPB groups reached a maximum level of 0.22 ± 0.07 and 2.4 ± 1.5 µg/L, respectively (p < 0.001). No strokes occurred. Patients without CPB receiving arterial and vein grafts released slightly more S100B (p < 0.05) than patients with only arterial grafting. In patients undergoing CPB, S100B increased slightly before aortic cannulation (p < 0.001), to the same level as the maximum reached for the non-CPB group.
Conclusions. Coronary artery bypass grafting with CPB caused a 10-fold greater increase in S100B than off-pump grafting. S100B release after off-pump sternotomy with vein grafting was slightly greater than in arterial grafting through a minithoracotomy.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Less invasive cardiac surgical techniques have the potential to decrease neurologic morbidity. Surgical technical advances have made off-pump CABG a safe and practical alternative to conventional CABG with cardiopulmonary bypass (CPB) in selected cases [2–4]. Off-pump grafting eliminates the potentially negative consequences of CPB, which is known to initiate a systemic inflammatory response [5]. Whatever neurologic consequences arise from CPB are eliminated in off-pump operations, as are potential embolization from cannulating and cross-clamping the aorta. Strokes correlate with the frequency of emboli detected by transcranial Doppler, 80% of which occur during application or release of the aortic cross-clamp [6].
berg and colleagues [7] demonstrated a decade ago a correlation between adenylate kinase, a serum marker of cerebral injury, and mental dysfunction after CPB. Another marker of cerebral injury, S100B, is a protein released from damaged astroglial and Schwann cells, which appears in serum only if there is also an increased permeability in the blood–brain barrier [8]. S100B is known to increase after CPB and to correlate with neurologic sequelae [9–12]. Previously Westaby and associates [12] reported that off-pump operations did not influence S100B release during CABG.
The purpose of the present work was to compare release of S100B during CABG with and without CPB. The serum concentration of S100B was measured using a recently developed immunoassay method with enhanced sensitivity. Furthermore, we investigated whether S100B release in off-pump operations differed between minithoracotomies, with only grafting of the left internal mammary artery to the left anterior descending coronary artery, and sternotomies, in which in addition veins grafts were anastomosed to the ascending aorta using a side-biting clamp.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Patients were grouped according to the surgical approach used. They were not randomized as their coronary artery anatomy determined the appropriate surgical approach. All patients were premedicated with morphine (7.5 to 15 mg). Anesthesia was induced with 10 µg/kg fentanyl, 70 µg/kg midazolam, and the patients were paralyzed with 0.1 mg/kg pancuronium. Both groups received mannitol (40 mg/kg) during the first hour of operation. Anesthesia was maintained by continuous infusion of fentanyl/midazolam (0.3/3.0 mg/h) until completion of the operation. Esmolol was occasionally used while suturing the anastomoses to the beating heart.
Two major groups of patients were studied, and the patient data are presented in Tables 1 and 2. The non-CPB patient group was suitable for CABG without the use of CPB, and it in turn comprised two subgroups. One subgroup was operated on through a left anterior, small thoracotomy (LAST operation [3]) and received only the left internal mammary artery to the left anterior descending coronary artery. The second subgroup received at least one, but not more than two, vein graft through a sternotomy and with a single application of the side-biting clamp. All but 1 patient in the sternotomy group received a left internal mammary artery to left anterior descending coronary artery graft.
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Protocol for blood sampling
Blood samples were drawn on seven occasions: before induction of anesthesia, at closure of the sternum or thoracotomy, and 6, 12, 24, and 48 hours and 6 days after closure. For the last 12 patients undergoing CPB, samples were also drawn, in addition to the time above, directly before skin incision, before the heparin bolus, after heparin bolus but immediately before cannulation, and before initiation of CPB.
Biochemical analysis
Eight milliliters of arterial blood were drawn using plain vacuum tubes, centrifuged, and frozen for batch analysis. S100B was analyzed by immunoassay Sangtec 100 Lia-mat (Sangtec Medical, Bromma, Sweden). Functional detection limit of the assay is 0.02 µg/L. Cystatin C, a low molecular weight protein marker of kidney function, was analyzed [13] using a latex-enhanced immunoturbindimetric assay (DAKO a/s, Glostrup, Denmark).
Statistics
Results are presented as means (± standard deviation) unless otherwise stated. Data were compared using two-way analysis of variance. When appropriate the Scheffe post hoc test was applied. The criterion for significance throughout was p < 0.05.
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Results |
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The values of S100B for the non-CPB and CPB groups are shown in Figure 1. The levels before induction of anesthesia did not differ for the two groups. The maximum value, measured at closure of the sternum or thoracotomy, for the non-CPB group was 10% of that found in the CPB group (0.22 ± 0.07 and 2.4 ± 1.5 µg/L, respectively; p < 0.001). Both groups returned to preoperative values 6 days after the operation. S100B release did not differ for the two types of oxygenators. The maximum value of S100B correlated with the time on CPB (Fig 2; r = 0.49; p < 0.02) and with the number of vein grafts (r = 0.54; p < 0.02).
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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A weakness of the present study is the lack of randomization, since the extent of coronary artery disease determined the surgical approach used. This selection illustrates our early experience with off-pump surgery, but leaves many factors uncontrolled. Consequently, the patients operated on with CPB with a need for more extensive revascularization might be generally more diseased and even have more atherosclerosis of the cerebral vessels, although this was not apparent in their history and screening of the carotid arteries. Although patients with less extensive revascularization had less S100B release, those patients operated on off-pump had far less release than those on-pump with the same number of anastomoses. Thus different severity of the atherosclerotic disease cannot explain the differences of S100B release between on- and off-pump surgical procedures.
S100B originates in astroglial and Schwann cells and belongs to a family of dimeric proteins [14]. The two subunits in S100B are identical (type ß). S100A1 (composed of 
) is found in striated muscle, heart, and kidney, whereas S100A1B (composed of ß) originates mostly in astroglial cells. The immunoassay used in this study uses three different monoclonal antibodies directed against the ß chain, and thus although S100B is the dominant form detected, even S100A1B will be measured. Normal blood concentration for S100B is considered to be less than 0.12 µg/L. Increases in serum S100B are believed to result if, and only if, there is both damage to astroglial or Schwann cells and also damage to the blood–brain barrier [15].
Inasmuch as S100B is excreted by glomerular filtration followed by reabsorption and degradation in the proximal tubule [16], renal dysfunction is a potential source of error when comparing concentrations of this marker in different groups of patients. Cystatin C is a low molecular weight protein whose serum concentration is not influenced by inflammation and whose elimination is similar to that of S100B [13]. It is far superior to serum creatinine and detects even mild glomerular dysfunction [17]. The small increases in S100B with operation seen in this study cannot have arisen from acute changes in glomerular filtration during the procedure, as serum cystatin-C was unchanged. S100B is not affected by heparin or protamine [18].
Although a marginal effect of heparin on S100B passage through the blood–brain barrier cannot be excluded, there is no published evidence supporting such changes. Svenmarker and colleagues [10] observed only a 23% reduction in S100B release when comparing a group using heparin-coated extracorporeal systems (with 1 mg/kg heparin bolus) with conventional CPB (3 mg/kg heparin bolus). The off-pump group described in this study also received 1 mg/kg heparin and had a 90% reduction in S100B release as compared with the CPB group with full heparinization. Thus it is highly unlikely that heparin can account for the difference in S100B release observed in our study.
What is the cause of the drastic reduction in the amount of S100B released after off-pump operation compared with conventional CABG in the present investigation: avoidance of CPB, cross-clamping, side-biting clamp, or aortic cannulation? Already after sternotomy, but before heparin bolus, an increase in S100B in the CPB patients corresponding to the maximum level in the non-CPB patients was detected. Sternotomy and the use of a side-biting clamp for proximal anastomoses on the ascending aorta resulted in a slightly, but significantly, larger increase in S100B compared with the LAST operation with only the use of the left internal mammary artery. However, this minimal extra increase in S100B refutes the view that the side-biting clamp is very important for the more subtle injury causing release of S100B in the absence of gross neurologic injury. From our data it is not likely that either the sternotomy, the aortic cannulation, or the side-biting clamp causes the major part of S100B release during conventional CABG with CPB. However, sternotomy or the side-biting clamp may account for the difference between patients in the sternotomy group and patients undergoing the LAST operation in the off-pump group.
What are left as potential causes of increased S100B release are the aortic cross-clamp and the CPB itself. The aortic cross-clamp has always been regarded as one of the major culprits of neurologic injury, and a cause of microembolization [6, 19]. However, it is not easy to see that there should be a major difference between the effects of the side-biting clamp and the cross-clamp on S100B release. In the present work S100B release correlated with duration of CPB, and this has also previously been shown by others [12], but not by Taggart and coworkers [11]. The fact that there may be a correlation between S100B release and duration of CPB, in combination with the fact that different conduct of CPB may have a significant influence on S100B release, is suggestive that CPB itself is the major determinant of S100B release. This may not be contrary to the concept that clamps on the ascending aorta may be the major determinant of gross neurologic injury. In addition, S100B release after CABG is decreased by the use of a filter in the arterial line of the extracorporeal circuit [20] and by using heparin-coated extracorporeal systems [10].
Earlier studies with the less sensitive analysis technique for S100B ascribed no increase to anesthesia or operation. We confirm in this study the lack of increase with 1 hour’s anesthesia, but we observed a small increase with operation, which has not been detected previously and which reaches significance before the heparin bolus is given. This marginal increase continues after heparin until initiation of CPB, after which the dramatic 10-fold increase occurs. This small increase with operation cannot be explained by this study, and the possibility of even extracerebral sources must be considered.
The mechanism behind the increase in S100B with CPB has not been explained by this or previous studies. The release may represent subtle brain injury accounting for the neurocognitive impairment after open heart operation [1], but no large study has yet established a conclusive correlation. Psychological and intellectual sequelae do, however, correlate with S100B after minor head injury [20]. Although the systemic inflammation induced by CPB [5] could conceivably increase blood–brain barrier permeability and increase the bioavailability of S100B, no changes in blood–brain barrier permeability were found in piglets after 2 hours of CPB with full heparinization [21]. Furthermore, the normal concentration of S100B in cerebral spinal fluid (1.7 µg/L) [22] is considerably less than the increases observed after CPB. Thus, permeability changes alone in the blood–brain barrier cannot account for the findings in this study.
Although S100B is known to have a half-life of about 2 hours, the concentration in patients without neurologic damage decreases to half its maximum value after about 5 hours postoperatively [9]. In the present study S100B in the non-CPB group decreased to half within 5 to 6 hours after sternal closure, and the level was then followed by a much slower rate of decline, suggesting continued release, but at a much lower rate than during the operation. Patients with postoperative neurologic complications tend to have prolonged release of S100B for 24 to 48 hours after operation [9]. S100B normalized for all patients in both groups within 6 days after operation, and none had clinical symptoms of neurologic damage.
In conclusion, CABG without CPB results in a 10-fold reduction in S100B released when compared with CABG with CPB, consistent with a major reduction in damage to the blood–brain barrier and to astroglial and Schwann cells with off-pump CABG. Cardiopulmonary bypass itself rather than aortic manipulation may be a major determinant of S100B release in routine cases without any gross neurologic injury.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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berg T., Ronquist G., Tydén H., et al. Release of adenylate kinase into cerebrospinal fluid during open-heart surgery and its relation to postoperative intellectual function. Lancet 1982;2:1139-1142.
ardemark H.-G., Gustafsson J., et al. S-100 protein and neuron-specific enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous system. Stroke 1987;18:911-918.ardemark H.-G., Gustafsson J., et al. S100 protein and neuron-specific enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous system. Stroke 1987;18:911-918.
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) cardiopulmonary bypass.