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Ann Thorac Surg 1998;66:1958-1962
© 1998 The Society of Thoracic Surgeons

Original Articles

Serum S100ß release after coronary artery bypass grafting: roller versus centrifugal pump

Saeed Ashraf, FRCSa, Kausik Bhattacharya, FRCSb, Sunny Zacharias, FRCSa, Pradeep Kaul, FRCSa, Philip H. Kay, DMa, Kevin G. Watterson, FRACSa

a Yorkshire Heart Centre, Leeds General Infirmary, Leeds, United Kingdom
b Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom

Accepted for publication May 30, 1998.

Address reprint requests to Dr Ashraf, Leeds General Infirmary, Yorkshire Heart Centre, Leeds, LS1 3EX, UK


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
Background. Microemboli generated during cardiopulmonary bypass (CPB) are implicated in the cerebral injury seen after coronary artery bypass grafting. Centrifugal pumps generate fewer microemboli than roller pumps. Increased S100ß levels have been reported after coronary artery bypass grafting, with levels greater than 1 ng/mL resulting in poorer neuropsychologic outcome. This study investigated the potential neurologic benefits of centrifugal pumps, by using S100ß as a marker for cerebral injury.

Methods. Thirty-two patients who had coronary artery bypass grafting were randomly assigned to two groups. Serial blood samples (preoperative, end of bypass, 30 minutes, and 2 and 24 hours after cardiopulmonary bypass) were taken and the serum analyzed for S100ß using a new immunoluminometric assay.

Results. Both groups were matched for age, number of grafts, and cardiopulmonary bypass and cross-clamp times. Postoperative serum S100ß levels were significantly higher in both groups than preoperative levels. Peak S100ß levels did not correlate with cardiopulmonary bypass time; however, 24-hour S100ß levels correlated with intubation time r = 0.40, p = 0.04). There was no significant difference in S100ß levels between the groups at any of the time points.

Conclusions. S100ß levels increased after coronary artery bypass grafting. Centrifugal pumps do not significantly decrease S100ß release. Persistently increased S100ß levels are associated with longer intubation times.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Cerebral injury is the most debilitating complication of cardiac operations requiring cardiopulmonary bypass (CPB). The reported incidence of stroke after coronary artery bypass grafting (CABG) is 0.9% to 5.9% [1]. Subtle cerebral injury can be detected by neuropsychometric testing in 61% of patients within a week postoperatively, and persists in one third of patients 6 months later [2]. Microemboli generated during CPB have been implicated in the origin of this subtle cerebral injury [3–5].

Echogenic particulate matter have been detected using ultrasound and correlated with adverse neuropsychologic outcome after CPB using a roller pump [4, 5]. The overall quantity of microemboli have been reduced by using membrane oxygenators and arterial line filters during CPB [6, 7]. Centrifugal pumps have been shown to generate fewer microemboli than roller pumps [8].

Elevated serum concentrations of the astroglial protein S100ß have been reported after CABG [9–11] and valve operations [10]. Arterial filters significantly reduced S100ß release [10]. Serum levels of S100ß greater than 1 ng/mL have been associated with a poorer neuropsychologic outcome.

An increase in the number of cardiac operations being performed on a more elderly population [13] has resulted in a substantial increase in the proportion of deaths after adverse neurologic events. Hence, simple methods of diagnosing and quantifying cerebral injury are of paramount importance.

We present a prospective randomized study that assessed the potential neurologic benefit of centrifugal pumps over roller pumps, using a new immunoluminometric assay to measure S100ß, a marker for cerebral injury.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
Thirty-two patients who had CABG were studied prospectively and randomly assigned to having a roller or centrifugal pump during CPB. Blood samples were taken on induction of anesthesia, at the end of CPB, 30 minutes, and 2 and 24 hours after the termination of CPB.

Anesthetic and surgical protocol
Each patient had effort-induced angina pectoris refractory to maximal antianginal therapy and multivessel coronary artery disease (more than 70% vessel occlusion). Patients entered into the study had ejection fractions greater than 40%. Exclusion criteria were unstable angina, myocardial infarction within the previous 3 months, reoperation, diabetes mellitus, liver or kidney failure, severe asthma or chronic obstructive airway disease, and oral anticoagulant or immunosuppressive therapy.

The techniques of anesthesia and CPB were standardized. After premedication, anesthesia was induced with fentanyl (30 µg/kg, intravenously), muscle relaxation was achieved with pancuronium bromide (0.1 to 0.2 mg/kg, intravenously). Mechanical ventilation was initiated (tidal volume, 10 to 15 mL/kg; rate, 12 to 15 breaths per minute) and anesthesia was supported by inhalation of 1% isoflurane. Operative monitoring was identical in all patients. The extracorporeal circuit consisted of either a Stockert roller pump (Stockert Instrumente, Munich, Germany) or a centrifugal vortex pump (Medtronic Biomedicus Inc, Minneapolis, MN), a hollow membrane oxygenator (D703A, Dideco, Mirandola, Italy), and polyvinylchloride tubes. The only difference in the entire perfusion circuit was the arterial pump. Patients were heparinized just before institution of CPB with 300 IU/kg, with additional dosing as necessary to maintain the activated clotting time longer than 480 seconds. Nonpulsatile extracorporeal circulation was initiated at flows of 2.4 to 2.6 L/m2 per minute. Moderate systemic hypothermia (28° to 30°C, nasopharyngeal) was uniformly used. Cardiac arrest was achieved by infusion of 1 L of cold blood cardioplegic solution and topical slush. All distal anastomoses were performed during a single period of cross-clamping, and the proximal anastomoses to the aorta were completed during the rewarming period. Extracorporeal circulation was terminated at a nasopharangeal temperature of 37°C. Heparin was neutralized after the end of CPB with protamine sulphate (1 mg/100 IU heparin).

S100ß assay
All samples were centrifuged for five minutes at 3,000 g. The resultant serum was frozen at -80°C and saved for batch analysis. S100ß levels were measured using a monoclonal immunoluminometric assay (Sangtec LIA 100; AB Sangtec Medical, Bromma, Sweden). This assay uses three monoclonal antibodies, SMST 12, SMSK 25, and SMSK 28, to detect the ß chains in the ßß and {alpha}ß dimers of S100. The assay involved adding the sample and the diluent (bovine serum albumen) into a plastic tube already coated with S100ß antibody. After incubating for 1 hour, the tube was washed three times with wash buffer and a luminescence-labeled antibody (tracer) was added. After a further 2-hour incubation the unbound tracer was washed out, and the residual antibody was measured using a luminometer. The mean duplicate luminometer count was compared to known standards and any value over the zero count was recorded.

Both analyses were performed in duplicate to reject those with more than 5% variation. This did not apply to any patients in this series.

All patients underwent detailed neurologic examination preoperatively and on a daily basis postoperatively for signs of cerebral injury.

Statistical analysis
SPSS for Windows (version 7.0; SPSS Inc, Chicago, IL) was used for data analysis. After testing the distribution of the data, the patient characteristics and serum S100ß levels were expressed using mean and standard error of the mean. Group comparisons were made using Student’s t test. The postoperative S100ß levels were compared with preoperative levels using a paired t test. Pearson’s correlation coefficient was used to identify correlations between S100ß and other variables. The scattergraphs are illustrated with a straight line denoting the best-fit line and with curved lines representing the 95% confidence intervals.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Patients
The patient characteristics are shown in Table 1. No patient had any preoperative history of stroke. Both groups were matched for age, number of grafts, and CPB time, and cross-clamp time. No patient required exploration for postoperative bleeding, and there were no operative deaths or significant adverse complications. All patients were discharged from the intensive care unit on the first postoperative day. No patient in this series had clinical evidence of a stroke.


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  		Table 1. Clinical Characteristics of the 32 Patients Who Had Coronary Artery Bypass Graftinga

 
S100ß levels
The temporal release pattern of S100ß is shown in Figure 1 and Table 2. The mean preoperative levels were similar in both groups (0.14 ng/mL [roller pump] compared with 0.13 ng/mL [centrifugal pump]). Peak values in both groups were recorded at the termination of CPB, with higher values in the roller pump group (2.26 ± 0.39 ng/mL versus 2.11 ± 0.27 ng/mL), although this difference did not reach significance (p = 0.75). All postoperative values were significantly higher compared with preoperative levels, except the 24-hour level in the centrifugal pump group (Table 3).



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  		Fig 1. An error bar graph showing the serum S100ß profiles in both groups. The boxes represent the mean value, with the whiskers showing the 95% confidence interval. (CPB = cardiopulmonary bypass; Preop = preoperative value).

 

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  		Table 2. S100ß Profiles in Both Groups of Patientsa

 

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  		Table 3. Comparison of Postoperative S100ß Levels With Preoperative Valuesa

 
In neither group did the postoperative S100ß levels correlate with the duration of CPB, but in the centrifugal pump group there was a significant relationship between cross-clamp time and peak S100ß levels (r = 0.66, p = 0.008; Fig 2). However, in the roller pump group there was no significant correlation between the cross-clamp time and peak S100ß levels.



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  		Fig 2. Scatterplot showing the relation between peak S100ß levels and cross-clamp time in the centrifugal pump group (r = 0.66, p = 0.008).

 
Considering all the patients, the 30-minute sample was a better predictor of the 24-hour levels than the sample taken immediately after bypass (r = 0.62, p = 0.001, compared with r = 0.32, p = 0.10; Fig 3). There was a significant but weak correlation between 24-hour S100ß levels and prolonged intubation (r = 0.40, p = 0.04; Fig. 4).



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  		Fig 3. Scatterplot showing the relation between 30-minute S100ß levels (r = 0.62, p = 0.001), and 24-hour S100ß levels (r = 0.32, p = 0.10) in all patients.

 


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  		Fig 4. Scatterplot showing the relation between 24-hour S100ß levels and intubation time in the centrifugal pump group (r = 0.40, p = 0.04).

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
Central nervous system complications, both overt and subtle, continue to blight the success of cardiac operations. With more operations undertaken in a more elderly population, the incidence of stroke after CABG has increased through the decades: 0.57% in 1979, 2.4% in 1983, and 5.9% in 1994 [12–14]. Truman and associates [15] demonstrated that 3.6% of 65 to 74 year olds suffered from postoperative neurologic deficit, whereas the figure increased to 8.9% in those over 75 years old. Many studies have implicated the microembolization of particulate and gaseous matter as a causal agent in postoperative neuropsychologic impairment [3–7]. Furthermore, reducing the number of microemboli has been associated with improved clinical outcome [6, 7].

In the present study we evaluated the potential clinical benefit of using a centrifugal pump in the CPB circuit, with S100ß as a marker for cerebral injury. The groups were matched for age, cross-clamp (ischemic) time, CPB time, and the number of grafts. The temporal release pattern of S100ß was similar to those reported in previous studies [9–11]. In contrast to the latter however, we were able to detect preoperative S100ß levels. Previous reports measuring S100ß used an immunoradiometric assay (Sangtec 100, AB Sangtec Medical, Bromma, Sweden), which had a lowest detection limit of 0.2 ng/mL. In the present study we used an immunoluminometric assay (Sangtec LIA 100, AB Sangtec Medical, Bromma, Sweden), which could measure S100ß to 0.02 ng/mL.

There were no significant differences between the groups at any of the sample times, preoperative (p = 0.74), end of CPB (p = 0.75), 30 minutes (p = 0.59), 2 hours (p = 0.12), and 24 hours (p = 0.75) postoperatively. These findings imply that for CBP times less than 90 minutes, a centrifugal pump does not reduce S100ß release compared with a roller pump, which raises the suspicion that other etiologic factors, such as hypoperfusion or systemic inflammatory response syndrome might significantly contribute to the total astroglial damage sustained during CPB. Toner and colleagues [16] demonstrated the presence of diffuse cerebral edema after CABG by using magnetic resonance imaging, which supports the hypothesis of astroglial damage secondary to inflammation. It remains to be seen whether centrifugal pumps will be beneficial if used during longer bypass times.

In the present study, we did not find a correlation between peak S100ß levels and duration of CPB; this result concurs with those of two other studies [10, 11]. However, there was a significant correlation between ischemic (cross-clamp) time and peak S100ß levels in the centrifugal pump group (r = 0.66, p = 0.008). The reason for this is unclear. A possible explanation is that myocardium might be a source of S100ß, which is unlikely as homogenized myocardium has 2,000 times less S100ß than homogenized brain cortex per weight of tissue [17]. Second, long ischemic times might evoke a greater release of local cytokines that could exert their effects on distant organs. More studies will be required to validate this speculation.

S100ß levels at 24 hours correlated significantly with the 2-hour level (r = 0.74, p < 0.001) and the 30-minute level (r = 0.62, p = 0.001) but did not correlate with the sample taken immediately after cessation of CPB (r = 0.32, p = 0.10). This result is not surprising, as hemodilution, mannitol in the prime, and mild hypothermia incurred during CPB might all affect the S100ß level. Once the patients had been uniformly rewarmed and excreted out the circuit prime, the relationship between subsequent S100ß measurements became apparent. With bedside biosensor technology, there might be a place in clinical practice to ascertain whether a patient has sustained a perioperative stroke using a blood sample 30 minutes postoperatively. There is good evidence to show that patients who have had neurologic complications after cardiac operations have markedly elevated S100ß levels [18].

Our data indicated that there might be a relationship between 24-hour S100ß levels and prolonged intubation (r = 0.40, p = 0.04). This result is plausable, as patients who have perioperative strokes take longer to extubate. In the present series there were no overt strokes; however, the data imply that patients who sustain a greater degree of astroglial damage take longer to wean from the ventilator. This conclusion is speculative as pulmonary characteristics were not analyzed in these patients. In our ongoing study we are prospectively recording patients who are slow to wean from the ventilator despite good cardiovascular and pulmonary values.

In conclusion, we showed that preoperative S100ß levels can be measured using the new immunoluminometric assay and that centrifugal pumps do not significantly reduce S100ß release compared with roller pumps when the mean bypass time is about 90 minutes.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

  1. Reed G., Singer D., Picard E., et al. Stroke following coronary artery bypass surgery. N Engl J Med 1988;319:1246-1250.[Abstract]
  2. Shaw P.J., Bates D., Cartlidge N.E.F., Heaviside D., Julian D.G., Shaw D.A. Early neurologic complications of coronary artery bypass surgery. BMJ 1985;291:1384-1387.
  3. Blauth C.I. Macroemboli and microemboli during cardiopulmonary bypass. Ann Thorac Surg 1995;59:1300-1331.[Abstract/Free Full Text]
  4. Stump D.A., Tegeler C.H., Rogers A.T., et al. Neuropsychologic deficits are associated with the number of emboli detected during cardiac surgery. Stroke 1990;24:A509.
  5. Pugsley W., Klinger L., Paschalis C., Treasure T., Harrison M., Newman S. The impact of microemboli during cardiopulmonary bypass on neuropsychological functioning. Stroke 1994;25:1393-1399.[Abstract]
  6. Padayachee T.S., Parsons S., Theobald R., Linley J., Gosling R.G., Deverall P.B. The detection of microemboli in the middle cerebral artery during cardiopulmonary bypass: a transcranial Doppler ultrasound investigation using membrane and bubble oxygenators. Ann Thorac Surg 1987;44:298-302.[Abstract]
  7. Padayachee T.S., Parsons S., Theobald R., Linley J., Gosling R.G., Deverall P.B. The effect of arterial filtration on the reduction of gaseous microemboli in the middle cerebral artery during cardiopulmonary bypass. Ann Thorac Surg 1988;45:647-649.[Abstract]
  8. Clark R.E., Goldstein A.H., Pacella J.J., et al. Small, low-cost implantable centrifugal pump for short-term circulatory assistance. Ann Thorac Surg 1996;61:452-456.[Abstract/Free Full Text]
  9. Westaby S., Johnsson P., Parry A., et al. Serum S-100 protein: a potential marker for cerebral events during cardiopulmonary bypass. Ann Thorac Surg 1996;61:88-92.[Abstract/Free Full Text]
  10. Taggart D.P., Mazel J., Bhattacharya K., et al. A comparison of serum S100ß levels during open and closed heart surgery. Ann Thorac Surg 1997;63:492-496.[Abstract/Free Full Text]
  11. Taggart D.P., Bhattacharya K., Meston N., et al. Serum S100 protein after cardiac surgery: a randomized trial of arterial line filtration. Eur J Cardiothorac Surg 1997;11:645-649.[Abstract]
  12. Blumenthal J.A., Mahanna E.P., Madden D.J., White W.D., Croughwell N.D., Newman M.F. Methodological issues in the assessment of neuropsychologic function after cardiac surgery. Ann Thorac Surg 1995;59:1345-1350.[Abstract/Free Full Text]
  13. Cosgrove D.M., Loop F.D., Lytle B.W., et al. Primary myocardial revascularization. Trends in surgical mortality. J Thorac Cardiovasc Surg 1984;88:673-684.[Abstract]
  14. Gardner T.J., Horneffer P.J., Manolio T.A., et al. Stroke following coronary artery bypass grafting: a ten year study. Ann Thorac Surg 1985;40:574-581.[Abstract]
  15. Truman K.J., McCarthy R.J., Najafi H., Ivankovich A.D. Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg 1992;104:1510-1517.[Abstract]
  16. Toner I., Peden C.J., Hamid S.K., Newman S., Taylor K.M., Smith P.L. Magnetic resonance imaging and neuropsychological changes after coronary bypass graft surgery. J Neurosurg Anesthesiol 1994;6:163-169.[Medline]
  17. Johnsson P. Markers for cerebral injury after cardiac surgery. J Cardiothorac Vasc Anesth 1996;10:120-126.[Medline]
  18. Johnsson P., Lundqvist C., Lindgren A., Ferencz I., Alling C., Stahl E. Cerebral complications after cardiac surgery assessed by S-100 and NSE levels in blood. J Cardiothorac Vasc Anesth 1995;9:694-699.[Medline]



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