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J Thorac Cardiovasc Surg 2000;119:148-154
© 2000 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

SERUM S-100 PROTEIN RELEASE AND NEUROPSYCHOLOGIC OUTCOME DURING CORONARY REVASCULARIZATION ON THE BEATING HEART: A PROSPECTIVE RANDOMIZED STUDY

From the Bristol Heart Institute^a and Department of Anaesthesia,^b University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom.

This work was supported by the Sir Siegmund Warburg’s Voluntary Settlement Fund and the British Heart Foundation.

Address for reprints: Gianni D. Angelini, FRCS, Bristol Heart Institute, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom (E-mail: G.D.Angelini{at}bristol.ac.uk).

	Abstract

Top Abstract Introduction Methods Results Conclusions References

 
Objectives: Our purpose was to establish whether coronary revascularization on the beating heart without cardiopulmonary bypass is less harmful to the brain than conventional surgery with cardiopulmonary bypass as indicated by measures of cognitive function or by changes in serum concentrations of S-100 protein, a recognized biochemical marker of cerebral injury.
Methods: We conducted a prospective randomized trial in which the assessors of the outcome measures were blind to the treatment received. Sixty patients without known neurologic abnormality, undergoing coronary revascularization, were prospectively randomized to 1 of 2 groups: (1) cardiopulmonary bypass (32°C-34°C) and cardioplegic arrest (on pump) with intermittent antegrade warm blood cardioplegia or (2) surgery on the beating heart (off pump). Neuropsychologic performance was assessed before and 12 weeks after the operation. Serum S-100 protein concentration was measured at intervals up to 24 hours after the operation.
Results: The groups had similar preoperative characteristics. There were no deaths or major neurologic complications in either group, nor was there any difference between groups in the chosen index of neurologic deterioration. Serum S-100 protein concentrations were higher in the on-pump group at 30 minutes, but any such difference between groups had disappeared 4 hours later. The extent of the changes in S-100 protein was unrelated to the index of neuropsychologic deterioration.
Conclusions: The changes in S-100 protein concentration suggest that the brain and/or blood-brain barrier may be more adversely affected during coronary artery surgery with cardiopulmonary bypass than during surgery on the beating heart, but that this may not be reflected in detectable neuropsychologic deterioration at 12 weeks.

	Introduction

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Coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB) is a safe, routine procedure with a mortality of 2% to 3% in elective cases. ¹ Nevertheless, it is still associated with significant morbidity, mostly because of the cytokine response to the nonphysiologic nature of CPB. ^2,3 Although gross cerebral events such as stroke are rare, between 2% and 6% of patients have some form of neurologic injury in the initial perioperative period. In addition, subtle neuropsychologic changes develop in 20% to 60%. ^4,5 These changes in cognitive function may persist with an incidence of 25% to 30% 8 weeks after the operation, with only slightly lower levels at 1 year. ⁶ The mechanisms of these deleterious effects of CPB on the central nervous system are multifactorial. These include hypoperfusion during CPB, ⁷ microemboli of a gaseous or particulate origin, ⁸ or inflammatory changes that effect an increase in permeability across the blood-brain barrier with resultant cerebral edema. ^9,10

A number of biochemical markers have been suggested in an attempt to quantify the neuronal injury at the time of insult, among them protein S-100. This is an acidic, calcium-binding protein found in high concentrations in glial and Schwann cells. ¹¹ The appearance of this protein in serum indicates both neuronal damage and increased permeability of the blood-brain barrier.

Recently, interest in coronary revascularization on the beating heart has been revived, with the suggestion that avoidance of CPB may reduce neuropsychologic damage. There are, however, no data available as part of a prospective randomized trial on the possible relation between a recognized marker of ischemic brain injury such as protein S-100 and neuropsychologic outcome in patients undergoing elective CABG with or without CPB.

	Methods

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Patient selection
With approval from the local research ethical committee, 60 patients undergoing first-time CABG were enrolled in the study. They were part of a larger prospective randomized study comparing on-pump and off-pump surgery. From July 1997 to July 1998, 246 patients underwent first-time CABG under the supervision of a single consultant (G.D.A.). During this period 127 patients were eligible for randomization. Two patients refused to consent on personal grounds. Of the 125 remaining patients, 62 were randomized to on-pump and 63 to off-pump surgery. Thirty patients from each group were suitable for neuropsychologic studies. All patients were fully informed and signed consent forms. Exclusion criteria included cardiac ejection fraction of less than 30%, myocardial infarction within the previous 1 month, disease involving the distal circumflex coronary artery, reoperation or combined valvular surgery, respiratory or renal impairment, and coagulopathy. Meticulous care was taken to exclude patients with previous psychiatric illness, previous stroke, or transient ischemic attacks, and any patient with suspected carotid artery disease underwent carotid duplex ultrasonography. The enrolled patients were prospectively randomized into 2 groups by card allocation: (1) on-pump group—conventional myocardial revascularization with CPB and cardioplegic arrest of the heart; (2) off-pump group—revascularization on the beating heart.

Anesthetic technique
Anesthetic technique was standardized for all patients. This consisted of propofol infusion at 3 mg · kg^–1 · h^–1 combined with remifentanil infusion at 0.5 to 1 µg · kg^–1 · min^–1. Neuromuscular blockade was achieved with 0.1 to 0.15 mg · kg^–1 of pancuronium or vecuronium and the lungs were ventilated to normocapnia with 45% to 50% oxygen in nitrogen. Propofol and remifentanil infusions were maintained throughout the operation. In the on-pump group, metaraminol or phentolamine was used as required to maintain the systemic pressure between 50 and 60 mm Hg. In the off-pump group, a mean arterial pressure of 60 mm Hg or above was maintained with metaraminol or fluids as indicated by the hemodynamic condition. Esmolol was used as necessary to maintain the heart rate less than 65 beats/min.

Heparin and protamine management
In the on-pump group, heparin was given at a dose of 300 IU · kg^–1 to achieve a target activated clotting time (ACT) of 480 seconds or above before the start of CPB. In the off-pump group, a heparin dose of 100 IU · kg^–1 was given before the start of the first anastomosis. The target ACT in this group was between 250 and 350 seconds. Protamine was used at the end to reverse the effect of heparin and return the ACT to preoperative levels.

Surgical technique

On-pump group
CPB was instituted by means of ascending aortic cannulation and a 2-stage venous cannulation via the right atrium. A standard CPB circuit was used consisting of a Bard tubing set (C. R. Bard, Inc, Santa Ana, Calif), which included a 40-µm filter, a Stöckert roller pump (Sorin Biomedica, Midhurst, United Kingdom), and a hollow-fiber membrane oxygenator (Monolyth, Sorin Biomedica, Midhurst, United Kingdom). The extracorporeal circuit was primed with 1000 mL of Hartmann solution, 500 mL of gelofusine, a 0.5 g · kg^–1 concentration of mannitol, 7 mL of 10% calcium gluconate, and 60 mg of heparin. Nonpulsatile flow was used. The flow rate throughout bypass was 2.4 L · m² · min^–1. Systemic temperature was allowed to vary between 32°C and 34°C. Myocardial protection was achieved by means of intermittent antegrade warm blood cardioplegia as described by Calafiore and associates. ¹²

Once all distal anastomoses had been completed, the aortic crossclamp was removed and the proximal anastomosis was carried out with partial clamping of the aorta.

Off-pump group
The method of exposure and stabilization used to carry out the distal anastomoses was a combination of the technique previously described by our group ¹³ and the use of the CTS retractor (CardioThoracic Systems, Cupertino, Calif). ¹⁴ The target vessel was exposed and snared above the chosen point for anastomosis by means of a 4-0 Prolene polypropylene suture (Ethicon, Inc, Somerville, NJ) with a soft piece of plastic "snugger" to prevent coronary injury. The coronary artery was then opened and the anastomosis performed with a continuous suture. Visualization was enhanced by a surgical blower-humidifier device (model SSVW-002; Surgical Site Visualization Wand; Research Medical Inc, Midvale, Utah) with a-inch polyvinyl chloride gas line and fluid administration set connected to a regulated gas source of medical air. An intracoronary shunt (Anastoflo Intravascular Shunt; Research Medical Inc) was used only if there was appreciable electrocardiographic or hemodynamic instability or excessive bleeding during the construction of the anastomosis.

Samples for serum S-100 protein analysis
Blood samples (4 mL) were collected from the central venous pressure line at induction of anesthesia, 30 minutes after cessation of CPB in the on-pump group or 30 minutes after completion of all anastomoses in the off-pump group, and 4, 12, and 24 hours after the operation. The samples were centrifuged within an hour of collection to separate the serum, which was frozen and stored at –20°C.

S-100 protein assay
The S-100 immunoradiometric assay (Sangtec 100; Sangtec Medical AB, Bromma, Sweden) is a monoclonal 2-site immunoradiometric (sandwich) assay. The method discriminates between the -subunit and ß-subunit (ß-S-100 is present in high concentration in glial cells and Schwann cells) and measures the ß-subunit of the S-100 protein as defined by the 3 monoclonal antibodies SMST 12, SMSK 25, and SMSK 28. All samples were independently analyzed by Cambridge Life Sciences, Cambridge, United Kingdom.

Clinical and neuropsychologic assessment
The preoperative assessment included all of the usual clinical and investigation measures. The general level of risk for cardiac operations was expressed in terms of the New York Heart Association classification and Parsonnet’s operative risk stratification. ¹⁵ Postoperative neurologic status was assessed daily by clinical examination until the patient was discharged from the hospital. The patient’s neurologic and neuropsychologic state was assessed a few days before the operation, to provide accurate baseline information, and 12 weeks after the operation. A suitably qualified and trained examiner, blinded to the surgical treatment, carried out the tests in a standardized manner. In accordance with the "Statement of Consensus on Assessment of Neurobehavioral Outcomes After Cardiac Surgery," ¹⁶ we subjected the patients to a battery of core tests that covered memory, language, psychomotor speed, attention, and concentration. This consisted initially of 2 tests from the Wechsler Memory Scale (WMS) and a battery of 5 neuropsychologic tests taken from the revised Wechsler Adult Intelligence Scale (WAIS). ¹⁷ These are accepted tests of global cognitive function. The tests were presented in a fixed order according to conventional practice, and the scores were arranged such that larger scores indicated better neuropsychologic performance.

In addition, because cognitive function may be influenced by mood, ¹⁶ each patient’s current mental health was assessed by means of the General Health Questionnaire (GHQ-30) ¹⁸ and Hospital Anxiety and Depression Scale (HAD). ¹⁹

Statistical methods
As in our group’s work in this area, ¹⁷ the principal outcome measure of change in cognitive function for each patient was the number of neuropsychologic tests showing deterioration between baseline and the assessment 12 weeks after the operation. The numbers recruited were based on the requirement for 90% power to detect a difference of 1.18 scores, with an alpha error set at 0.05. This was the same difference that we saw in our previous study ¹⁷ between patients who received CPB perfusion at 32°C and those who received it at 37°C. The difference in this measure between on-pump and off-pump groups was examined in a single variable model by means of the Student t test and in a multivariable model to examine for the effects of any documented confounders. A stepwise multiple regression was undertaken, offering age, the changes in scores for Hospital Anxiety and Hospital Depression in the General Health Questionnaire, and the treatment (on pump or off pump) as explanators. This analysis, which examined only the direction of change without taking into account the magnitude, was supported by a multivariate analysis of variance (MANOVA), using a general linear model and offering age and the scores for Hospital Anxiety and Hospital Depression as possible confounders.

For effects on S-100 protein over time, the prospectively planned analysis was a repeated-measures analysis of variance (ANOVA), applied to the data from the 4 collection times after the preoperative sample. This was to examine for effects of time, group, and group-time interaction. When the data were obtained, the concentration values at most of the measurement times were not normally distributed, so that the probability estimates from the ANOVA were potentially unreliable. For supporting analyses, the area under the concentration curve (AUC) from the second sample time was calculated by triangulation as a summary measure for each patient. This measure was not normally distributed. A Mann-Whitney U test was used to examine whether this measure varied between groups (on pump or off pump). Subsidiary Mann-Whitney testing was also undertaken on the concentrations at each sampling time. A Kruskal-Wallis test was used to examine for variation with the primary outcome variable (number of deteriorations in neuropsychologic scores) and a Spearman rank correlation to examine for variation with age.

All descriptive statistics and inferential testing were carried out by means of procedures in StatView (SAS Institute, Inc, Cary, NC) or Minitab 10.1 for Windows (Minitab Inc, State College, Pa).

	Results

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Table I indicates the distributions of age, sex, extent of disease, left ventricular function, and number of grafts of the patients in each group. In the inferential testing that was undertaken to check on the effectiveness of the randomization, the only notable result was that the observed difference in age between the 2 groups was to be expected in only 5.4% of random allocations of this sort. None of the patients who were referred for duplex carotid ultrasonography had a carotid stenosis greater than 50%. There were no deaths, major neurologic complications, or intraoperative myocardial infarctions in either group. Intubation time, intensive care stay, and length of hospital stay were significantly shorter in the off-pump group than in the on-pump group(Table II).

View larger version (23K): [in this window] [in a new window]   Fig. 1. Deteriorations in neuropsychologic test score in the on-pump and off-pump groups.

S-100 protein concentration
Fig 2 shows the distributions of S-100 protein concentrations in the 2 groups at the different sampling times, with "box and whisker" symbols used to indicate medians, interquartile ranges, and total ranges. The prospectively planned repeated-measures ANOVA identified a highly significant (P = .02) effect of group (on pump or off pump) and a very highly significant effect of time (P = .01) and group time interaction (P = .02) (ie, the difference between groups depended on the sampling time). Testing at individual sampling times with Bonferroni correction showed a highly significant difference (P = .01) at the 30-minute sampling time but not at subsequent sampling periods. The reliability of the P values is called into question by the skewedness of the data, as indicated inFig 2. Analysis of residuals showed significant non-normality in their distribution about the ANOVA model, and this could not be usefully reduced by a simple logarithmic transformation. The suspect findings of the repeated-measures ANOVA were supported by the difference in AUC of the S-100 protein concentrations between the 2 treatment groups. The median AUC in the on-pump group was 3.14 µg · h^–1 · L^–1 with an interquartile range from 1.89 to 6.90, whereas in the off-pump group it was 2.19 with an interquartile range from 0.80 to 3.52 (Mann-Whitney test, P = .6). The Bonferroni-corrected Mann-Whitney tests on the concentrations at each sampling time indicated that any difference in AUC was largely due to the difference in concentration at 30 minutes.Table IV shows the median AUCs and interquartile ranges in the groups characterized by number of neuropsychologic deteriorations. There was no obvious trend (Kruskal-Wallis test, P = .2). The very large AUC in 1 of the 3 patients with 5 score deteriorations was in a patient whose baseline S-100 concentrations were already high. The Spearman rank correlation for AUC with age was 0.507 (P = .05).

View larger version (23K): [in this window] [in a new window]   Fig. 2. Serum S-100 protein levels (micrograms per liter) up to 24 hours after the operation in the on-pump and off-pump groups. Data are presented as medians with interquartile and total ranges.

	Conclusions

Top Abstract Introduction Methods Results Conclusions References

Currently, serum S-100 protein is widely recognized as the most accurate biochemical marker of neuronal injury. ^5,8,11 The most conservative, nonparametric analysis of the serum S-100 protein concentrations over time gave only 94% confidence that there was a bigger rise in the on-pump group. Even the apparently more discriminating but also more suspect repeated-measures ANOVA indicated that any such difference had been measured only at 30 minutes after the operation and had essentially disappeared by 4 hours. Even if the existence of a short-lasting difference in S-100 protein concentrations between the on-pump and off-pump groups is accepted, it is not necessarily attributable to the presence or absence of the pump. The randomization happened to produce a slight preponderance of relatively older patients in the on-pump group, and the AUC of the S-100 protein concentrations tended to increase with increasing age. Both the association with age and the rapid disappearance of elevated postperfusion concentrations of S-100 protein are in accordance with observations by other authors. ^5,11,29 Westaby and associates ⁵ speculated that the elevations reflect diffuse microembolic cerebral injury together with increased permeability of the blood-brain barrier rather than irreversible cerebral damage through neuronal ischemia. Their studies show a correlation of S-100 protein not only with the duration of CPB but also with the presence of carotid artery stenoses. ⁸ The clearance of S-100 protein is reduced by reduction in glomerular filtration rate. This may be a plausible explanation for the transient rise in S-100 protein in the on-pump group, but further studies would need to confirm this. Our results may support the hypothesis that, at least in carefully selected, relatively young patients undergoing elective operations, with no previous history of neurologic injury, modern CPB causes only a transient loss of cerebral autoregulation with increased permeability of the blood-brain barrier resulting in temporary, functional rather than long-term, structural changes. It remains to be seen whether this is so in more elderly patients with pre-existing neurologic deficits.

	Acknowledgments

 
We thank Amanda Burston for her invaluable help with the neuropsychologic testing and Simon Howell for his help in preparing this manuscript.

	References

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