Department of Anaesthetics and Intensive Care Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK
Abstract
The identification of a serum marker to assist in the diagnosis of cerebral injury after cardiac surgery is potentially useful. S100 protein is an early marker of cerebral damage. It is released after cardiac surgery performed under cardiopulmonary bypass (CPB). Its level is correlated with the duration of CPB, deep circulatory arrest and aortic cross-clamping. Increased levels of S100 protein are correlated with the age of the patient and the number of microemboli, especially during aortic cannulation. Perioperative cerebral complications such as stroke, delayed awakening and confusion are associated with increased levels of S100 protein directly after bypass and from 15 to 48 h after it. In addition, increased levels of S100 protein are related to neuropsychological dysfunction after cardiac surgery. S100 protein has early and late release patterns after CPB; the early pattern may be due to sub-clinical brain injury. The late release pattern may be due to perioperative cerebral complications. Patients undergoing intracardiac operations combined with coronary artery bypass surgery are more susceptible to brain injury and have higher levels of S100 after CPB. Furthermore, adults and children undergoing deep circulatory arrest are more susceptible to brain injury, in terms of higher S100 protein release after CPB. Serum S100 protein levels are reduced after using arterial line filtration and covalent-bonded heparin to coat the inner surface of the CPB circuit.
Br J Anaesth 2000; 85: 28798
Keywords: surgery, cardiovascular; complications, arrest, cardiac
Despite advances in anaesthesia, cardiopulmonary bypass (CPB) and surgical techniques, cerebral injury remains a major source of morbidity after cardiac surgery.9 25 51 58 69 71 78 The diagnosis of cerebral injury currently relies on clinical neurological examination, computed axial tomography (CT) or magnetic resonance imaging (MRI). However, these methods are not always suitable for use immediately after cardiac surgery when patients may be unconscious, sedated and artificially ventilated, or haemodynamically unstable, and thus unable to cooperate. The identification of a biochemical serum marker to assist in the diagnosis of cerebral injury would potentially be useful.
One way to demonstrate the adequacy of a particular biochemical marker is to establish a correlation between a plasma level and neurological or neuropsychological outcome. Another possibility would be to establish an association with some variable that is considered relevant to the neuropsychological outcome, for example number of microemboli,68 69 duration of CPB,47 or the use of arterial filters.68 Other methods might involve changing the CPB strategy or surgical technique, or using neuroprotective drugs (e.g. GM1 ganglioside,30 magnesium sulphate (MgSO4)40 53 56 57 84) or anti-inflammatory drugs (e.g. methylprednisolone, aprotinin29), to study the effect of this change or beneficial effect on biochemical marker levels.42
S100 protein is an early marker for brain damage, which might be valuable to gauge the timing and extent of cerebral damage after CPB. Recently, elevated serum levels of S100 have been detected after adult cardiac operations complicated by neurological injury.5 10 93
In this review, the pattern of S100 protein release and its relation to postoperative neurological outcome after cardiac operations with different CPB techniques will be discussed.
What is S100 protein?
In 1965, Moore isolated a subcellular fraction from bovine brain, which was thought to contain nervous system-specific proteins.62 This fraction was called S100 because the constituents were soluble in 100% saturated ammonium sulphate at neutral pH. The S100 protein family contains 16 members based on amino acid sequence homology and similar structural properties.95 S100 protein is an acidic calcium-binding protein (molecular weight 21 kDa) found in high concentrations in glial and Schwann cells. It exists in various forms depending on alpha or beta unit configuration. The beta subunit is highly brain specific. The beta-beta (S100ß) units are present in glial and Schwann cells, the alpha-beta (S100
ß) subunits appear in glial but not in Schwann cells,6 39 whereas alpha-alpha (S100a0) subunits are present in striated muscles, heart and kidney. S100 protein is metabolized in the kidney and excreted in urine, and has a biological half-life of
2 h.91
The exact functions of S100 proteins are not well known. As S100 proteins are mostly present intracellularly, the majority of the molecules will function as intracellular calcium receptor proteins.95 In addition, Zimmer and colleagues suggested that S100 proteins modulate a wide range of intracellular processes including inter-cell communication, cell structure, growth, energy metabolism, contraction and intracellular signal transduction. Furthermore, S100ß protein is involved in promoting axonal growth, glial proliferation, neuronal differentiation and calcium homeostasis.18 34 77 More importantly, S100ß protein is considered as a contributing factor in Alzheimers disease and acquired immune deficiency syndrome (AIDS).54 82 Interestingly, studies using animal models have suggested that extracellular S100 protein may play a role in learning and memory.20 45
S100 protein assay
Two methods for S100 protein analysis have been described.
(1) Monoclonal two-site immunoradiometric assay (Sangtec 100; Sangtec Medical AB, Bromma, Sweden), which has a lower detection limit of 0.2 µg litre1.93
(2) Immunoluminometric assay (Sangtec LIA100; AB Sangtec Medical, Bromma, Sweden) which can measure S100 protein to 0.02 µg litre1.3
Both types of assay use three monoclonal antibodies (SMST12, SMSK 25, SMSK 28) to detect the ß chains in the ßß and ß dimers of S100 protein.
S100 protein is normally not detectable in serum, but appears after a stroke, subarachnoid haemorrhage, head injury or CPB.35 42 66 67 93 The lower limit of detection ranges from 0.02 to 0.2 µg litre1, depending on the type of assay.3 93 S100 protein levels in excess of 0.5 µg litre1 are considered pathological.93
S100 protein is thermostable and its assay is not affected by heparin, protamine or propofol.21 Similarly, haemolysis has no effect on the analysis of S100 protein samples.22 Samples can therefore be taken throughout surgery involving CPB. S100 protein is stable on storage of the whole blood sample for up to 48 h, either room temperature or at 4°C, before and after CPB operations.75
S100 protein release in non-cardiac surgery patients
S100 protein in pathological conditions
Increased levels of S100 protein have been observed in Alzheimers disease, dementia associated with Downs syndrome and in AIDS. Elevation of serum S100 protein is directly related to an increased gene expression.2 31 82 In fact, the position of the S100ß gene is on the long arm of chromosome 21 which is also involved in the translocation causing Downs syndrome.17
Interestingly, Lindberg and colleagues49 found high levels of S100 protein before and after CPB in children with Downs syndrome. However, there was no significant change in S100 protein concentrations after CPB compared with the pre-bypass levels. The authors49 suggested that the increased concentrations of S100 protein in children with Downs syndrome may be explained by duplication of chromosome 21, possibly in conjunction with a more permeable bloodbrain barrier.
In Alzheimers disease, there is DNA amplification in regions near to the localization site of S100ß protein. However, the correlation between the increased levels of S100 protein and features seen in Alzheimers disease or Downs syndrome is not clear.55 It is possible that the abnormally high S100 protein levels could induce alterations in neurite outgrowth, and glial cell proliferation and morphology, and also affect calcium homeostasis leading to cell death.17
S100 protein after minor head injury
Ingebrigsten and colleagues38 reported increased serum levels of S100 protein after minor head injury. Minor head injury is characterized by a lack of demonstrable focal neurological deficit and apparent clinical recovery.92 But, Waterloo and colleagues92 found that the raised levels of S100 protein after minor head injury are associated with specific dysfunction on tests of attention, 12 months after injury. The authors suggested that the increased serum levels of S100 protein may be of prognostic value for long-standing neurocognitive abnormalities after minor head injury.92
S100 protein in patients with acute stroke
High S100 protein concentrations have been detected in 7181% of patients with acute ischaemic stroke, but not in healthy subjects.15 19 Patients with detectable S100 protein had significantly larger brain lesions. S100 protein levels were increased in patients with larger infarctions at 10 h and thereafter following the onset of symptoms.19 Neurological outcome scores, as assessed by the Scandinavian stroke scale,76 were inversely correlated with serum levels of S100 protein determined after 10 h (r=0.56, P<0.05), 24 h (r=0.8, P<0.05) and 72 h (r=0.78, P<0.05). Three patients who had fatal outcomes had the highest serum S100 concentrations.19
The peak levels of S100 protein were recorded on the third day after the stroke.15 61 Missler and colleagues61 found that the peak levels were correlated with the infarct volume when measured by volumetric CT scan (r=0.75, P<0.001), and with the clinical outcome assessed by the Glasgow outcome scale (r=0.51, P<0.001). In addition, Büttener and colleagues15 observed that patients with severe neurological deficits on admission, extensive infarction and the space-occupying effect of ischaemic oedema, had significantly higher serum S100 protein concentrations. These studies suggest that serum S100 protein concentration during acute stroke is a useful marker of infarct size and clinical outcome. Furthermore, it might be useful in monitoring the effects of new therapies in acute cerebral disease.
S100 protein after cardiac arrest
Rosén and colleagues72 used S100 protein levels for prognostic evaluation in 41 patients after cardiac arrest. The highest levels of S100 protein were found on the first day after arrest. Moreover, S100 protein levels on day 2 correlated with the degree of coma (r=0.49, P<0.01) and the period of anoxia on days 1 and 2 (r=0.50, P<0.01, and r=0.60, P<0.01, respectively). Interestingly, all patients with a S100 protein level 0.2 µg litre1 on day 2 after cardiac arrest died within 14 days, and 89% of patients with levels below this value survived. It is clear that the increase in S100 protein after cardiac arrest reflects the degree of hypoxic brain damage and can help to predict the short-term outcome.
Cardiac surgery and S100 protein
Patterns of S100 protein release after cardiac surgery
Adult cardiac surgery
Blomquist and co-workers10 studied the pattern of S100 protein release during and after cardiac surgery. In one group of patients, samples were collected after heparin administration, 20 min after the start of CPB, at the end of CPB, and then at 3, 6, 12, 24 and 48 h after the end of CPB. In a second group, the course of S100 protein release was defined by samples taken: before anaesthesia; before the start of surgery; before the administration of heparin; and at 10 and 40 min after the start of CPB. At the end of CPB, samples were collected every 15 min for 90 min; thereafter samples were taken at 2, 3, 4, 5, 6, 8, 10 and 20 h after CPB. In the first group, detectable concentrations of S100 protein were found 20 min after the start of CPB. Maximum levels (mean (SD), 2.43 (0.3) µg litre1) occurred at the end of CPB; thereafter concentrations declined to 1.2 (0.2) µg litre1 at 3 h after the end of CPB. An increase in S100 protein level was observed at 5 h post-CPB and was followed by a steady decrease throughout the period of study. In the second group, a similar pattern was observed. Maximum levels of S100 protein (1.96 (0.38) µg litre1) were noted at the end of CPB. The levels then stabilized 5 h after CPB, followed by a steady decrease until the end of the study. Before CPB, anaesthesia of 2 h or more in combination with surgery did not initiate any release of S100 protein into serum. Westaby and colleagues93 confirmed that elevations in serum levels of S100 did not occur in patients who underwent coronary artery bypass surgery without CPB. Furthermore, S100 did not appear in the serum of patients who had thoracic surgery without CPB48 (Table 1).
|
Jönsson and colleagues43 characterized the S100 protein release pattern after CPB in 515 patients undergoing coronary artery bypass surgery, 85 (16.5%) of whom had pre-operative cerebrovascular disease. Samples were taken at the end of CPB, and after 5, 15 and 48 h. Serum levels of S100 protein decreased gradually with time after termination of CPB. An early increase in S100 protein at the end of CPB and up to 5 h was related to patient age (r=0.59, P<0.001;87 r=0.29, P<0.000143), and duration of CPB (r=0.89, P<0.001;93 r=0.58, P<0.001;49 r=0.93, P<0.00126). In addition, Jönsson and colleagues43 found that patients with a previous history of stroke or transient ischaemic attack had higher S100 protein levels directly after CPB than patients who did not have such a history (mean (SD), 3.3 (2.4) vs 2.2 (1.8) µg litre1, P<0.001). Furthermore, patients with pre-operative impaired renal function (serum creatinine >177 µmol litre1) had higher S100 protein levels at 5 h after CPB.43
The relationship of increased levels of S100 soon after CPB to age suggests more cerebral vulnerability in older patients. Age is known to be a risk factor for increased neurological injury after cardiac operations,37 83 90 and is the most important predictor of stroke following coronary artery bypass grafting surgery.64 Interestingly, increased age has been found to predispose to impaired cognitive function after cardiac surgery.63 65 The most likely explanation is the increasing prevalence of arteriosclerosis with occult cerebrovascular disease as well as an increased risk of embolism from ascending aortic plaques in older patients.9
After cardiac surgery, most of the neurological injuries have been thought to be due to macroemboli (200 µm in diameter or greater) and microemboli (less than 200 µm in diameter).1214 50 60 71 74 81 Macroemboli (associated with atherosclerotic plaque disruption) are believed to precipitate focal defects, whereas particulate microemboli (consisting of white cell and platelet aggregates, or fat) may be implicated in more subtle cerebral dysfunction.52
Patients with pre-existing cerebrovascular disease such as a past history of stroke, transient ischaemic attack or an atheromatous aorta, may have subclinical cerebral pathology, which predisposes to early S100 protein release after CPB.43 In addition, patients with a previous history of cerebrovascular disease are generally believed to be at greater risk of further cerebral injury during CPB.70 Primary perioperative cerebral complications such as delayed awakening, confusion or stroke are associated with higher levels of S100 protein at 1548 h after CPB.43
Early release of serum S100 protein after CPB is associated with different pre- and perioperative events and it is difficult to determine the exact cause of its release (Table 2). The level of S100 protein at which stroke or any cerebral complication can be diagnosed is not entirely clear. In addition, the patterns of S100 protein release give little or no information about the anatomical distribution of the injury and its functional impact. However, it is generally considered an early indicator of brain injury that has occurred either during or after CPB. In particular, its value is that it can be measured at a time when other diagnostic techniques (e.g. neurological and neuropsychological examinations, CT scan, MRI) may not be suitable or are not able to detect such injuries.
|
Recently, in neonates and infants undergoing open-heart surgery, Abdul-Khaliq and colleagues1 found a significant and continuous increase of S100 protein compared with pre-bypass levels, at 5 min on CPB, and 5 min before and 5 min after aortic cross-clamping. Peak levels were reached at the end of CPB. Interestingly, they also recorded a concomitant elevation of malondialdehyde (a marker of radical-induced lipid peroxidation, which may provide information on excessive generation of free radical from membrane injury) parallel to the increased S100 protein, especially after declamping and at the end of CPB. An important pathogenic factor involved in the reperfusion injury is the generation of oxygen-free radicals.8 27 59 Abdul-Khaliq and colleagues1 suggested that injured astrocytes may release S100 protein, which penetrates the injured endothelial barrier and enters the blood. This assumption is supported by a simultaneous increase in malondialdehyde concentrations. Significant contamination of malondialdehyde from other organs is unlikely, because blood samples were from veins which drain the brain, and malondialdehyde only has a half-life of 10 min. The significance of such observations requires further neurophysiological and neurodevelopmental follow-up studies.
High serum levels of S100 protein have been associated with increased levels of the serum cytokine inflammatory mediators, interleukin 6 and 8 (IL-6 and IL-8). After paediatric cardiac surgery, IL-6 increased at the end of CPB and correlated with S100 at 2 h after CPB (r=0.55, P=0.03). IL-8 correlated with S100 protein at 24 h after CPB (r=0.77, P=0.002).4 The authors suggested that increased S100 protein levels after cardiac surgery may, in part, be cytokine mediated.4
Thus, serial measurements of S100 protein with identification of early and late release patterns may, in the future, provide a marker for the more accurate diagnosis of cerebral injury after CPB. In addition, further studies need to be performed to identify the S100 protein release patterns after warm CPB in adults and children undergoing open-heart surgery.
The recommended timing for S100 protein estimation, when studying adult and paediatric patients undergoing cardiac surgery, is illustrated in Table 3.
|
|
|
S100 protein and neuropsychological dysfunction after cardiac surgery
Grocott and colleagues33 found an association between serum S100 protein level and neurocognitive dysfunction after CPB surgery. In addition, Kanbak and colleagues44 found a moderate correlation (r=0.43) between the Visual Aural Digit Span test (VADST) and serum S100 protein concentrations after CPB. Recently, Kilminster and colleagues46 studied S100 protein release during and 5 h after the onset of CPB, and neuropsychological tests preoperatively and for 68 weeks after surgery in 130 patients undergoing cardiac surgery. They46 found that less S100 protein release was associated with better neuropsychological performance, and the change in neuropsychological tests accounted for 23% of the variance of S100 protein area under the curve (AUC) release. With further experience, S100 protein may provide a prognostic indicator for patients with overt cerebral injury. However, the serum level of S100 protein gives no idea about the site or the clinical effects of any cerebral injury.
S100 protein release in patients without overt neurological dysfunction
High levels of S100 protein were recorded soon after CPB but decreased by 24 h postoperatively in between 11 and 87% of patients who recovered without overt neurological injury5 10 41 43 87 (Table 6). Interestingly, early subtle cognitive dysfunction occurs in up to 70% of patients after CPB,51 and it is associated with increased levels of S100 protein after CPB.33 44 46
|
Grocott and colleagues32 confirmed the association between elevated levels of S100 after CPB and the number of middle cerebral artery microemboli detected by transcranial Doppler, especially those occurring during the period of aortic cannulation. In addition, Babin-Ebell and colleagues7 observed that the release of S100 protein (calculated as AUC) was related to thrombin formation assessed by thrombinantithrombin complex (TAT), and to the total embolus count (r=0.71, P=0.0001, and r=0.42, P=0.009, respectively) during cardiac surgery. The bloodbrain barrier is based on the endothelial lining of the vasculature and, under normal circumstances, is not permeable to proteins.28 The systemic inflammatory response syndrome and endothelial cell activation and injury are well known to occur after cardiac operations.11 16 The endothelium leukocyte interaction with the release of inflammatory mediators leads to damage to endothelial integrity, sticking of leukocytes in the microcapillary bed and microcirculatory dysfunction.49 The increased endothelial permeability of the bloodbrain barrier could explain the augmented release of S100 protein in the blood after CPB.
Harris and colleagues36 have shown that cardiac surgical patients investigated using MRI within 1 h of surgery all showed signs of brain oedema. None of the patients experienced any major neurological complications after CPB. Such oedema may be regarded as indicative of cytotoxic reactions or vasogenic disorders, both of which are known to compromise the bloodbrain barrier.73 Using MRI, cerebral pathology has been documented in 30% of patients without overt clinical signs after CPB.88
S100 protein after CPB with deep circulatory arrest
Cerebral dysfunction after cardiac surgery and after reconstructive surgery involving the aortic arch in particular, is a major concern: it can lead to a very long and costly rehabilitation period. Serum S100 protein was evaluated in 10 adults before, during and after reconstructive surgery of the thoracic aorta with deep hypothermic arrest.5
Retrograde cerebral perfusion was used in eight out of the 10 patients. All patients had an increase in serum S100 protein levels immediately after CPB, followed by a decrease on the first day after surgery. The patient with the highest S100 values, both after CPB and 1 day after surgery, developed a postoperative stroke, which was verified as several frontal cerebral infarctions on CT (Table 4). There was a significant correlation with a linear relationship between the levels of S100 and the duration of circulatory arrest after CPB, with the highest correlation seen on the first postoperative day (Table 7). The duration of absent cerebral perfusion (the duration of circulatory arrest minus the duration of retrograde cerebral perfusion) correlated significantly with S100 protein level on the first postoperative day (Table 7). However, there was no significant correlation between the level of S100 protein either immediately after CPB or on the first postoperative day and the duration of CPB (Table 7). The highest correlation was seen on the first postoperative day, when the duration of absent cerebral perfusion was tested against serum levels of S100 protein. This indicates that the duration of absent cerebral perfusion and circulatory arrest are damaging to the brain, despite the use of protective deep hypothermia and partial retrograde cerebral perfusion. Furthermore, the highest correlation seen on the first postoperative day indicates the lasting effect of circulatory arrest and periods of absent cerebral perfusion on S100 protein release. Despite the lack of a significant correlation between the duration of CPB and serum levels of S100 protein, it is difficult to exclude the effect of CPB per se on S100 protein (Table 7). The lack of a significant correlation might be explained by the greater impact of the duration of circulatory arrest on the S100 protein level or by a much wider range in the duration of circulatory arrest than in the duration of CPB. In a preliminary study by Kumar and colleagues48 of four groups of patients (Table 1), the highest level of S100 after CPB was found in patients who underwent aortic arch surgery with circulatory arrest.
|
S100 protein and cerebroprotective innovations
Two randomized studies have been performed to examine the effect of different therapeutic strategies on S100 protein after CPB surgery. Taggart and colleagues86 studied the level of S100 protein in 40 patients undergoing CABG using a membrane oxygenator. Patients were randomly allocated to have a 43-µm heparin-coated arterial line filter or no filtration. Both the magnitude and persistence of S100 protein release was less in the filter group after CPB (Table 8). S100 protein was elevated in both groups at skin closure after CPB (the median and interquartile range for the non-filter group was 0.3 (00.55) µg litre1 compared to 0 (00.39) µg litre1 in the filter group). In addition, S100 protein was still detected in four patients in the non-filter group at 5 and 24 h after CPB. By contrast, it was not detected in any patient in the filter group at the same time points (Table 8). This study showed the benefit of arterial line filtration during CPB in improving cerebral protection particularly in terms of S100 protein release. This improvement may be due to a reduction in embolic load in the arterial line filter group, as the level of S100 protein appears to be correlated with the number of microemboli during CPB.32 Furthermore, Pugsley and colleagues68 reported a reduction in the incidence of microemboli detected by transcranial Doppler sonography when a 40-µm arterial line filter was used with a bubble oxygenator. More importantly, this strategy resulted in a reduction in both neuropsychological deficits and neurological injury in the form of a lower incidence of drowsiness, incoordination, nystagmus and depressed reflexes 24 h after surgery in the filter group (eight out of 50 in the filter group vs 19 out of 50 in the non-filter group), following CPB.68
|
In the future, better strategies to reduce or eliminate the systemic inflammatory response during CPB need to be developed. Additionally, further studies to evaluate the effect of these strategies on S100 protein, neurological and neuropsychological outcome, need to be performed.
Conclusions
S100 protein can be considered an early marker of cerebral injury after CPB. As a marker for cerebral damage, it is possible that S100 protein will have the potential to differentiate between the benefits and adverse effects of different perfusion strategies (e.g. choice of temperature, pulsatility, pH management) and surgical techniques. Furthermore, it can be used for evaluating the therapeutic effects of neuroprotective drugs, and with further experience, as a prognostic tool for an already existing neurological injury.
References
1 Abdul-Khaliq H, Blasig IE, Baur MO, Hohlfeld M, Alexi-Meskhisvili V, Lange PE. Release of cerebral protein S100 into blood after reperfusion during cardiac operations in infants: Is there a relation to oxygen radical induced lipid peroxidation? J Thorac Cardiovasc Surg 1999; 117: 10278
2 Allore R, OHanlon D, Price R, et al. Gene encoding subunit of S100 protein is on chromosome 21: implications for Down syndrome. Science 1988; 239: 13113[ISI][Medline]
3 Asharaf S, Bhattacharya K, Zacharias S, Kaul P, Kay PH, Watterson KG. Serum S100ß release after coronary artery bypass grafting: roller versus centrifugal pump. Ann Thorac Surg 1998; 66: 195862
4 Ashraf S, Bhattacharya K, Tian Y, Watterson K. Cytokine and S100B levels in paediatric patients undergoing corrective cardiac surgery with or without total circulatory arrest. Eur J Cardiothorac Surg 1999; 16: 327
5 Astudillo R, Van der Linden J, Radergan K, Hasson L-O, Åberg B. Elevated serum levels of S100 protein after deep hypothermic arrest correlate with the duration of circulatory arrest. Eur J Cardiothorac Surg 1996; 10: 110713[Abstract]
6 Aurell A, Rosengren LE, Karlsson B, Olsson JE, Zbornikova V, Haglid KG. Determination of S100 and glial fibrillary acidic concentrations in cerebrospinal fluid after brain infarction. Stroke 1991; 22: 12548[Abstract]
7 Babin-Ebell J, Misoph M, Müllges W, Neukam K, Reese J, Elert O. Intraoperative embolus formation during cardiopulmonary bypass affects the release of S100B. Thorac Cardiovasc Surg 1999; 47: 1669[ISI][Medline]
8 Blasing IE, Grune T, Schönheit K, et al. 4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion injury of the myocardium. Am J Physiol 1995; 269: H1422
9 Blauth CI, Cosgrove DM, Webb BW, et al. Atheroembolism from the ascending aorta. J Thorac Cardiovasc Surg 1992; 103: 110412[Abstract]
10 Blomquist S, Johnsson P, Luhrs C, et al. The appearance of S-100 protein in serum during and immediately after cardiopulmonary bypass surgery: a possible marker for cerebral injury. J Cardiothorac Vasc Anesth 1997; 11: 699703[ISI][Medline]
11 Boyle EM, Pohlman TH, Johnson MC, Verrier ED. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg 1997; 63: 27784
12 Breuer AC, Franco I, Marzewski D, Soto-Velasco J. Left ventricular thrombi seen by ventriculography are significant risk factor for stroke in open-heart surgery. Ann Neurol 1981; 10: 1034
13 Breuer AC, Furlan AJ, Hanson MR, et al. Central nervous system complications of coronary artery bypass graft surgery: prospective analysis of 421 patients. Stroke 1983; 14: 6827[Abstract]
14 Bull DA, Neumayer LA, Hunter GC, et al. Risk factors for stroke in patients undergoing coronary artery bypass grafting. Cardiovasc Surg 1993; 1: 1825[Medline]
15 Büttener T, Weyers S, Postert T, Sprengelmeyer R, Kuhn W. S100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction. Stroke 1997; 28: 19615
16 Cremer J, Martin M, Redl H, et al. Systemic inflammatory response syndrome after cardiac operations. Thorac Surg 1996; 61: 171420
17 Fano G, Biocca S, Fulle S, Mariggio MA, Belia S, Calissano P. The S100 protein: a protein family in search of a function. Progress Neurobiol 1995; 46: 7182[ISI][Medline]
18 Fano G, Mariggio M, Angelella P, Antonica N, Fulle S, Calissano P. The S100 protein causes an increase of intracellular calcium and death of PC12 cells. Neuroscience 1993; 53: 91925[ISI][Medline]
19 Fassbender K, Schmidt R, Schreiner A, et al. Leakage of brain-originated proteins in peripheral blood: temporal profile and diagnostic value in early ischemic stroke. J Neurol Sci 1997; 148: 1015[ISI][Medline]
20 Fazeli MS, Errington ML, Dolphin AC, Bliss TVP. Extra cellular proteases and S100 protein in long term potentiation in the dentate gyrus of the anaesthetized rat. Adv Exp Med Biol 1990; 268: 36975[Medline]
21 Gao F, Harris DN, Sapsed-Byrne S, Sharp S. Neurone-specific enolase and Sangtec 100 assays during cardiac surgery: Part I the effects of heparin, protamine and propofol. Perfusion 1997; 12: 1635[Medline]
22 Gao F, Harris DN, Sapsed-Byrne S, Sharp S. Neurone-specific enolase and Sangtec 100 assays during cardiac surgery: Part III Does haemolysis affect their accuracy? Perfusion 1997; 12: 1717[Medline]
23 Gao F, Harris DN, Sapsed-Byrne S, Wilson J. Sangtec 100 release with hypothermic and normothermic bypass. Perfusion 1997; 12: 456
24 Gao F, Harris DN, Sapsed-Byrne S. Time course of neurone-specific enolase and S100 protein release during and after coronary artery bypass grafting. Br J Anaesth 1999; 82: 2667
25 Gardner TJ, Horneffer PJ, Manolio TA, et al. Stroke following coronary artery bypass grafting a ten year study. Ann Thorac Surg 1985; 40: 57481[Abstract]
26 Gazzolo D, Vinesi P, Geloso MC, et al. S100 protein in children subjected to cardiopulmonary bypass. Clin Chem 1998; 44: 105860
27 Giese H, Mertsch K, Blasing IE. Effect of MK 801 and U83836E on a porcine brain capillary endothelial cell barrier hypoxia. Neurosci Lett 1995; 191: 16972[ISI][Medline]
28 Gillinov AM, Davis EA, Curtis WE, et al. Cardiopulmonary bypass and the blood brain barrier: an experimental study. J Thorac Cardiovasc Surg 1991; 104: 11105[Abstract]
29 Gott JP, Cooper WA, Schmidt FE, et al. Modifying risk of extracorporeal circulation: trial of four antiinflammatory strategies. Ann Thorac Surg 1998; 66: 74754
30 Grieco G, dHollosy M, Culliford AT, Jonas S. Evaluating neuroprotective agents for clinical anti-ischemic benefit using neurological and neuropsychological changes after cardiac surgery under cardiopulmonary bypass: methodological strategies and results of a double-blind, placebo-controlled trial of GM1 ganglioside. Stroke 1996; 27: 85874
31 Griffin WST, Stanley LC, Ling C, et al. Brain interleukin 1 and S100 protein immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA 1989; 86: 76115
32 Grocott HP, Croughwell ND, Amory DW, White WD, Kirchner JL, Newman MF. Cerebral emboli and serum S100ß during cardiac operations. Ann Thorac Surg 1998; 65: 164550
33 Grocott HP, Croughwell ND, Verkerk GC, et al. Serum S100B as a predictor of neurologic and neuropsychologic outcomes after cardiac surgery. Anesth Analg 1998; 86: S65
34 Haglid K, Yang Q, Hamberger A, Bergman S, Widerberg A, Danielson N. S-100ß stimulates neurite outgrowth in the rat sciatic nerve grafted with a cellular muscle transplants. Brain Res 1997; 753: 196201[ISI][Medline]
35 Hardemark HG, Ericsson N, Kotwica Z, et al. S100 protein and neuron specific enolase in CSF after experimental traumatic or focal ischaemic brain damage. J Neurosurg 1989; 71: 72731[ISI][Medline]
36 Harris DNF, Bailey SM, Smith PLC, Taylor KM, Oatridge A, Bydder GM. Brain swelling in first hour after coronary bypass surgery. Lancet 1993; 342: 5867
37 Heyer E, Delphinn E, Adams D. Cerebral dysfunction after cardiac operations in elderly patients. Ann Thorac Surg 1995; 60: 171622
38 Ingebrigsten T, Rommer B, Kongstand P, Langbakk B. Increased serum concentrations of protein S100 after minor head injury: a biochemical serum marker with prognostic value. J Neurosurg Psychiatry 1995; 59: 1034
39 Isobe T, Takahsi K, Okuyama T. S100a protein is present in neurons of central and peripheral nervous tissue. J Neurochem 1984; 43: 14946[ISI][Medline]
40 Izumi Y, Roussel S, Pinard E, Seylaz J. Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 1991; 11: 102530[ISI][Medline]
41 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: 6949[ISI][Medline]
42 Johnsson P. Markers of cerebral ischaemia after cardiac surgery. J Cardiothorac Vasc Anesth 1996; 10: 1206[ISI][Medline]
43 Jönsson H, Johnsson P, Alling C, Westaby S, Blomquist S. Significance of serum S100 release after coronary artery bypass grafting. Ann Thorac Surg 1998; 65: 163944
44 Kanbak M, Avci A, Yener F, Koramaz I, Aypar Ü. Cerebral injury assessed by S100ß protein and neuropsychologic tests after coronary artery bypass surgery. Br J Anaesth 1999; 82: (Suppl 1) A.292
45 Karpiak SE, Seroksz M, Rapport MM. Effects of antisera to S100 protein and to synaptic membrane function on maze performance and EEG. Brain Res 1976; 102: 31321[ISI][Medline]
46 Kilminster S, Treasure T, McMillan T, Holt DW. Neuropsychological change and S100 protein release in 130 unselected patients undergoing cardiac surgery. Stroke 1999; 30: 186974
47 Kornfeld DS, Zimberg S, Malm JR. Psychiatric complications of open-heart surgery. N Engl J Med 1965; 273: 28792[ISI]
48 Kumar P, Dhital K, Hossein-Nia M, Patel S, Holt D, Treasure T. S-100 protein release in a range of cardiothoracic surgical procedures. J Thorac Cardiovasc Surg 1997; 113: 9534
49 Lindberg L, Olsson AK, Anderson K, Jögi P. Serum S100 protein levels after pediatric cardiac operations: a possible new marker for postoperative cerebral injury. J Thorac Cardiovasc Surg 1998; 116: 2815
50 Lynn GM, Stefanko K, Reed III JF, Gee W, Nicholas G. Risk factors for stroke after coronary artery bypass. J Thorac Cardiovasc Surg 1992; 104: 151823[Abstract]
51 Mahanna EP, Blumenthal JA, White WD, et al. Defining neuropsychological dysfunction after coronary artery bypass grafting. Ann Thorac Surg 1996; 61: 13427
52 Mangano DT, Mora Mangano CT. Perioperative stroke encephalopathy and CNS dysfuncton. J Intensive Care Med 1997; 12: 14860
53 Marinow MB, Harbaugh KS, Hoopes PJ, Pikus HJ, Harbaugh RE. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible cerebral ischemia. J Neurosurg 1996; 85: 11724[ISI][Medline]
54 Marshak DR, Peese SA, Stanley LC, Griffin WST. Increased S100ß neurotrophic activity in Alzheimers disease temporal lobe. Neurobiol Aging 1991; 13: 17[ISI]
55 Marshak DR, Pena LA. Potential role of S100 protein in Alzheimers disease: an hypothesis involving mitotic protein kinase. Prog Clin Biol Res 1992; 379: 289307[Medline]
56 McDonald JW, Silverstein FS, Johnston MV. Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats. Neurosci Lett 1990; 109: 2348[ISI][Medline]
57 McIntosh TK, Vink R, Yamakami I, Faden AL. Magnesium protects against neurological deficit after brain injury. Brain Res 1989; 482: 25260[ISI][Medline]
58 McKhann GM, Goldsborough MA, Borowicz LMJ, et al. Predictors of stroke risk in coronary artery bypass patients. Ann Thorac Surg 1997; 63: 51621
59 Mertsch K, Grune T, Landhoff A, Saupe N, Siems WG, Blasig IE. Hypoxia and reoxygenation of the brain endothelial cells in vitro: a comparison of biological and morphological response. Cell Mol Biol 1995; 41: 24353[ISI]
60 Mills SA. Risk factors for cerebral injury and cardiac surgery. Ann Thorac Surg 1995; 59: 17969
61 Missler U, Wiesmann M, Christine F, Kaps M. S100 protein and neuron-specific enolase concentrations in blood as indicators of infarction volume and prognosis in acute ischemic stroke. Stroke 1997; 28: 195660
62 Moore B. A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun 1965; 19: 73944[ISI][Medline]
63 Newman M, Karmer D, Croughwell N, et al. Differential age effects of mean arterial pressure and rewarming on cognitive dysfunction after cardiac surgery. Anesth Analg 1995; 81: 23642[Abstract]
64 Newman M, Wolman R, Kanchuger M, et al. Multicentre preoperative stroke risk index for patients undergoing coronary artery bypass surgery. Circulation 1996; 94: (Suppl 2) 7480[ISI]
65 Newman MF, Croughwell ND, Blumenthal JA, et al. Effect of aging on cerebral autoregulation during cardiopulmonary bypass: association with postoperative cognitive dysfunction. Circulation 1994; 90(part 2): II-243II-49
66 Persson L, Hardemark H, Edner G, Ronne E, Mendel Hartving I, Pahlman S. S-100 protein in cerebrospinal fluid of patients with subarachnoid haemorrhage: a potential marker of brain damage. Acta Neurochir 1988; 93: 11622[ISI][Medline]
67 Persson L, Hardemark HG, 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: 9118[Abstract]
68 Pugsley W, Klinger L, Paschalis C, Treasure T, Harrsion M, Newman S. The impact of microemboli during cardiopulmonary bypass on neuropsychological functioning. Stroke 1994; 25: 13939[Abstract]
69 Pugsley W, Treasure T, Klinger L, Newman MF, Pascalis C, Harrison M. Microemboli and cerebral impairment during cardiac surgery. Vasc Surg 1990; 24: 3443[ISI]
70 Redmond JM, Greene PS, Goldborough MA, et al. Neurologic injury in cardiac surgical patients with a history of stroke. Ann Thorac Surg 1996; 61: 427
71 Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. New Engl J Med 1996; 335: 185763
72 Rosén H, Rosengren L, Herlitz J, Blomstrand C. Increased serum levels of the S100 protein are associated with hypoxic brain damage after cardiac arrest. Stroke 1998; 29: 4737
73 Rowland LP, Fink ME, Rubin L. Cerebrospinal fluid: blood-brain barrier, brain edema, and hydrocephalus. In: Kandel ER, Schwartz JH, Jessel TM, eds. Principles of Neural Science, East Norwalk, CT: Prentice-Hall, 1991; 105060
74 Sakakibara Y, Shiihara H, Terada Y, Ino T, Wanibuchi Y, Furuta S. Central nervous system damage following cardiopulmonary bypass surgery: a retrospective analysis of 1386 cases. Jpn J Surg 1991; 21: 2531[Medline]
75 Sapsed-Byrne S, Gao F, Harris DN. Neurone-specific enolase and Sangtec 100 assays during cardiac surgery: Part II Must samples be spun within 30 min? Perfusion 1997; 12: 1679[Medline]
76 Scandinavian Stroke Study Group. Multicenter trial of hemodilution in ischemic stroke: background and study protocol. Stroke 1985; 16: 88590[ISI][Medline]
77 Selinfreund R, Bargar S, Pledger W, Van Eldik L. Neurotrophic protein S100ß stimulates glial cell proliferation. Proc Natl Acad Sci USA 1991; 88: 35548[Abstract]
78 Shaw PJ, Bates D, Cartlidge NE, Heaviside D, Julian DG, Shaw DA. Early neurological complications of coronary artery bypass surgery. BMJ 1985; 291: 13847[ISI][Medline]
79 Shepard R, Simpson D, Sharp J. Energy equivalent pressure. Arch Surg 1966; 93: 73040[ISI][Medline]
80 Singh AK, Bert AA, Feng WC, Rotenberg FA. Stroke during coronary bypass grafting using hypothermic versus normo thermic perfusion. Ann Thorac Surg 1995; 59: 849
81 Slogoff S, Girgis KZ, Keats AS. Etiologic factors in neuropsychiatric complications associated with cardio pulmonary bypass. Anesth Analg 1982; 61: 90311[Abstract]
82 Stanley LC, Mark RE, Woody RC, et al. Glial cytokines as neuropathogenic factors in HIV infection: pathogenic similarities to Alzheimers disease. J Neuropathol Expt Neurol 1994; 53: 2318[ISI][Medline]
83 Stump DA, Newman SP, Coker LH, Wallenhaupt SL, Roy RC. The effect of age on neurologic outcome after cardiac surgery. Anesth Analg 1992; 74: S310
84 Stys PK, Ransom BR, Waxman SG. Effects of polyvalent cations and dihydropyridine calcium channel blockers on recovery of CNS white matter from anoxia. Neurosci Lett 1990; 115: 2939[ISI][Medline]
85 Svenmarker S, Sandström E, Karlsson T, et al. Clinical effects of heparin coated surface in cardiopulmonary bypass. Eur J Cardiothorac Surg 1997; 11: 95764[Abstract]
86 Taggart DP, Bhattacharya K, Meston N, et al. Serum S100 protein concentration after cardiac surgery: a randomized trial of arterial line filtration. Eur J Cardiothorac Surg 1997; 11: 6459[Abstract]
87 Taggart DP, Mazel JW, Bhattacharya K, et al. Comparison of serum S100 beta levels during coronary artery bypass grafting and intracardiac operations. Ann Thorac Surg 1997; 63: 4926
88 Toner I, Peden CJ, Hamid SK, Newman S, Taylor KM, Smith PL. Magnetic resonance imaging and neuropsychological changes after coronary bypass graft surgery: preliminary findings. J Neurosurg Anesth 1994; 6: 1639[ISI][Medline]
89 Tonninger W, Jandrasits O, Grimm M, Schmid R, Haider W, Grubhofer G. Comparison of S100 protein release during normothermic and mild hypothermic cardiopulmonary bypass. Br J Anaesth 1998; 80: (Suppl 2) A.71
90 Tuman K, McCarthy RJ, Najafi H, Ivankovich AD. Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg 1992; 104: 15107[Abstract]
91 Usui A, Kato K, Abe T, et al. S100a0 protein in blood and urine during open-heart surgery. Clin Chem 1989; 35: 19424
92 Waterloo K, Ingebrigtsen T, Rommer B. Neuropsychological function in patients with increased serum levels of protein S100 after minor head injury. Acta Neurochir 1997; 139: 2632[ISI][Medline]
93 Westaby S, Johnsson P, Parry AJ, et al. Serum S100 protein, a potential marker for cerebral events during cardiopulmonary bypass. Ann Thorac Surg 1996; 61: 8892
94 Wolman RL, Nussmeier NA, Aggarwal A, et al. Cerebral injury after cardiac surgery; identification of a group at extraordinary risk. Stroke 1999; 30: 51422
95 Zimmer DB, Cornwall EH, Landar A, Song W. The S100 protein family: history, function, and expression. Brain Res Bull 1995; 37: 41729[ISI][Medline]