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Ann Thorac Surg 2001;71:667-672
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Is there a relationship between cognitive dysfunction and systemic inflammatory response after cardiopulmonary bypass?

Stephen Westaby, FRCSa, Kjell Saatvedt, MD, PhDa, Samantha White, MAa, Takahiro Katsumata, MD, PhDa, Willem van Oeveren, PhDb, Peter W. Halligan, PhDc

a Oxford Heart Centre, John Radcliffe Hospital, Oxford, England, UK
b University of Groningen, Groningen, The Netherlands
c Department of Psychology, Cardiff University, Cardiff, Wales, UK

Accepted for publication September 9, 2000.

Address reprint requests to Dr Westaby, Oxford Heart Centre, John Radcliffe Hospital, Oxford OX3 9DU, England
e-mail: swestaby{at}ahf.org.uk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. The systemic inflammatory reaction (SIR) is assumed to be one of the factors that causes cerebral dysfunction after cardiopulmonary bypass (CPB). The aim of the present study was to evaluate the relationship between the SIR and postoperative cognitive performance at 5 days and 3 months.

Methods. One hundred patients undergoing coronary artery bypass grafting were studied. Inflammatory markers and markers of coagulation and fibrinolysis were determined at several time points during and after the operation. Correlation analysis between maximum levels of the different markers and early and late performance was performed.

Results. No overall association was found between the maximum levels of the inflammatory markers and early and late function.

Conclusions. Notwithstanding limitations of statistical power established markers of systemic inflammatory reaction showed no relationship with outcome at 5-day or 3-month follow-up in this subset of patients.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a higher risk of neurologic and deficits than other types of major surgery [1]. Different etiologic mechanisms have been proposed to account for these problems [2–5]. Interaction between blood and foreign surfaces produces a "whole body inflammatory response," which may result in renal and pulmonary dysfunction, but the cerebral effects are less well understood [6, 7]. Although a causal relationship has been suggested between the inflammatory reaction and dysfunction [8], as yet no clear evidence exists to link this response to cognitive impairment. The aim of this study was to establish whether elevated levels of inflammatory mediators correlate with neuropsychological or functional measures. In order to test blood foreign surfaces interaction alone, cardiotomy suction was eliminated from the system.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Patients
With ethics committee approval, we prospectively studied 100 elective first-time coronary bypass patients at the Oxford Heart Center, John Radcliffe Hospital, without a previous history of neurological events or psychiatric illness. Those with acute coronary syndromes were excluded to eliminate the added anxiety of a recent illness. We also excluded patients with renal or hepatic dysfunction and diabetes. The patients were included in a randomized controlled trial of a surface modifying agent in the CPB circuit, the results of which showed no statistical difference on the inflammatory, coagulation, fibrinolytic or neuropsychological measures. Each patient underwent a comprehensive neuropsychological assessment, administered by a research psychologist (Table 1).


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  		Table 1. Neuropsychological Tests Performed and Cognitive Domains Evaluated

 
Anesthesia
Patients were premedicated with morphine (10 to 15 mg) and scopolamine (0.3 to 0.4 mg). Anesthesia was induced with fentanyl (1 mg), pancuronium (8 mg), and etomidate (4 to 10 mg). Before CPB anesthesia was maintained with a combination of oxygen, nitrous oxide, and halothane and during CPB with propofol (6 mg · kg-1 · h-1).

Conduct of operation
All operations were performed with Cobe flat sheet membrane oxygenators and bypass circuits (COBE Cardiovascular Inc., Denver, Colorado) using a pump flow of 2.4 L/m2 per minute cooling toward 32°C. The mean arterial pressure was maintained between 50 and 80 mm Hg and {alpha}-arterial stat CO2 management was employed. Myocardial protection was achieved with anterograde crystalloid cardioplegia. We did not employ vent suction and blood shed into the mediastinum was discarded. No cardiotomy blood was returned to the circulation. Blood loss was minimized by careful surgery. Anticoagulation during bypass was monitored with the activated clotting time (Hemochron 800; International Technidyne Corp, Edison, NJ). Additional heparin was administered if the activated clotting time was shorter than 400 seconds. No patients received aprotinin. Heparin was neutralized by means of protamine chloride infusion (3 mg/kg) after the completion of CPB. We did not use autotransfusion of shed mediastinal blood or cell saver in order to prevent return of extrinsic inflammatory mediatrors to the blood stream.

Markers of inflammation, coagulation, and fibrinolysis
Blood samples were taken from the indwelling radial artery catheter after heparinization but before the start of CPB, 5 minutes and 20 minutes after the start of CPB, 5 minutes after the release of the aortic cross clamp, at the end of CPB, and the first postoperative day.

Complement release products C4a were measured by radioimmunoassay (Biotrak, Amersham, Buckinghamshire, UK), whereas the terminal complement complex C5b-9 was determined by enzyme linked immunosorbent assay (Quidel, San Diego, CA). Interleukin-6 (IL-6) as a cytokine marker was determined by enzyme-linked immunosorbent assay (Biotrak, Amersham).

Platelet degranulation was assessed using ß-thromboglobulin, measured by immunoassay (Kodak Clinical Diagnosis Ltd., Amersham, Buckinghamshire, UK, and Diagnostica Stago, Boehringer Mannheim, Germany). Thromboxane B2 was measured by means of an enzyme immunoassay (Biotrak, Amersham).

Prothrombin activation was indicated by fragment F1+2, which was determined by enzyme linked immunoassay (Dade Behring, Marburg, Germany). D-dimer was measured in plasma by means of an enzyme immuno assay (Biopool, Ume, Sweden).

Neuropsychological performance
Each patient underwent a comprehensive neuropsychological examination administered by the same psychologist (SW). Tests were carried out preoperatively (1 day before the operation), before hospital discharge (5 days postoperatively), and again at 3 months postoperatively. All tests used have been described in detail elsewhere [9–13]. Table 1 list the neuropsychological tests and provides a brief description of the cognitive domains evaluated. In addition to neuropsychological performance, other measures of psychological and quality of life performance including functional and emotional measures were also measured preoperatively and at follow-up. These tests were as follows: (1) Short Form 36 (multidimensional measure of subjective health status) [11]; (2) Health Complaints Scale (measures of somatic and cognitive complaints) [12]; (3) BADs Dysexecutive Questionnaire (sampling areas of behavioral, cognitive, and emotional changes from a subjective and objective point of view) [13]; and (4) Hospital Anxiety and Depression Scale [10]. The National Adult Reading Test (NART) was used to estimate premorbid intelligence.

Statistics
Clinical and biochemical data are expressed as mean and standard deviation. Neuropsychological performance involved calculating the change scores (preoperative minus predischarge and preoperative minus follow-up) for each patient on every test. Likewise change scores (preoperative minus follow-up) were also calculated for each of the four functional measures. Change scores were then correlated with maximum levels of each of the inflammatory markers and presented as Pearson‘s correlation coefficients, adopting the conservative 0.01 level as significant given the large number of correlations. Continuous variables were compared using Student’s t test (two-tailed) with significance at the 0.05 level. Computerized statistical analysis was undertaken using the SPSS for windows (version 7) statistical program (SPSS, Inc, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Patients
Ninety-seven patients recovered uneventfully. One patient was reoperated on owing to excess postoperative bleeding from a left internal mammary side branch. One patient had a perioperative stroke and another died from multiple organ failure after a perioperative myocardial infarction. Patient characteristics and surgical data are presented in Table 2.


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  		Table 2. Patient Characteristics and Operative Data

 
The levels of the different inflammatory mediators are reported in Table 3.


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  		Table 3. Group Means and Direction of Change From Preoperative to Postoperative Group Means for All Serum Inflammatory Markers

 
Neuropsychological performance
Ninety-five patients satisfactory completed the preoperative assessment. The mean estimated IQ for the group was 108. Before hospital discharge (5 days postoperatively) 79 patients were comprehensively assessed. Two patients were excluded because of stroke and multiple organ failure. The other 14 surviving patients declined the time-consuming examination at this time. However, at 3 months postoperatively only 4 declined the examination and 89 patients completed all tests. Using group mean scores neuropsychological side effects were observed (Tables 4 and 5). At 5 days postoperatively, the patient group showed no change in performance on 6 tests (Bells; Digits span forward and backward; Trail-making tests A and B; SOMCT). There were also no changes on these same 6 tests at the 3-month follow-up. Patients showed a significant decrease in performance at 5 days, however, on 5 tests (AMIPB; AVLT, both immediate and delayed recall; Grooved pegboard test; and Stroop). At 3-month follow-up, only performance on the AVLT (delayed recall) remained significantly impaired. All other tests showed a significant improvement compared with preoperative scores, with the exception of the AVLT (immediate recall), which showed no difference. Pearson’s correlation coefficients for maximum levels of measured blood tests versus neuropsychological and functional change scores are presented in Tables 6 and 7.


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  		Table 4. Group Means and Direction of Change From Preoperative to Postoperative for Neuropsychologic Tests

 

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  		Table 5. Group Means and Direction of Change from Preoperative to Follow-up for Neuropsychologic Tests

 

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  		Table 6. Preoperative Versus Discharge Neuropsychological Change Scoresa

 

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  		Table 7. Preoperative Versus Follow-up Neuropsychological Change Scoresa

 
No significant correlations were found between the inflammatory markers and neuropsychological or functional change scores. Other psychological and functional measures are reported in Table 8.


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  		Table 8. Preoperative Versus Follow-up Functional Change Scores

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Magnetic resonance imaging studies of the brain immediately after CPB have shown cerebral edema presumably caused by the whole body inflammatory response [14]. In turn the morphologic cerebral changes are thought to give rise to the neurocognitive impairment said to occur in a large proportion of cases after CPB [8, 14]. If the SIR measures used are sensitive indicators of neurocognitive changes consequential upon cardiac surgery then all patients demonstrating elevated SIR levels should demonstrate detectable neuropsychological changes. Our findings, however, suggest that the inflammatory reaction through blood foreign surface interaction cannot alone be directly responsible for the typical pattern of neuropsychological impairment observed after coronary artery bypass surgery with extracorporeal circulation. We could not observe any overall relationship between inflammatory mediators and objective neuropsychological changes as predicted. Furthermore this lack of association was independently confirmed on the other psychological and quality of life measures.

Our findings receive support from recent comparative studies of coronary surgery with and without CPB with similar incidence of neuropsychological dysfunction [15, 16]. This despite the fact that the inflammatory reaction is significantly less after nonpump versus conventional bypass groups [17]. With similar neuropsychological outcome but markedly different levels of inflammatory markers it is unlikely that blood foreign surface interaction can be the causative agent. Different etiologic mechanisms have been proposed as triggers for subtle cerebral injury after CPB. These include hypoperfusion, hyperperfusion, microembolism, and potential harmful mediators of the inflammatory response. To date we are not aware of similar prospective studies to determine the degree of inflammation and its relationship to neuropsychological outcome. We found no indication that inflammatory response contributes directly to cognitive decline as has been suggested.

The cause of cerebral injury after CPB must be sought elsewhere and is probably multifactorial. It has been demonstrated that neuropsychological decline correlates with microembolic load during bypass [18]. Furthermore it has been shown that both microembolic rates and neuropsychological decline can be reduced by incorporation of filters in the CPB circuit [19]. These findings suggest that microemboli may be the major cause of subtle cerebral injury after CPB. This suggestion is reinforced by the fact that serum S100 protein levels during CPB are very low in CABG cases without cardiotomy suction [20] and considerably greater in valve patients who undergo air embolism and large volume cardiotomy suction [21].

Cardiotomy suction and retransfusion of shed mediastinal blood increase the embolic load, increase the levels of inflammatory mediators, and may affect the homeostasis during cardiac surgery [22–24]. Elimination of cardiotomy suction, as in the present study, provided thus a more pure test of blood foreign surface interaction expressed as SIR. For possible future projects it is important to acknowledge this when evaluating any possible relation between SIR and neuropsychological and functional change scores.

Limitations of the present study include the restricted range of inflammatory markers measured. The mediators chosen cover the classic markers of complement activation, coagulation and fibrinolysis used in previous studies of the inflammatory response to CPB [6, 7, 25, 26]. Because this was a negative outcome study there is always concern about whether a sufficient number of patients were included to definitively rule out the possibility of such a relationship. That said, the findings were based on the performance of a prospective study of 100 patients. Relatively small changes observed in the levels of the inflammatory markers or the neuropsychological and functional scores will also reduce the likelihood of detecting any association. However, all markers of inflammation except F1+2 showed a significant change during the study period and a significant group mean deterioration was detected in 5 out of the 11 neuropsychological tests. Our results thus clearly indicate that cognitive dysfunction observed after CPB (particularly at discharge when most neuropsychological performance has understandably deteriorated) do not statistically correlate with pathologic values obtained on standard measures of SIR. Although widely assumed in the cardiothoracic literature, this clinical and predictive relationship has never been formally evaluated in any large scale study. Furthermore, the neuropsychology test battery and measures of SIR would have to be grossly insensitive not to find any association.

The outcome of this formal study to investigate the putative association suggests that factors other than the systemic inflammatory response are probably responsible for cognitive dysfunction after cardiopulmonary bypass.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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