Correlation Between NF-κB Expression And Neuronal Damage And Postoperative Neuropsychological Disorders In Cardiac Surgery

BACKGROUND With the rapid development of surgical technology,anesthesia level,monitoring technology and perfusion technique,the mortality due to direct heart problems as myocardial infraction,heart failure or fatal arrhythmia in open heart surgery with cardiopulmonary bypass(CPB) has decreased significantly.However,in recent years,the mortality caused by complications occurred in central nervous system has increased from 7.2%to 19.6%. Dysfunction of nervous system,such as delirium and postoperative cognitive dysfunction(POCD),has become main postoperative complication,which results in increasing hospital stay and costs,mortality and other complications. It seriously affected the life quality and determined outcome of patients who underwent cardiac surgery,which has attracted great attention.CPB is one of the most important factors that affected POCD.Cerebral embolism,spasm and abnormal perfusion of brain tissue are the main reasons that led to primary brain injury and excessive inflammatory response activated by various nuclear factors and cytokines are the main cause of secondary brain injury.Preventing cerebral embolism,improving blood supply of brain tissue,avoiding ischemia and hypoxia of brain tissue and suppressing early release of nuclear factors and cytokines are the key to keep brain from injury in cardiac surgery.It was found that systemic inflammatory response syndrome(SIRS) induced by CPB plays an important role in acute neuronal injury caused by ischemia of brain tissue.Lessening inflammatory response is an effective method to relieve post-CPB brain injury.The release of various inflammatory mediators and anti-inflammatory ones are mediated by nuclear factor kappa B(NF-κB).NF-κB is the core of inflammatory response.Thus, to suppress the activation of NF-κB may play an important role in reducing systemic inflammatory response and protecting brain from injury.AIMS To examine the change of peripheral blood neutrophils NF-κB activation,plasma IL-6 and S-100βprotein levels,and to determine the relationship between NF-κB expression, plasma IL-6 and S-100βprotein levels and neuronal damage in cardiac surgery,thus providing insights into the pathophysiology of post-CPB neuronal injury.PATIENTS AND METHODS Thirty NYHAⅡ～Ⅲclass patients(18 males and 12 females) aged 18～60 years,undergoing elective cardiac valve replacement under CPB were randomly divided into 2 groups:ulinastatin(UTI) group(Group U,n=15) and control group(Group C,n=15).In group U,UTI(12,000U/kg) was given intravenously after the induction of anesthesia,6,000U /kg UTI was added to the priming solution,and 6,000U /kg UTI was given about 5 min before the aortic decamping.In Group C, normal saline was given instead of UTI.Written informed consent was obtained in all cases and the local ethical committee approved the protocol.Exclusion criteria included: subjects undergoing aortic arch/root procedures and those with calcified aorta,recent stroke,severe preoperative neurologic deficits,known high-grade carotid stenosis, advanced hepatic disease(cirrhosis),and chronic renal failure.Subjects who were unable to complete the neuropsychologic test due to severe cognitive impairment, psychiatric disease were also excluded.Procedures were completed by surgeons following the same conventional operative approach at our institution,including induction of general anesthesia,invasive monitoring,midline sternotomy,and systemic heparinization.CPB was initiated via cannulation of the vena cava and ascending aorta with a nonpulsatile system,membrane oxygenator,and a 40μm arterial filter.For all patients,mild hypothermic CPB(minimum temperature 28-34℃) and alpha-stat pH management was used. Mean blood pressure was maintained at between 50 and 80 mmHg using conventional vasoactive medications.Blood samples were taken from the central venous line and immediately sent for centrifugation at 3000 r.p.m,for 10 min after induction of anesthesia(T1),at the end of CPB(T2), 24h after operation(T3) for determination of plasma IL-6 and S-100βprotein levels and neutrophils NF-κB activation(T1,T2).The plasma samples were frozen at -70℃until the time of assay.Enzyme Linked Immunosorbent Assay(ELISA) was used for testing IL-6 levels and radio-immunity analysis(RIA) was used to measure the content of S100βprotain.The peripheral blood neutrophils nuclear factor activation was detected by flow cytometry-based method. Neurocongnitive outcome was evaluated by Mini-Mental State Examination(MMSE) and Abbreviated Mental Test(AMT) before and 3d,7d after operation.A patient was considered to have neurological dysfunction if the MMSE score was＜23 points or AMT score was＜7 points.Statistics were performed using the SPSS statistical package version 10.0.Results are presented as means±standard deviation.Differences between groups were compared using independent-samples t-test.Within-group comparisons were made using the one-way ANOVA.Associations between NF-κB level and concentration of S100B protein and IL-6 were made based on Spearman's Rho.A P value less than 0.05 was considered to be statistically significant.RESULTS Five patients were subsequently excluded from the analysis because of refusal to complete neuropsychologic assessment prior to discharge or having a hemolysed blood sample that was of insufficient quality for analysis.Thus, 25 patients were included in the analysis.According to the criteria defined earlier,6 of 25 patients(24%,3 patients in Group U and 3 in Group C respectively,P＞0.05) presented with neuropsychological disorders after surgery.Compared with T1 time point in both group,the plasma IL-6 level increased markedly at the end of CPB(T2,P＜0.01) and still higher than baseline value at 24h after operation(T3,P＜0.05). The level of IL-6 at T2 time point were lower in Group U compared with group C(P＜0.01).Compared with T1 time point in group C,the plasma S100B protein level increased markedly at the end of CPB(T2,P＜0.01) and still higher than baseline value at 24h after operation(T3,P＜0.05).In group U,the S100B protein level increased at the end of CPB(T2,P＜0.05) too,and decreased to baseline value at 24h after operation. At T2 time point,the level of S100B protein were lower in Group U compared with group C(P＜0.05).Neutrophils NF-κB was activated at the end of CPB in both groups(P＜0.05),but the intervention group was lower than control group(P＜0.05).In addition,neutrophils NF-κB activation was correlated with plasma IL-6 level(r=0.771,P＜0.01) and S100B concentration (r=0.686,P＜0.01)CONCLUSIONS It was found that inhibiting NF-κB activation was helpful to attenuate inflammatory cytokines and brain injury of patients undergone cardiac surgery with CPB.But this did not lower the incidence of POCD.The development of more effective prevention strategies remains an important goal.