| Objective:This study intends to analyze the differential expression of genes in myocardial tissue in patients with sevoflurane anesthesia during cardiopulmonary bypass surgery by transcriptomics method and screen out the target genes of sevoflurane-induced myocardial protection,as well as investigate its cardioprotective mechanism.It is also proposed to investigate the effects of sevoflurane inhalation anesthesia on postoperative brain function in patients undergoing cardiac valve replacement surgery through randomized controlled clinical study.In addition,the effect of delayed postoperative neurocognitive recovery on rehabilitation of patients undergoing cardiac valve replacement was retrospectively analyzed by propensity match.Methods:The first part:The study was to screen differentially expressed genes in the collected myocardial specimens by transcriptomics,and to explore the protective roles and the possible mechanism of these genes in patients undergoing heart valve replacement with sevoflurane inhalation under cardiopulmonary bypass on the cellular level.The trial included 120 patients with cardiac surgery in the Second Affiliated Hospital of the Army Military Medical University from March 2017 to September 2017.The inclusion criteria were: 18-65 years old,middle school or above,without prior heart valve replacement,ASA classification II-III,NYHA cardiac function grade II-III.Exclusion criteria: ASA classification greater than grade IV;those with a history of neurological and psychiatric disorders;those with severe liver or kidney dysfunction;those with a history of alcohol or opioid abuse.Patients were randomly divided into the sevoflurane group and the propofol group.All patients routinely underwent anesthesia and heart valve replacement under cardiopulmonary bypass.During the operation,the sevoflurane group was given sevoflurane(1.0-1.5 MAC)for maintenance.The propofol group was given propofol(2.0-3.0 mg/kg/h)for maintenance.Blood samples were collected before surgery,immediately after surgery,and 24 hours after surgery to detect cTnI concentration.About 5-15 minutes after the start of CPB(giving cardiac arrest to cause the heart to stop,open the heart immediately)40 patients with left atrial myocardial specimens,10 of them were subjected to transcriptomics analysis and 30 were used as follow-up verification samples.After constructing the cDNA library,transcriptomic analysis of the patient's myocardial tissue was performed using RNA-Seq to screen for differentially expressed genes.After pretreatment of H9C2 cells with 2.5% sevoflurane,oxygen and glucose deprivation/ reperfusion(OGD/R)injury model was established to detect the expression changes of the genes selected before and after sevoflurane treatment.Genes down-regulation and overexpression were conducted by siRNA and plasmid vector,repectively.Cell vi ability,proliferation and apoptosis were analyzed after OGD/R injury.The second part:This study was the effect of randomized controlled clinical study of sevoflurane inhalation anesthesia on postoperative brain function in patients undergoing cardiac valve replacement surgery.The trial included 300 patients who underwent cardiac valve replacement under cardiopulmonary bypass.The inclusion criteria were: 18-65 years old,middle school or above,and ASA classification II-III patients.Exclusion criteria were: life expectancy less than 3 months,preoperative cognitive dysfunction(preoperative simple mental state test(MMSE)score ?23),history of neurological and psychiatric disorders,severe liver or kidney dysfunction,history of alcohol and opioids abuse.Patients were randomized 1:1 to the sevoflurane or propofol group using a stratified randomization method.All patients were continuously monitored for ECG,oxygen saturation,end-tidal carbon dioxide,non-invasive blood pressure,invasive arterial pressure and central venous pressure after entering the operating room.For both groups of patients,induction with standard intravenous anesthesia(etomidate 0.05-0.4 mg/kg,sufentanil 0.5-2 ?g/kg,midazolam 0.05-0.2 mg/kg,rocuronium 0.6-1.2)mg/kg).Intubation was performed when the patient's BIS value fell to 40-50,and mechanical ventilation was established using a tidal volume of 6-8 ml/kg.During the operation,sevoflurane(1.0-1.5 MAC)or propofol(2.0-3.5 mg/kg/h)was administered according to the randomization.Midazolam,sufentanil and rocuronium were administered as needed based on changes in patient vital signs and hemodynamics.BIS was maintained at 40-60 by adjusting the rate of drug infusion to maintain blood pressure and heart rate by 20% above and below baseline.CPB and surgical procedures were performed in accordance with normal procedures.The patient cognitive test was performed 1 day before surgery and 7 days after surgery(the test scale consisted of 4 neuropsychological tests: visual language learning test,concept conversion test,stroop color word interference test,symbolic digital test).The occurrence of delayed neurocognitive recovery in patients was determined through calculating the Z score.Secondly,postoperative delirium was assessed for seven days after surgery using the Intensive Care Screening Scale(ICDSC)twice daily(8:00AM-10 AM and 6:00PM-8:00 PM).During 7-day follow-up,postoperative delirium was judged to exist if the ICDSC score was 4 points or more on any day.Postoperative rehabilitation was assessed by data on major complications,ICU stay,and length of stay during hospitalization,three months after surgery.In addition,the trial also collected preoperative basic population data of the two groups of patients;preoperative basic cognitive level(MMSE scale),mental state(HAD scale);and recorded the type of surgery,intraoperative dose,amount of fluid,surgery duration and other data.The third part : A retrospective analysis of the effect of delayed neurocognitive recovery on rehabilitation of patients who were assessed using propensity matching postoperative rehabilitation.According to the delay of postoperative neurocognitive recovery in the patients obtained in the second part,patients was divided into delayed neurocognitive recovery group(group D)and the non-delayed neurocognitive recovery group(N group).And the age and anesthesia as covariate,1:1 propensity score matching got 100 patients,comparing postoperative rehabilitation in two group such as hospital stay,ICU stay,postoperative complications and cardiac function indexes.Results:1.Results of the study on the cardioprotective effect and mechanism of sevoflurane1.1 The blood cTnI concentration(0.85±0.64 vs.1.24±0.94ng/mL,P=0.012)in the sevoflurane group was significantly lower than that in the propofol group,and the ICU residence time(3.2±1.0 vs.3.7±1.1d,P=0.019)was shorter than that in the propofol group.1.2 In transcriptome analysis,146 genes showed the most significant changes,a mong which THAP11 was the most significantly down-regulated gene(P<0.001),and the mRNA level of THAP11 in patients' atrial muscle tissues was positively correl ated with the cTnI level 24 hours after surgery(correlation coefficient =0.751).P <0.001).1.3 Sevoflurane pretreatment can induce down-regulation of THAP11 gene in H9C2 cells,promote cell proliferation,increase cell activity after OGD/R injury,and reduce cell apoptosis caused by OGD/R injury.However,up-regulation of THAP11 level can eliminate the protective effect of sevoflurane pretreatment on OGD/R injury in cardiomyocytes.2.Results of the study on the brain protective effect of sevofluraneFrom 2016.10-2018.4 among the 1616 patients undergoing cardiac valve surgery,300 patients who met the inclusion criteria were selected and randomly divided into sevoflurane group(n=150)or propofol group(n=150).According to the principle of intentional analysis,the experimental data of 300 patients were statistically analyzed.The results showed that there was no significant difference in the incidence of delayed neurocognitive recovery(19.3%[29/150]vs.23.3%[35/150],P=0.398,relative risk 0.83,95%CI: 0.59-1.28)and delirium(24%[36/150]vs.24.7%[37/150],P=0.893,relative risk 0.97,95%CI: 0.65-1.45)between the sevoflurane group and the propofol group.There was no difference in postoperative activity score,length of stay,postoperative complications between the two groups.In the age-based subgroup analysis,there was no difference in the incidence of perioperative neurocognitive disorders and other rehabilitation outcomes between the two groups(P > 0.05).There was no difference in preoperative and intraoperative data and main outcome analysis between the two groups among the 284 patients who actually completed postoperative follow-up(141 in the sevoflurane group and 143 in the propofol group).3.Effect of delayed neurocognitive recovery on rehabilitation of patients undergoing cardiac valve replacement surgeryThe age and anesthesia that play significant roles on patients' rehabilitation were selected as matching covariate.A 1:1 propensity match was made according to th e incidence of DNR in 300 patients,and 100 patients were finally matched.There were 50 patients in the delayed neurocognitive recovery group(group D)and 50 patients in the non-delayed neurocognitive recovery group(group N)for statistical analysis.Th e results showed that the ICU stay in group D(3.9±1.6 vs.3.3±0.7d,P=0.012)and the hospital stay in group D(23.1±7.3 vs.19.5±4.1d,P=0.003)were longer than those in group N.On the 7th day after surgery,the Katz Index activity score(2.9±1.1 vs.3.4±0.8,P=0.025)of group D was lower than that of group N.There was no significant difference in postoperative cardiac function between this two groups.Conclusion:Sevoflurane can protect the myocardium of patients undergoing cardiac valve replacement under cardiopulmonary bypass by down-regulating the expression of THAP11.Moreover,down-regulation of THAP11 can enhance cell viability and inhibit apoptosis,which may be a new target for cardiprotection.However,the cerebral protective effect of sevoflurane on patients undergoing heart valve replacement under cardiopulmonary bypass is not different from that of propofol,and the postoperative recovery of patients is not significantly improved.Postoperative delayed neurocognitive recovery can significantly influence postoperative rehabilitation in patients undergoing cardiac valve replacement surgery. |
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