【作者】 朱彦慧；

【导师】 邹承伟；

【作者基本信息】 山东大学 ， 外科学（心外科）（专业学位）， 2022， 博士

【摘要】 [目的]冠状动脉旁路移植术(Coronary Artery Bypass Grafting,CABG)是冠心病三支病变和左主干病变的标准治疗方法。非体外循环下CABG手术(Off-Pump CABG,OPCAB)借其创伤小、不需体外循环、较低的早期死亡率和并发症发生率的优点,已经成为我国各个心脏中心常规开展的冠心病手术治疗方式。然而,在OPCAB术后患者中仍然可以观察到明显的全身炎症反应和局部心肌缺血,其机制与体外循环下手术并不完全相同,并且与患者的不良预后密切相关。因此,早期识别OPCAB手术后有不良预后风险的患者可能有助于调整住院期间的治疗策略。前白蛋白(Prealbumin,PA),又称转甲状腺素蛋白(Transthyretin,TTR),是肝脏细胞合成的一种快速转运蛋白,其主要生理功能是运输视黄醇和甲状腺素T3以及T4。与其他血清蛋白相比,前白蛋白不受肝脏疾病及血制品输注的显著影响,且半衰期短、更新速率快,较白蛋白更为敏感。在炎症反应、应激及感染等病理状态下,血清前白蛋白水平的降低与多种疾病严重程度以及外科手术后的并发症密切相关。在临床工作中我们发现,OPCAB患者术后早期血清PA水平也存在较大差异,有的仅轻度下降,有的下降较明显,其与术后并发症的发生及预后之间是否有一定的联系,目前国内外尚无报道。因此我们进行了一项大样本的回顾性研究,旨在探究前白蛋白水平与OPCAB早期并发症之间的关系及其预测价值。本研究回顾性收集了山东省立医院心外科2014年1月至2019年7月期间连续完成择期OPCAB手术的1002例患者的特征性资料,采集术后6～12小时内空腹静脉血样本中前白蛋白的数值,探讨PA水平变化与这些预后指标之间的关系并评估其预测价值,以期在术后早期识别有不良预后风险的患者,从而指导围术期治疗并及时调整护理策略,有助于患者的术后恢复。[研究方法](1)选取2014年1月至2019年7月连续在山东省立医院心外科行OPCAB手术的患者为研究对象。采集所有患者的人口统计学和共病、手术因素、术后处理、并发症和临床转归的信息。所有患者术前5～7天停用口服抗血小板药,期间给予低分子肝素抗凝治疗,应用欧洲心血管手术危险因素评分系统(European System for Cardiac Operative Risk Evaluation,EuroSCORE)Ⅱ对所有患者进行术前评分。(2)所有纳入患者均采用经口气管插管全身麻醉,手术均由同一主刀医生完成,采用非体外循环下冠状动脉旁路移植术。经胸部正中切口开胸,桥血管吻合完成后,常规应用瞬时测血流量技术(Transit Time Flow Measurement,TTFM)测血流并记录数据,以桥血管血流波形良好且搏动指数≤5作为血流满意的指标,必要时需要重新搭桥。(3)手术结束后进入心外监护室。PaO2维持在80～120mmHg之间,PaCO2维持在35～45mmHg之间。患者在血流动力学稳定、无过度出血(心包纵隔引流连续3小时<50 mL/h)、自主呼吸好、血气分析氧分压满意时拔除气管插管。术后6～12小时内采集所有患者的第一次空腹静脉血样本,获取血常规、心肌酶及生化指标并每日监测。维持血红蛋白大于8g/dL,白蛋白大于35g/L,及时处理电解质失衡,以维持正常范围。应用降压药或正性肌力药将病人有创动脉压的收缩压维持在90～140mmHg之间。当患者的临床状况趋于稳定时,从监护室转出到普通病房。(4)术后实验室指标的采集于6～12h内完成,根据文献报道,以使用最多的170mg/L作为分界点,将患者分为两组:PA<170mg/dL的患者为“低”PA组,PA≥170mg/L被归类为“正常”PA组。主要观察指标为:住院死亡率和术后并发症,包括肺部感染、胸腔积液、新发心房颤动(Atrial Fibrillation,AF),肝功能损害、脑血管事件(Cerebrovascular Event,CVE)、切口问题、呼吸衰竭、术后心肌梗死(Myocardial Infarction,MI)、低左室射血分数(Left Ventricular Ejection Fraction,LVEF)、需要血液透析的急性肾功能衰竭(Acute Renal Failure,ARF),次要观察指标为:术后拔管时间、重症监护室住院时间、术后住院时间、正性肌力药物使用和应用主动脉内球囊反搏(Intra-Aortic Balloon Pump,IABP)。(5)统计分析使用GraphPad Prism 9.0软件,分类变量表示为每组的频率和百分比,采用卡方检验进行差异性分析,连续变量以中位数(25%～75%四分位数间距)表示,采用Mann-Whitney非参数检验进行差异性分析,对比两组之间的基线资料及术后指标。连续变量之间的相关性采用Spearman相关系数。P<0.05认为结果具有统计学差异,P<0.001具有显著统计学差异。(6)通过单因素logistic回归分析与术后主要并发症相关的因子,其中有预测价值的因子进入多因素logistic回归分析,剔除具有混杂效应或相互作用的因素,明确PA的预测价值,通过绘制受试者工作曲线(Receiver Operating Characteristic,ROC)评价PA的预测效能。[结果](1)基线资料对比:两组患者之间EuroSCORE Ⅱ评分、人口统计学资料、共病、手术资料及术前心功能指标没有差异(P>0.05);正常PA组术前的白蛋白水平较高,42.1 vs 40.9(g/L),具有显著统计学意义,P<0.001,但相关性分析结果显示,术后前白蛋白水平和白蛋白、体重指数和年龄之间的相关性非常弱。(2)术后资料对比:低PA组术后重症监护病房住院时间、术后住院时间和拔管时间均明显长于正常PA组(P<0.001);低PA组使用正性肌力药物的患者比例为26.94%,显著高于正常PA组;低PA组患者术后6～12小时内中性粒细胞数(×109/L)略高于正常组,12.78 VS 12.39(P=0.02),但这种差异临床意义可能不大。术后并发症方面,总体发病率从高到低依次是肺部感染(19.3%)、新发房颤(17.1%)、胸腔积液(10.1%)、肝功能损害(6.3%)、低LVEF(5.9%)、术后心梗(3.2%)、呼吸衰竭(1.5%)、CVE(1.5%)、切 口问题(1.4%)、住院死亡(0.5%)、ARF(0.3%)和 IABP 使用(0.1%)。低PA组肺部感染(29.11%)、胸腔积液(16.09%)、新发房颤(23.87%)、切口问题(2.35%)和呼吸衰竭(2.35%)的发生率均高于正常组,其中最常见的术后并发症是肺部感染和新发房颤。对术后发生率较高的肺部感染和新发房颤进一步分析。(3)前白蛋白水平降低可以作为术后发生肺部感染的危险因素(OR=0.977,95%CI:0.971-0.982,P<0.0001),低PA水平与肺部感染发生率增加相关,其他危险因素包括女性、合并慢性肺部疾病、年龄较大、手术时间较长、术后拔管时间较长、术后中性粒细胞增多和术前白蛋白水平较低,多因素logistic回归分析结果显示,前白蛋白降低是术后肺部感染的独立危险因素(矫正OR=0.979,95%CI:0.973-0.985,P<0.0001),其他独立危险因素为年龄、手术时间、术后拔管时间、术后中性粒细胞水平和术前白蛋白水平。ROC曲线分析结果表明,术后前白蛋白水平对肺部感染具有较大的预测价值(AUC=0.742,95%CI:0.704-0.781,P<0.0001),最佳截断值为 179.5(mg/L),且将 PA 水平与术后拔管时间联合用于术后肺部感染的预测可进一步提高效能。前白蛋白水平降低是术后新发房颤的独立危险因素(矫正OR=0.985,95%CI:0.980-0.991,P<0.0001),且ROC曲线结果显示低PA的预测价值优于年龄因素。[结论](1)OPCAB术后早期前白蛋白水平下降的患者中术后发生肺部感染、胸腔积液、切口问题、呼吸衰竭等肺部并发症和新发房颤的风险更高,住院期间正性肌力药物的使用率更高。(2)OPCAB术后早期前白蛋白水平下降的患者拔管时间、ICU住院时间和住院时间更长。(3)术后早期前白蛋白水平与患者术前营养状态关系不大。(4)术后早期前白蛋白水平下降对OPCAB患者术后早期主要心脑血管事件的发生率没有影响。(5)术后早期前白蛋白水平是OPCAB患者术后肺部感染和新发房颤的独立预测因子。(6)术后早期前白蛋白水平下降对OPCAB患者术后肺部感染具有较高的预测价值,最佳预测截断值是179.5g/L。(7)OPCAB术后前白蛋白水平对术后早期主要并发症具有重要的预测价值。更多还原

【Abstract】 ObjectiveCoronary artery bypass grafting(CABG)is the standard treatment for three vessel lesions and left main artery lesions of coronary heart disease.Off-pump CABG(OPCAB)has become a routine surgical treatment of coronary heart disease in various heart centers in China because of its advantages of small trauma,no need for cardiopulmonary bypass,low early mortality and complication rate.However,obvious systemic inflammatory response and local myocardial ischemia can still be observed in patients after OPCAB.Its mechanism is not exactly the same as that of surgery under cardiopulmonary bypass,and is closely related to the adverse prognosis of patients.Therefore,early identification of patients at risk of poor prognosis after OPCAB surgery may help to adjust the treatment strategy during hospitalization.Prealbumin(PA),also known as transthyretin(TTR),is a rapid transporter synthesized by liver cells.Its main physiological function is to transport retinol,thyroxine T3 and T4.Compared with other serum proteins,prealbumin is not significantly affected by liver diseases and blood product infusion,and has short half-life and fast renewal rate,which is more sensitive than albumin.Under the pathological conditions of inflammation,stress and infection,the decrease of serum prealbumin level is closely related to the severity of a variety of diseases and complications after surgery.In clinical work,we found that there were also great differences in the early postoperative serum PA level of OPCAB patients,some only decreased slightly,some decreased significantly.Whether there is a certain relationship between PA and the occurrence and prognosis of postoperative complications has not been reported at home or abroad.Therefore,we conducted a large sample retrospective study to explore the relationship between prealbumin level and early complications of OPCAB and its predictive value.This study retrospectively collected the characteristic data of 1002 patients who completed elective OPCAB surgery in the Department of cardiac surgery of our hospital from January 2014 to July 2019.We collected the value of prealbumin in fasting venous blood samples within 6～12 hours after operation,discussed the relationship between the change of PA level and these prognostic indicators,and evaluated its predictive value.This study can help us identify patients at risk of poor prognosis early after operation,so as to guide perioperative treatment and timely adjust nursing strategies,which is helpful for patients’ postoperative recovery.Methods(1)Patients who underwent OPCAB surgery in cardiac surgery of Shandong Provincial Hospital from January 2014 to July 2019 were selected as the research object.The demographic and comorbidity,surgical factors,postoperative management,complications and clinical outcomes of all patients were collected.All patients stopped using antiplatelet drugs for 5～7 days before operation,and were treated with low molecular weight heparin during the period.All patients were scored with the EuroSCORE Ⅱ system before operation for cardiovascular operative risk evaluation.(2)All patients were treated with general anesthesia through oral endotracheal intubation.The operation was completed by the same surgeon.Off pump coronary artery bypass grafting was used.After thoracotomy through the median chest incision and the completion of bridge vessel anastomosis,the blood flow was measured and recorded by transit time flow measurement(TTFM).The blood flow waveform of bridge vessel was good and Pulsate Index≤5 was taken as the index of satisfactory blood flow.If necessary,it was necessary to bypass again.(3)After the operation,enter the extracardiac care unit.PaO2 is maintained between 80～120mmhg and PaCO2 is maintained between 35～45mmhg.The endotracheal intubation was removed when the patient had stable hemodynamics,no excessive bleeding(pericardial and mediastinal drainage for 3 hours<50ml/h),good spontaneous breathing and satisfactory oxygen partial pressure of blood gas analysis.The first fasting venous blood samples of all patients were collected within 6～12 hours after operation.Blood routine,myocardial enzymes and biochemical indexes were obtained and monitored every day.Maintain hemoglobin greater than 8g/dl and albumin greater than 35g/L,and timely deal with electrolyte imbalance to maintain the normal range.The systolic blood pressure of patients with invasive arterial pressure was maintained between 90～140mmHg with antihypertensive drugs or positive inotropic drugs.When the patient’s clinical condition tends to be stable,he is transferred from the intensive care unit to the general ward.(4)The collection of postoperative laboratory indexes was completed within 6～12h.According to the literature report,taking the most used 170mg/L as the dividing point,the patients were divided into two groups:Patients with PA<170mg/dL were classified as "low"PA group,and patients with PA≥170mg/L were classified as "normal" PA group.The main outcome measures were in-hospital mortality and postoperative complications,including pulmonary infection,pleural effusion,new onset atrial fibrillation(AF),liver function damage,cerebrovascular event(CVE),incision problems,respiratory failure,perioperative myocardial infarction(MI)Low left ventricular ejection fraction(LVEF)and acute renal failure(ARF)requiring hemodialysis.The secondary observation indexes were:postoperative extubation time,hospitalization time in intensive care unit,postoperative hospitalization time,use of positive inotropic drugs and application of intra-aortic balloon pump(IABP).(5)The Graphpad Prism 9.0 software was used for statistical analysis.The classified variables were expressed as the frequency and percentage of each group,and the chi-square test was used for difference analysis.The continuous variables were expressed as the median(25%～75%InterQuartile Range),and the Mann-Whitney nonparametric test was used for difference analysis.The baseline data and postoperative indexes between the two groups were compared.Spearman correlation coefficient is used for the correlation between continuous variables.P<0.05 is considered to have statistical difference,and P<0.001 has significant statistical difference.(6)Univariate logistic regression analysis was used to analyze the factors related to the main postoperative complications.Among them,the factors with predictive value entered the multivariate logistic regression analysis to eliminate the factors with confounding effect or interaction,clarify the predictive value of PA,and evaluate the predictive efficiency of PA by drawing the receiver operating characteristic(ROC).Results(1)Comparison of baseline data:there was no difference between the two groups in EuroSCORE II,demographic data,comorbidity,surgical data and preoperative cardiac function indexes(P>0.05).The preoperative albumin level of normal PA group was higher,42.1 vs 40.9(g/L),which was statistically significant,P<0.001,but the correlation analysis showed that the correlation between preoperative albumin level and albumin,body mass index and age was very weak.(2)Comparison of postoperative data:the length of stay in ICU,postoperative length of stay and extubation time in low PA group were significantly longer than those in normal PA group(P<0.001);The proportion of patients using positive inotropic drugs in low PA group was 26.94%,which was significantly higher than that in normal PA group;The number of neutrophils in low PA group within 6～12 hours after operation(×10 μg/L)was slightly higher than that in the normal group,12.78 vs 12.39(P=0.02),but this difference may be of little clinical significance.Overall incidence rate was high from low to low,followed by pulmonary infection(19.3%),new onset atrial fibrillation(17.1%),pleural effusion(10.1%),liver function impairment(6.3%),low LVEF(5.9%),perioperative myocardial infarction(3.2%),respiratory failure(1.5%),CVE(1.5%),incision problem(1.4%),hospital death(0.5%),ARF(0.3%)and IABP use(0.3%).The incidence of pulmonary infection(29.11%),pleural effusion(16.09%),new onset atrial fibrillation(23.87%),incision problems(2.35%)and respiratory failure(2.35%)in the low PA group were higher than those in the normal group.The most common postoperative complications were pulmonary infection and new onset atrial fibrillation.The higher incidence of pulmonary infection and new onset atrial fibrillation will be further analyzed.(3)The decrease of prealbumin level can be used as a risk factor for postoperative pulmonary infection(OR=0.977,95%CI:0.971-0.982,P<0.0001).Low PA level is associated with the increased incidence of pulmonary infection.Other risk factors include female,complicated with chronic lung disease,older age,longer operation time,longer extubation time.The results of multivariate logistic regression analysis showed that the decrease of prealbumin was an independent risk factor for postoperative pulmonary infection(Corrected OR=0.979,95%CI:0.973-0.985,P<0.0001).Other independent risk factors were age,operation time,postoperative extubation time,postoperative neutrophil level and preoperative albumin level.The results of ROC curve analysis showed that the preoperative albumin level had great predictive value for pulmonary infection(AUC=0.742,95%CI:0.704-0.781,P<0.0001),and the best cut-off value was 179.5(mg/L),and the efficiency of PA level combined with postoperative extubation time in predicting postoperative pulmonary infection was further improved.The decrease of prealbumin level was an independent risk factor for postoperative new onset atrial fibrillation(Corrected OR=0.985,95%CI:0.980-0.991,P<0.0001),and the ROC curve showed that the predictive value of low PA was better than that of age.Conclusions(1)Among patients with decreased prealbumin levels in the early stage after OPCAB,the risk of postoperative pulmonary infection,pleural effusion,incision problems,respiratory failure and other pulmonary complications and new onset atrial fibrillation is higher,and the use rate of positive inotropic drugs is higher during hospitalization.(2)Patients with decreased prealbumin levels in the early stage after OPCAB had longer extubation time,ICU hospitalization time and hospitalization time.(3)The early postoperative prealbumin level had no relationship with the preoperative nutritional status of patients.(4)The decrease of prealbumin level in the early postoperative period had no significant effect on the incidence of major cardiovascular and cerebrovascular events in patients with OPCAB.(5)Early postoperative prealbumin level is an independent predictor of postoperative pulmonary infection and new onset atrial fibrillation in patients with OPCAB.(6)The decrease of prealbumin level in the early stage after operation has high predictive value for postoperative pulmonary infection in OPCAB patients,and the best predictive cut-off value is 179.5g/L.(7)The prealbumin level after OPCAB has important has important predictive value for early major postoperative complications.更多还原