【作者】 刘丹；

【导师】 王学斌；

【作者基本信息】 大连医科大学 ， 急诊医学（专业学位）， 2023， 硕士

【摘要】 背景:脓毒症(sepsis)是指宿主遭受感染后发生免疫失衡,从而导致一系列器官功能障碍的全身炎症反应。因其病情进展迅速,但早期脏器损伤评估困难,干预滞后,危及患者生命,是重症加强治疗病房患者的主要死因之一。在脓毒症的多种并发症中,脓毒症相关急性肾损伤(Sepsis-associated acute kidney injury,S-AKI)是脓毒症患者的常见并发症,导致脓毒症患者医疗费用增加、住院时间延长及死亡率增高,给社会带来了沉重负担。早期预测S-AKI发生并准确评估AKI严重程度,可以为临床医生早期做出医疗干预提供依据,可能降低患者死亡率。由于技术及伦理方面的限制,目前对S-AKI发病机制的研究大多来自于动物模型、体外细胞研究及S-AKI死亡患者的病理资料,以上研究认为S-AKI发病机制与炎症因子和凝血功能障碍有关。因此,本课题拟通过临床研究,研究凝血指标在脓毒症患者血液中的检测水平以及与S-AKI的关系,以明确凝血指标是否可以作为S-AKI发生的预测指标、严重程度评估的指标和预后预测的指标。目的:本研究通过收集脓毒症患者入重症加强治疗病房当时血液的凝血指标(包括凝血酶原时间(PT)、凝血酶时间(TT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)、D-二聚体、国际标准化比值(INR)、血小板计数),同时收集炎性指标(包括C反应蛋白(C-reactive protein,CRP)、白细胞介素-6(Interleukin-6,IL-6)、降钙素原(procalcitonin,PCT)),收集肾功能指标(包括血肌酐(Serum creatinine,Scr)、血胱抑素C(Serum cystatin C,Cys C)),结合血乳酸、SOFA评分、APACHE II评分,研究凝血指标对S-AKI发生的预测价值和评估S-AKI严重程度的价值,并比较不同指标对S-AKI患者28天病死的预测价值。为临床S-AKI预防及治疗提供新思路。方法:回顾性分析2017年01月至2021年10月,上海市东方医院重症加强治疗病房收治的脓毒症患者(284例)的临床资料。包括一般资料(性别、年龄),基础资料(基础疾病、感染部位)和入重症加强治疗病房当时的实验室检测结果(凝血指标、CRP、IL-6、PCT、肾功能、动脉血气分析),统计入院后24小时内的急性生理与慢性健康评分(APACHE II评分)和入重症加强治疗病房当时的序贯器官衰竭评分(SOFA评分)。分析入院后7天内的血肌酐和尿量,统计28天病死情况。1.在研究凝血指标预测S-AKI发生的组中,根据KDIGO指南,剔除入院时已诊断S-AKI的患者51例,再分析剩余233例脓毒症患者入院后第2-7天的血肌酐和尿量的情况,根据是否出现AKI分为AKI组(127例)和非AKI组(106例)。统计两组的凝血指标(包括PT、TT、APTT、FIB、D-二聚体、INR、血小板计数),炎性指标(包括CRP、IL-6、PCT),肾功能指标(Scr、Cys C),血乳酸、SOFA评分、APACHE II评分,再进行平均水平的比较。在统计学上有差异的指标,采用二元Logistic回归分析筛选出S-AKI发生的独立预测因子,最后对各个独立预测因子进行预测价值评估。2.在研究凝血指标评估S-AKI严重程度组,分析284例脓毒症患者入院后7天内的血肌酐和尿量,根据KDIGO AKI分期标准将脓毒症患者(284例)分为AKI1期(63例)、AKI 2期(51例)、AKI 3期(64例)、非AKI组(106例),比较四组凝血指标、SOFA评分及APACHE II评分的平均水平,进行各凝血指标与SOFA评分、APACHE II评分的相关分析。3.统计28天存活状态,将S-AKI患者(178例)分为存活组(103例)和死亡组(75例)。比较两组凝血指标、SOFA评分、APACHE II评分的平均水平,在统计学上有差异的指标,采用二元Logistic回归分析筛选出S-AKI死亡的独立危险因素,最后对各个独立危险因素进行预测价值评估。结果:1、凝血指标预测S-AKI发生的价值AKI组与非AKI组患者相比较,AKI组的PT、APTT、D-二聚体、INR、C-反应蛋白、IL-6、降钙素原、血胱抑素C、血乳酸、SOFA评分、APACHE II评分明显高于非AKI组(P=0.000、P=0.000、P=0.000、P=0.000、P=0.010、P=0.000、P=0.000、P=0.000、P=0.000、P=0.000、P=0.000),AKI组FIB、血小板计数明显低于非AKI组(P=0.000、P=0.039)。两组间入重症加强治疗病房当时的血肌酐差异无统计学意义。运用二元Logistic回归分析筛选出PT、APTT、INR、血胱抑素C、血乳酸是S-AKI发生的独立预测因素(P=0.003、P=0.001、P=0.008、P=0.000、P=0.023)。再绘制这5个独立预测因素的ROC曲线,结果显示PT、APTT、INR、血胱抑素C、血乳酸的曲线下面积分别为:0.891、0.798、0.655、0.877、0.817。2、凝血指标评估S-AKI严重程度的价值比较非AKI组、AKI 1期、AKI 2期和AKI 3期患者的凝血指标、SOFA评分及APACHE II评分的平均水平,结果显示不同组别的上述各指标差异均有统计学意义(P<0.05),再进行四组之间两两比较,结果显示只有PT在任意两组间的差异具有统计学意义,且发现凝血指标与SOFA评分、APACHE II评分之间有相关性。PT、APTT、D-二聚体与SOFA评分的相关系数分别为:r=0.390,P=0.000;r=0.370,P=0.000;r=0.380,P=0.000,PT、APTT、D-二聚体与APACHE II评分的相关系数分别为:r=0.323,P=0.000;r=0.308,P=0.000;r=0.347,P=0.000。3、不同指标预测S-AKI患者28天病死的价值存活组和死亡组之间比较各凝血指标、SOFA评分、APACHE II评分的平均水平,结果显示两组间PT、APTT、D-二聚体、INR、SOFA评分、APACHE II评分差异具有统计学意义(P=0.000、P=0.000、P=0.000、P=0.000、P=0.000、P=0.042)。运用二元Logistic回归分析筛选出S-AKI患者28天病死的独立危险因素有PT、INR、SOFA评分(P=0.002、P=0.001、P=0.000)。再绘制这些独立危险因素预测28天病死的ROC曲线,PT、INR、SOFA评分的曲线下面积分别为:0.786、0.741、0.764。结论:1.凝血指标PT、APTT、INR、肾功能指标血胱抑素C、血乳酸是S-AKI发生的独立预测因素,其中凝血指标PT的曲线下面积最大。2.凝血指标PT、APTT、D-二聚体对S-AKI的严重程度具有评估价值。3.凝血指标PT、INR及SOFA评分为S-AKI患者28天病死的独立危险因素,其中凝血指标PT的曲线下面积最大。更多还原

【Abstract】 Background:sepsis refers to systemic inflammatory reactions with sepsis,which occur after host infections,resulting in a series of organ dysfunction.It is one of the main causes of death for patients in intensive care unit because of the rapid progression of the disease,but the difficulty of early organ injury assessment and delayed intervention.In Sepsis in a variety of complications,Sepsis associated with acute kidney injury(Sepsis – associated acute kidney injury,S-AKI)is a common complication of patients with Sepsis,leading to Sepsis patients medical costs increase,length of hospital stay and increased mortality,brings heavy burden to the society.Early prediction of the occurrence of S-AKI and accurate assessment of the severity of AKI can provide a basis for clinicians to make early medical intervention,which may reduce the mortality of patients.Due to technical and ethical limitations,current studies on the pathogenesis of S-AKI are mostly based on animal models,in vitro cell studies and pathological data of patients who died of S-AKI.The above studies believe that the pathogenesis of S-AKI is related to inflammatory factors and coagulation dysfunction.Therefore,this subject intends to study the detection level of coagulation indexes in the blood of sepsis patients and its relationship with S-AKI through clinical studies,so as to clarify whether coagulation indexes can be used as predictors of S-AKI occurrence,severity evaluation and prognosis prediction.Purpose:In this study,blood clotting indexes(including prothrombin time(PT),thrombin time(TT),activated partial thrombin time(APTT),fibrinogen(FIB),D-dimer,International standardized ratio(INR),and platelet count)of sepsis patients at the time of admission to the ICU were collected.Inflammatory markers(including C-reactive protein(CRP),Interleukin-6(IL-6),procalcitonin(PCT)),Renal function indicators(including Serum creatinine(Scr)and Serum cystatin C(Cys C))were collected,combined with blood lactic acid,SOFA score and APACHEII score.To study the predictive value of coagulation indexes for the occurrence of S-AKI and the evaluation of the severity of S-AKI,and to compare the predictive value of different indexes for 28 days of death in patients with S-AKI.It provides a new idea for the prevention and treatment of clinical S-AKI.Methods:In this study,blood clotting indexes(including prothrombin time(PT),thrombin time(TT),activated partial thrombin time(APTT),fibrinogen(FIB),D-dimer,International standardized ratio(INR),and platelet count)of sepsis patients at the time of admission to the ICU were collected.Inflammatory markers(including C-reactive protein(CRP),Interleukin-6(IL-6),procalcitonin(PCT)),Renal function indicators(including Serum creatinine(Scr)and Serum cystatin C(Cys C))were collected,combined with blood lactic acid,SOFA score and APACHEII score.To study the predictive value of coagulation indexes for the occurrence of S-AKI and the evaluation of the severity of S-AKI,and to compare the predictive value of different indexes for 28 days of death in patients with S-AKI.It provides a new idea for the prevention and treatment of clinical S-AKI.1.In the group that studied the prediction of S-AKI by coagulation index,51 patients diagnosed with S-AKI at admission were excluded according to KDIGO guidelines,and the creatinine and urine volume of the remaining 233 patients with sepsis at 2-7 days after admission were analyzed,and they were divided into AKI group(127 cases)and non-AKI group(106 cases)according to the presence or absence of AKI.Coagulation indexes(including PT,TT,APTT,FIB,D-dimer,INR,and platelet count),inflammatory indexes(including CRP,IL-6,PCT),renal function indexes(Scr,Cys C),blood lactic acid,SOFA score,and APACHEII score of the two groups were analyzed,and then the average levels were compared.For indicators with statistical differences,binary Logistic regression analysis was used to screen out the independent predictors of S-AKI occurrence.Finally,the predictive value of each independent predictor was evaluated.2.Blood creatinine and urine volume of 284 sepsis patients within 7 days after admission were analyzed in the group that studied coagulation indicators to assess S-AKI severity.According to KDIGOAKI staging criteria,284 patients with sepsis were divided into AKII stage(63 cases),AKIII stage(51 cases),AKIIII stage(64cases)and non-AKI group(106 cases).The coagulation index,SOFA score and APACHEII score of the four groups were compared.The correlation analysis of each coagulation index with SOFA score and APACHEII score was carried out.3.After 28 days of survival,178 patients with S-AKI were divided into survival group(103 cases)and death group(75 cases).The average level of blood coagulation index,SOFA score and APACHEII score of the two groups were compared,and the indicators with statistical differences were screened out by binary Logistic regression analysis.Finally,the predictive value of each independent risk factor was evaluated.Results:1.Value of coagulation index in predicting S-AKI occurrence Patients in AKI group and non-AKI group were compared.PT,APTT,D-dimer,INR,C-reactive protein,IL-6,procalcitonin,blood cystatin C,blood lactic acid,SOFA score and APACHE II score in AKI group were significantly higher than those in non-AKI group(P=0.000,P=0.000,P=0.000,P=0.010),P=0.000,P=0.000,P=0.000,P=0.000),the FIB and platelet count in AKI group were significantly lower than those in non-AKI group(P=0.000,P= 0.039).There was no significant difference in serum creatinine between the two groups at the time of admission to the ICU.Binary Logistic regression analysis showed that PT,APTT,INR,cystatin C and blood lactic acid were independent predictors of S-AKI(P=0.003,P=0.001,P=0.008,P= 0.000,P= 0.023).ROC curves of these five independent predictors were plotted,and the results showed that the areas under the curves of PT,APTT,INR,cystatin C and blood lactic acid were 0.891,0.798,0.655,0.877 and 0.817,respectively.2.Value of coagulation indexes in evaluating the severity of S-AKI The average level of coagulation index,SOFA score and APACHE II score of patients in non-AKI group,AKI stage 1,AKI stage 2 and AKI stage 3 were compared,and the results showed that the differences of the above indexes in different groups were statistically significant(P < 0.05),and then pairwise comparison between the four groups was conducted.The results showed that only PT was statistically significant between any two groups,and a correlation was found between coagulation index and SOFA score and APACHE II score.The correlation coefficients between PT,APTT and D-dimer and SOFA score were r=0.390,P=0.000,respectively.r=0.370,P=0.000;r=0.380,P=0.000,the correlation coefficients of PT,APTT,D-dimer and APACHE II score were r=0.323,P=0.000,respectively.r= 0.308,P=0.000;r=0.347,P=0.000.3.Value of different indicators in predicting 28-day death in S-AKI patients The average levels of each coagulation index,SOFA score and APACHE II score were compared between the survival group and the death group.The results showed that PT,APTT,D-dimer,INR,SOFA score and APACHE II score were significantly different between the two groups(P=0.000,P=0.000,P=0.000,P=0.000,P=0.042).Binary Logistic regression analysis was used to screen out the independent risk factors of 28-day death in S-AKI patients,including PT,INR,SOFA score(P=0.002,P=0.001,P=0.000).Then the ROC curve for predicting 28-day death by these independent risk factors was drawn,and the areas under the curve of PT,INR and SOFA scores were 0.786,0.741 and 0.764,respectively.Conclusion:1.Coagulation index PT,APTT,INR,renal function index cystatin C and blood lactic acid were independent predictors of S-AKI occurrence,among which coagulation index PT had the largest area under the curve.2.Coagulation indexes PT,APTT and D-dimer are valuable for evaluating the severity of S-AKI.3.PT,INR and SOFA scores were independent risk factors for 28-day death in S-AKI patients,among which PT had the largest area under the curve.更多还原