可溶性CD73与脓毒性休克的交互作用对90 d病死率的影响——来自前瞻性FINNAKI研究的二次分析

The interaction between soluble CD73 and 90-day mortality from patients with non-septic shock and sepsis shock:a secondary analysis from the prospective FINNAKI study

目的基础研究表明,可溶性CD73(sCD73)可抑制炎症反应,限制持续免疫细胞激活引起的过度组织损伤。芬兰一项前瞻性观察性急性肾损伤(FINNAKI)研究表明,sCD73与脓毒症90 d病死率无关。本研究通过对FINNAKI研究数据进行二次分析,旨在进一步探讨sCD73水平与脓毒症患者90 d病死率的关系在脓毒性休克与非脓毒性休克中是否一致。方法FINNAKI研究是2011年9月1日至2012年2月1日在芬兰17个重症监护病房(ICU)进行的一项前瞻性观察性队列研究,该研究患者的脓毒症/脓毒性休克诊断参照脓毒症1.0(Sepsis-1)诊断标准,收集该研究中患者的一般资料、治疗情况、并发症及90 d病死率等资料。为了评估sCD73与90 d病死率的关系在脓毒性休克和非脓毒性休克患者中的区别(即交互作用),采用似然比检验,将乘积项(sCD73×脓毒性休克或非脓毒性休克)纳入多因素Logistic回归方程,进行交互检验;采用脓毒症3.0(Sepsis-3)诊断标准进行敏感性分析;采用广义相加模型(GAM)对脓毒性休克和非脓毒性休克患者中sCD73与90 d病死率关系的交互作用进行验证。结果共纳入588例连续入院的严重脓毒症/脓毒性休克患者,90 d死亡164例,90 d病死率为27.89%。基于Sepsis-1诊断标准,非脓毒性休克患者159例,脓毒性休克患者429例。与非脓毒性休克患者比较,脓毒性休克患者血乳酸(Lac)水平、序贯器官衰竭评分(SOFA)、1 d液体平衡及机械通气、12 h急性肾损伤(AKI)、肾脏替代治疗(RRT)、术后入ICU比例均明显升高,急诊入ICU比例明显降低。基于Sepsis-3诊断标准,非脓毒性休克患者383例,脓毒性休克患者205例;两组间临床资料分析结果与基于Sepsis-1的分析结果类似。基于Sepsis-1,非脓毒性休克与脓毒性休克患者90 d病死率差异无统计学意义〔23.90%(38/159)比29.37%(126/429),P>0.05〕;但基于Sepsis-3,脓毒性休克患者90 d病死率明显高于非脓毒性休克患者〔37.56%(77/205)比22.72%(87/383),P<0.01〕。多因素Logistic回归分析和交互检验显示,无论使用Sepsis-1还是Sepsis-3,在非脓毒性休克和脓毒性休克患者中,调整了所有混杂因素后(除外合并症数量),sCD73与90 d病死率的关系显著不同,即存在交互作用,Sepsis-1和Sepsis-3的交互检验P值分别为0.046、0.027。在非脓毒性休克患者中,sCD73与90 d病死率呈正向关联〔Sepsis-1:优势比(OR)=1.46,95%可信区间(95%CI)为0.99~2.13,P=0.053;Sepsis-3:OR=1.34,95%CI为1.02~1.74,P=0.034〕。在脓毒性休克患者中,sCD73与90 d病死率有负向关联趋势(Sepsis-1:OR=0.91,95%CI为0.69~1.20,P=0.494;Sepsis-3:OR=0.80,95%CI为0.55~1.17,P=0.249)。GAM模型验证结果与Logistic回归方程交互检验结果一致。结论在非脓毒性休克和脓毒性休克患者中,sCD73与90 d病死率的关系显著不同,即存在交互作用。在非脓毒性休克患者中,sCD73与90 d病死率呈正向关联;在脓毒性休克患者中,sCD73与90 d病死率有负向关联趋势。

Objective Fundamental researches have shown that soluble CD73(sCD73)can inhibit inflammatory response and limit excessive tissue damage caused by continuous immune cell activation.A Finnish prospective,observational study of acute kidney injury(FINNAKI)showed no association between sCD73 and 90-day mortality in sepsis patients.Clinical data of this study was used for secondary analysis to explore whether the relationship between sCD73 and 90-day mortality was consistent in septic shock and non-septic shock patients.Methods The FINNAKI study was a prospective,observational cohort study conducted in 17 intensive care units(ICUs)in Finland from September 1st,2011 to February 1st,2012.Sepsis/septic shock was defined according to Sepsis-1 definition.Demographic characteristics,treatment,comorbidities and 90-day mortality of the patients were analyzed.To evaluate the difference(interaction test)between the relationship of sCD73 and 90-day mortality in septic shock and non-septic shock patients,likelihood ratio test was used to integrate the product term(sCD73×septic shock or non-septic shock)into multivariable Logistic regression.Sensitivity analysis was performed with the definition of Sepsis-3.The interaction between sCD73 and 90-day mortality in patients with septic shock and non-septic shock were verified by generalized additive model(GAM).Results A total of 588 patients with severe sepsis/septic shock were enrolled.164 patients died in 90 days,and the 90-day mortality was 27.89%.Based on the Sepsis-1 definition,there were 159 non-septic shock patients and 429 septic shock patients.Compared with the non-septic shock patients,lactate(Lac)level,sequential organ failure assessment(SOFA)score,fluid balance on the first day,and ratio of mechanical ventilation,12-hour acute kidney injury(AKI),renal replacement therapy(RRT),and postoperative ICU transition in the septic shock patients were significantly increased and the proportion of emergency admission to ICU was significantly decreased.Based on the Sepsis-3 definition,there were 383 non-septic shock patients and 205 septic shock patients;the results of clinical data analysis between the two groups were similar to those based on Sepsis-1.Based on Sepsis-1,there was no significant difference in 90-day mortality between non-septic shock and septic shock patients[23.90%(38/159)vs.29.37%(126/429),P>0.05].However,based on Sepsis-3,the 90-day mortality of patients with septic shock was significantly higher than that of patients with non-septic shock[37.56%(77/205)vs.22.72%(87/383),P<0.01].Multivariate Logistic regression analysis and interaction test showed that after adjusting all confounding factors(except the number of complications)in non-sepsis shock and sepsis shock patients,sCD73 and 90-day mortality were significantly different in both Sepsis-1 and Sepsis-3.The P values for interaction tests were 0.046 and 0.027,respectively.In patients with non-septic shock,sCD73 tended to be positively associated with 90-day mortality[Sepsis-1:odds ratio(OR)=1.46,95%confidence interval(95%CI)was 0.99-2.13,P=0.053;Sepsis-3:OR=1.34,95%CI was 1.02-1.74,P=0.034].In septic shock patients,sCD73 tended to be negatively associated with 90-day mortality(Sepsis-1:OR=0.91,95%CI was 0.69-1.20,P=0.494;Sepsis-3:OR=0.80,95%CI was 0.55-1.17,P=0.249).The results of GAM model validation were consistent with the results of Logistic regression equation cross validation.Conclusions The relationship between sCD73 and 90-day mortality is significantly different from patients with non-sepsis shock and sepsis shock.In patients with non-sepsis shock,sCD73 is trend to positively associated with 90-day mortality,and there is a negative trend between sCD73 and 90-day mortality in patients with septic shock.