西维来司他钠对行体外循环心脏瓣膜置换术老年患者肺功能的保护作用及机制

Role and mechanism of sivelestat sodium in protecting lung function in elderly patients undergoing aortic valve replacement under cardiopulmonary bypass

目的观察西维来司他钠对行体外循环心脏瓣膜置换术老年患者肺功能的保护作用,探讨其可能机制。方法2021年10月—2022年10月河南省人民医院行体外循环心脏瓣膜置换术老年患者76例,38例麻醉诱导前10min静脉泵注西维来司他钠0.2mg/(kg·h)至机械通气脱机者为观察组,38例以相同速率静脉泵注生理盐水至机械通气脱机者为对照组。2组分别于切皮前(T_(0))、术毕即刻(T_(1))、术后24h(T_(2))、术后48h(T_(3))采集颈内静脉血,采用Ficoll密度梯度离心法分离外周血单个核细胞(PBMCs),采用实时荧光定量PCR法检测PBMCs中白细胞介素(IL)-18、IL-1βm RNA相对表达量,采用Westernblot法检测PBMCs NLRP3、caspase-1、消皮素D(GSDMD)蛋白相对表达量,观察T_(3)时PBMCs形态变化。2组分别于T_(0)、T_(1)、T_(2)、T_(3)时采集桡动脉血行血气分析,测定pa(O_(2))、pa(CO_(2)),计算肺泡-动脉血氧分压差(PA-aDO_(2))、氧合指数(OI)和呼吸指数(RI)。记录2组体外循环时间、主动脉阻断时间、手术时间、麻醉时间、术中失血量及液体入量、术后机械通气时间、ICU治疗时间、首次下床活动时间、住院时间等;比较2组术中窦性心动过缓/过速、低血压/高血压、呼吸抑制及术后皮肤瘙痒、恶心呕吐、感染等发生情况。结果观察组T_(0)时pa(O_(2))、pa(CO_(2))、血氧饱和度、PA-aDO_(2)、RI、OI与对照组比较差异均无统计学意义(P>0.05),T_(1)、T_(2)、T_(3)时PA-aDO_(2)、RI均低于对照组(P<0.05),OI均高于对照组(P<0.05);2组T_(1)、T_(2)、T_(3)时PA-aDO_(2)、RI均高于T_(0)时(P<0.05),OI均低于T_(0)时(P<0.05)。T_(3)时对照组PBMCs肿胀、变圆,气泡状突出物形成,形态大小不一,细胞膜裂解形成碎片,细胞间隙增宽、排列紊乱;观察组PBMCs形态改变较对照组明显减轻。观察组PBMCs IL-18、IL-1βm RNA及NLRP3、caspase-1、GSDMD蛋白相对表达量T_(0)时与对照组比较差异均无统计学意义(P>0.05),T_(1)、T_(2)、T_(3)时均低于对照组(P<0.05);2组T_(1)、T_(2)、T_(3)时IL-18、IL-1βm RNA及NLRP3、caspase-1、GSDMD蛋白相对表达量均高于T_(0)时(P<0.05)。观察组术后机械通气时间[(33.3±8.0)h]、ICU治疗时间[(51.9±7.8)h]均短于对照组[(39.9±9.6)、(61.7±8.4)h](t=3.256,P=0.002;t=5.270,P<0.001),体外循环时间、主动脉阻断时间、手术时间、麻醉时间、术中失血量及液体入量、围手术期悬浮红细胞及血浆输注量、首次下床活动时间、术后住院时间与对照组比较差异均无统计学意义(P>0.05)。2组术中均无呼吸抑制和深静脉血栓发生,术中窦性心动过缓、窦性心动过速、低血压、高血压及术后恶心呕吐、皮肤瘙痒、感染发生率比较差异均无统计学意义(P>0.05)。结论西维来司他钠通过调控NLRP3炎性信号通路抑制PBMCs细胞焦亡保护行体外循环心脏瓣膜置换术老年患者术后肺功能,不增加围手术期不良事件的发生。

Objective To observe the role of sivelestat sodium in protecting lung function in elderly patients undergoing aortic valve replacement under cardiopulmonary bypass,and to explore its mechanism.Methods Seventy-six elderly patients underwent aortic valve replacement under cardiopulmonary bypass in Henan Provincial People's Hospital from October 2021 to October 2022,among whom 38 patients received intravenous pumping of 0.2 mg/(kg·h)sivelestat sodium 10 min before anesthesia induction till the end of mechanical ventilation(observation group),while the other 38patients received intravenous,pumping of normal saline(control group).The venous blood samples were collected from both groups at the following time points:before skin incision(T_(0)),immediately after surgery(T_(1)),24 h after surgery(T_(2)),and 48 h after surgery(T_(3)).Peripheral blood mononuclear cells(PBMCs)were isolated from the blood samples using Ficoll density gradient centrifugation.Real-time fluorescence quantitative PCR was used to detect the relative expressions of interleukin(IL)-18 and IL-1βmRNA in PBMCs.Western blot technique was used to detect the relative expressions of NLRP3,caspase-1,and gasdermin D(GSDMD)proteins in PBMCs.The morphological changes of PBMCs at T_(3) were observed.Arterial blood gas analysis was conducted at T_(0),T_(1),T_(2) and T_(3) to measure pa(O_(2)),pa(CO_(2)),alveolar-arterial oxygen partical pressure difference(P_(A-a)DO_(2)),oxygenation index(OI),and respiratory index(RI).The durations of cardiopulmonary bypass,aortic cross-clamping,surgery and anesthesia,intraoperative blood loss and fluid intake,intraoperative ventilation duration,length of ICU stay,time to first ambulation after surgery,and length of hospital stay were recorded.The intraoperative sinus bradycardia/tachycardia,hypotension,/hypertension,respiratory depression,and postoperative skin itching,nausea/vomiting and infection were compared between two groups.Results At T_(0),there were no significant differences in the pa(O_(2)),pa(CO_(2)),oxygen saturation,P_(A-a)DO_(2),RI and OI between two group(P>0.05).At T_(1),T_(2) and T_(3),the values of P_(A-a)DO_(2) and RI were lower,while OI values were higher in observation group than those in control group(P<0.05).The values of P_(A-a)DO_(2) and RI were higher and the OI values were lower at T_(1),T_(2) and T_(3) than those at T_(0) in both groups(P<0.05).At T_(3),the morphological changes of PBMCs in control group included swelling,roundness,bubble-like protrusions,variable sizes,cell membrane lysis,fragmentation,widened intercellular gaps,and disorganized arrangement,which were milder in observation group.At T_(0),there were no significant differences in the relative expressions of IL-18 mRNA,IL-1βmRNA,NLRP3 protein,caspase-1 protein and GSDMD protein between two groups(P>0.05).However,at T_(1),T_(2) and T_(3),the relative expressions of IL-18 mRNA,IL-1β mRNA,NLRP3 protein,caspase-1 protein and GSDM1 protein were lower in observation group than those in control group(P<0.05),which were higher than those at T_(0) in both groups(P<0.05).The duration of postoperative mechanical ventilation and length of ICU stay were shorter in observation group[(33.3±8.0),(51.9±7.8)h]than those in control group[(39.9±9.6),(61.7±8.4)h](t=3.256,P=0.002;t=5.270,P<0.001).There were no significant differences in the durations of cardiopulmonary bypass,aortic cross-clamping,surgery and anesthesia,intraoperative blood loss and fluid intake,perioperative transfusion of packed red blood cells and fresh frozen plasma,time to first ambulation after surgery,and length of hospital stay between two groups(P>0.05).Both groups had no respiratory depression or deep vein thrombosis during surgery.The incidences of sinus bradycardia,sinus tachycardia,hypotension,hypertension,postoperative nausea/vomiting,skin itching and infection were similar between two groups(P>0.05).Conclusion Sivelestat sodium exerts a protective effect on postoperative lung function in patients undergoing aortic valve replacement under cardiopulmonary bypass by modulating the NLRP3 inflammatory signaling pathway and inhibiting pyroptosis of PBMCs,and it does not increase the perioperative adverse events.