不同阶段脓毒症对非去极化肌松药药效学的影响

The effects of sepsis at different stage on pharmacodynamics of rocuronium and cisatruim in rat diaphragm

目的观察不同阶段脓毒症对大鼠膈肌顺式阿曲库铵和罗库溴铵的药效学影响。方法健康雄性SD大鼠48只(郑州大学基础医学院实验动物中心提供),周龄8周,体重220~250 g,随机分为4组,每组12只:空白对照组(Con)、假手术组(Sham)、盲肠结扎穿孔后9 h组(CLP9)、盲肠结扎穿孔后18 h组(CLP18)。采用序贯给药的方法,应用左膈神经-半膈肌标本,由生物信号采集处理系统记录分析数据,得到两种肌松药的累积浓度-效应曲线,从而计算出50%抑制浓度(IC50)、LogiC50、斜率(slope)。组间比较采用t检验,多组间比较采用单因素重复测量方差分析,进一步组间两两比较采用SNK-q检验。结果与对照组比较,两种药物Sham组IC50LogiC50(顺阿曲库铵0.951±0.009比0.963±0.003,罗库溴铵0.887±0.001比0.890±0.002),斜率(顺阿曲库铵-5.461±0.028比-5.435±0.027,罗库溴铵-1.967±0.055比-1.971±0.054)差异无统计学意义(顺阿曲库铵:t=1.157、0.667,P>0.05;罗库溴铵:t=1.064、0.139,P>0.05);与假手术组比较,CLP9、CLP18组顺阿曲库铵IC50LogiC50增大(CLP91.259±0.005比0.963±0.003,CLP181.496±0.007比0.963±0.003),斜率减小(CLP9-3.262±0.035比-5.435±0.027,CLP18-2.731±0.027比-5.435±0.027),差异有统计学意义(CLP9:t=46.810、48.610,P<0.01;CLP18:t=63.480、69.680,P<0.01);与CLP9组比较,CLP18组顺阿曲库铵IC50LogiC50增大(1.496±0.007比1.259±0.005),斜率减小(-2.731±0.027比-3.262±0.035),差异有统计学意义(t=24.370、11.930,P<0.01);与假手术组比较,CLP9、CLP18组罗库溴铵IC50LogiC50增大(CLP91.125±0.054比0.890±0.002,CLP181.302±0.068比0.890±0.002),斜率增大(CLP9-2.903±0.009比-1.971±0.054,CLP18-3.291±0.068比-1.971±0.054),差异有统计学意义(CLP9:t=10.540、41.040,P<0.01;CLP18:t=14.710、36.910,P<0.01);与CLP9组比较,CLP18组罗库溴铵浓度效应曲线右移,IC50LogiC50增大(1.302±0.068比1.125±0.054),斜率增大(-3.291±0.068比-2.903±0.009),差异有统计学意义(t=4.978、13.780,P<0.01)。结论脓毒症不仅降低顺阿曲库铵和罗库溴铵对膈肌的肌松效应,还降低了膈肌与顺阿曲库铵亲和力,增加了膈肌与罗库溴铵的亲和力,其影响程度与脓毒症程度相关。

Objective To evaluate the effects of sepsis on pharmacodynamics of rocuronium and cisatracucrium in rat diaphragm.Methods Forty eight SD male rats(8 weeks old)weighing 220-250 g were randomly divided into 4 groups:control group(Con group,n=12);sham operation group(Sham group,n=12);cecal ligation and puncture(CLP)-operated 9 h group.(CLP9 group,n=12);cecal ligation and puncture(CLP)-operated 18 h group(CLP18 group,n=12).The cumulative concentration effect curve of the two muscle relaxants was obtained by the method of sequential administration and the left phrenic nerve-hemidiaphragm,and then the half maximal inhibitory concentration(IC50),LogiC50 and slope were calculated.Results Compared with the control group,there was no significant difference in IC50 LogiC50(cisatracurium:0.951±0.009 vs.0.963±0.003,rocuronium:0.887±0.001 vs.0.890±0.002)and slope(cisatracurium:-5.461±0.028 vs.-5.435±0.027,rocuronium:-1.967±0.055 vs.-1.971±0.054)between the two drugs in sham group(cisatracurium:t=1.157,0.667,P>0.05;rocuronium:t=1.064,0.139,P>0.05);compared with sham operation group,the concentration effect curve of cisatracurium in CLP9 group and CLP18 group shifted to the right,the IC50 and LogiC50 increased(CLP91.259±0.005 vs.0.963±0.003,CLP181.496±0.007 vs.0.963±0.003),but the slope decreased(CLP9-3.262±0.035 vs.-5.435±0.027,CLP18-2.731±0.027 vs.-5.435±0.027),the difference was statistically significant(t=24.370,11.930,P<0.01);Compared with CLP9 group,the concentration effect curve of cisatracurium in CLP18 group shifted to the right,the IC50 LogiC50 increased(1.496±0.007 vs.1.259±0.005),but the slope decreased(-2.731±0.027 vs.-3.262±0.035),the difference was statistically significant(t=24.370,11.930,P<0.01);compared with sham operation group,the concentration effect curve of rocuronium in CLP9 and CLP18 groups shifted to the right,the IC50 LogiC50 increased(CLP91.125±0.054 vs.0.890±0.002,CLP181.302±0.068 vs.0.890±0.002)and slope also increased(CLP9-2.903±0.009 vs.-1.971±0.054,CLP18-3.291±0.068 vs.-1.971±0.054),the difference was statistically significant(CLP9:t=10.540,41.040,P<0.01;CLP18:t=14.710,36.910,P<0.01);Compared with CLP9 group,the concentration effect curve of rocuronium in CLP18 group shifted to the right,the IC50 LogiC50 increased(1.302±0.068 vs.1.125±0.054)and slope also increased(-3.291±0.068 vs.-2.903±0.009),the difference was statistically significant(t=4.978,13.780,P<0.01).Conclusion Sepsis not only reduces the muscle relaxant effect of cisatracurium and rocuronium on diaphragm,but also reduces the affinity between diaphragm and cisatracurium,and increases the affinity of diaphragm to rocuronium.The degree of influence is related to the degree of sepsis.