限制性液体复苏对脓毒性休克外周血单个核细胞Toll样受体4信号通路及心功能的影响

The effect of conservative fluid management on Toll-like receptor 4 signal pathway of peripheral blood mononuclear cells and cardiac function in patients with septic shock

目的探讨不同液体复苏策略对脓毒性休克患者心功能的影响。方法采用前瞻性研究方法。收集2014年1月至2015年4月符合脓毒性休克诊断标准的48例患者。24h达到复苏目标后根据液体复苏策略，分为限制性液体复苏组（CLFM组）和开放性液体管理组（LLFM组），其中CLFM组20例，LLFM组28例。比较两组血流动力学指标、TLR4信号通路mRNA水平、血清心肌损伤标志物水平。两组间比较采用t检验，非正态分布的计量资料采用Mann-WhitneyU检验，计数资料采用χ2检验，采用多因素Logistic回归分析预后影响因素。结果CLFM组第3、7天的心功能指数（CFI）为（5．01±1．41）／min、（5．39±1．48）／min，心脏指数（CI）为（3．43±0．50）、（3．73±0．76）mL·min-1·m-2；LLFM组第3、7天的CFI和CI分别为（4．28±1．22）／min、（4．22±1．63）／min和（3．31±1．24）、（3．09±1．14）mL·min-1·m-2；两组第7天CFI和cI指标比较差异有统计学意义（t值分别为2．546、2．185，均P〈0．05）。CLFM组和LLFM组第3天TLR4mRNA分别为3．0±1．1和4．8±1．4（t=4．786，P〈0．01），第7天分别为1．6±0．5和4．0±1.1（t=9．089，P〈0．01）；第3天NF-κB mRNA分别为3．5±1．1和6．8±1．5（t=8．354，P〈0．01），第7天分别为2．4±0．5和5．7±0．9（t=14．820，P〈0．01）。CLFM组血清TNF-α和IL-1β在第3天、第7天低于LLFM组（均P〈0．01）。Logistic回归分析发现，液体平衡状态（OR=1．236，95%CI：0．78-1．692，P=0．033）、CFI（OR=3．263，95％CI：1．136～7．936，P=0．027）、急性生理学与慢性健康评分Ⅱ（OR=2．064，95％CI：1．248～2．898，P=0．003）是影响死亡的独立危险因素。结论CLFM可能通过抑制TLR4／NF-κB信号通路，减少心肌抑制因子TNF—α和IL-1β的产生，从而改善心功能状态，降低病死率。

Objective To evaluate the effect of different fluid resuscitation strategies on the cardiac function in patients with septic shock. Methods Forty-eight patients met diagnostic criteria of septic shock were enrolled prospectively between January 2014 and April 2015. Patients were divided into conservative late fluid management （CLFM） group （n： 20） and liberal late fluid management （LLFM） group （n= 28） after achieving early goal-directed therapy within 24 h. Haemodynamic parameters, mRNA levels in Toll-like receptor 4 （TLR4） signal pathway and serum levels of myocardial damage markers were compared. Student t-test was used to compare means between two groups. Quantitative data that were not normally distributed were compared by Mann-Whitney U test. Qualitative data were compared using χ2 test. Multivariable Logistic regression analysis was used to identify the independent predictors for prognosis. Results The cardiac function index （CFI） in CLFM group were （5.01± 1. 41）/min and（5.39±1.48）/min on day 3 and day 7, respectively, and the cardiac index （CI） were （3.43±0.50） and （3.73±0.76） mL ·min -1 . m-2 on day 3 and day 7, respectively. The CFI and CI in LLFM group were （4. 28±1.22）/min, （4. 22±1.63）/min and （3.31±1.24）, （3.09±1.14） mL · min-1· m-2respectively on day 3 and day 7. The differences between two groups were statistically significant on day 7 （t=2. 546, 2. 185, both P〈0.05）. The TLR4 mRNA levels were 3.0±1. 1 in CLFM group compared to 4.8±1.4 in LLFM group on day 3 （t=4. 786,P〈0.01） and 1.6±0.5 compared to 4.0± 1.1 on day 7 （t=9. 089, P〈0.01）. Nuclear factor （NF）-κB mRNA levels were 3.5±1. 1 in CLFM group compared to 6.8±1.5 in LLFM group on day 3 （t=8. 354, P〈0.01） and 2.4±0.5 compared to 5.7±0.9 （t= 14. 820, P〈0.01） on day 7. The levels of serum tumor necrosis factor （TNF）-α and interleukin （IL）-1β in CLFM group were lower than those in LLFM group on day 3 and day 7 （all P〈0.01）. Multivariable Logistic regression analysis showed that fluid balance （OR = 1. 236, 95 % CI： 0.78 - 1. 692, P = 0. 033）, CFI （OR=3. 263, 95%CI： 1. 136-7. 936, P=0. 027） and acute physiology and chronic health evaluation Ⅱ （OR=2. 064, 95%CI： 1. 248-2. 898, P=0. 003） were the independent predictors for 28-day mortality. Conclusions CLFM may inhibit the product of myocardial depressant factors TNF-α and IL-1β through attenuating TLR4/NF-κB signal pathway activation and thus to improve myocardial function and decrease mortality.