严重脓毒症早期应用连续性血液净化的时机及其器官保护作用：一项随机双盲对照研究

The organ protective effects and timing of continuous blood purification in the treatment of severe sepsis：a double-blind randomized controlled trial

目的：探讨早期连续性血液净化（CBP）治疗对严重脓毒症患者的器官保护作用和应用时机选择。方法采用双盲随机对照研究方法，选择2013年1月至2015年1月武汉市第一医院重症医学科收治的年龄35~80岁且急性生理学与慢性健康状况评分系统Ⅱ（APACHEⅡ）评分≥20分的严重脓毒症患者74例，按随机数字表法分为对照组和治疗组，每组37例。两组均依据2012年严重脓毒症治疗指南给予常规治疗，治疗组在常规治疗基础上进行连续性静脉-静脉血液滤过（CVVH）。观察两组患者治疗前及治疗后24、48、72h病情评分、肝肾等器官功能指标、血浆或超滤液中炎性因子水平以及治疗后2周的临床结局。结果两组患者治疗后APACHEⅡ评分、多器官功能障碍综合征（MODS）评分、急性肺损伤Murray评分和全身炎症反应综合征（SIRS）评分均逐渐下降，血中白细胞计数（WBC）、降钙素原（PCT）、乳酸（Lac）、肿瘤坏死因子-α（TNF-α）、白细胞介素（IL-6、IL-8）、内毒素水平逐渐降低，尿素氮（BUN）、肌酐（SCr）、丙氨酸转氨酶（ALT）、氧合指数（PaO2/FiO2）均呈现好转趋势。治疗后48h，治疗组各项病情评分、血中WBC、PCT、Lac和炎性因子以及肝肾等器官功能指标即较对照组改善更为明显〔APACHEⅡ评分（分）：15.5±4.7比20.3±5.3，MODS评分（分）：4.6±1.4比7.3±2.2，Murray评分（分）：1.4±0.5比1.7±0.6，SIRS评分（分）：2.9±0.8比3.7±1.0， WBC（×109/L）：1.1±0.5比1.6±0.5，PCT（μg/L）：26.7±12.0比32.4±14.1，Lac（mmol/L）：7.6±2.2比9.3±2.8， TNF-α（μg/L）：96.3±17.4比153.4±24.2，IL-6（μg/L）：146.8±20.6比213.8±29.2，IL-8（μg/L）：287.1±43.6比354.5±56.2，内毒素（kEU/L）：1.4±0.5比2.6±0.8，BUN（mmol/L）：8.7±3.6比18.5±6.4，SCr（μmol/L）：143±39比197±42，ALT（U/L）：141±27比183±34，PaO2/FiO2（mmHg，1mmHg＝0.133kPa）：150.3±45.4比124.7±32.1，均P＜0.05〕，直到72h仍有显著性。治疗组治疗后24h和48h超滤液中可检测到TNF-α、IL-6、IL-8和内毒素，与血浆水平的下降趋势基本一致。治疗组MODS发生率（10.8%比29.7%，χ2＝4.423，P＝0.038）、病死率（5.4%比13.5%，χ2＝4.674，P＝0.032）均较对照组明显下降，机械通气时间（d：3.1±0.6比5.3±1.7，t＝2.103，P＝0.045）、重症加强治疗病房（ICU）住院时间（d：8.5±1.7比13.2±2.4，t＝2.245，P＝0.042）也较对照组明显缩短。结论早期CBP治疗可明显清除严重脓毒症患者体内的炎性因子，有效防治MODS的发生并能改善患者的预后。

Objective To investigate the organ protective effects and the timing of continuous blood purification （CBP） in the treatment of severe sepsis. Methods A double-blind randomized controlled trial was conducted. Seventy-four patients with severe sepsis aged between 35 years and 80 years with acute physiology and chronic health evaluation Ⅱ （APACHEⅡ） scores over 20 admitted to Department of Critical Care Medicine of the First Hospital of Wuhan from January 2013 to January 2015 were enrolled. They were divided into control group （n = 37） and treatment group （n = 37） by random number table method. All patients in these two groups received conventional therapy following the guidelines for management of severe sepsis in 2012. In addition the patients in treatment group received continuous veno-venous hemofiltration （CVVH）. The critical score, liver and kidney function indexes, etc., levels of pro-inflammatory cytokines in plasma and ultra filtrate before and 24, 48, and 72 hours after treatment, and the clinical picture 2 weeks after treatment in two groups were observed. Results APACHE Ⅱ scores, multiple organ dysfunction syndrome （MODS） scores, Murray scores of acute lung injury, and systemic inflammatory response syndrome （SIRS） scores of the patients of the above two groups were gradually declined after the treatment. The levels of white blood cell count （WBC）, procalcitonin （PCT）, lactate （Lac）, tumor necrosis factor-α （TNF-α）, interleukins （IL-6 and IL-8）, and endotoxin gradually lowered. Levels of blood urea nitrogen （BUN）, serum creatinine （SCr）, alanine transaminase （ALT） and the oxygenation index （PaO2/FiO2） showed a tendency of lowering. There were statistically significant differences in scores of critical illness, WBC, PCT, Lac, pro-inflammatory cytokine, liver and kidney function indexes, etc. between treatment group and control group 48 hours after treatment （APACHE Ⅱ score： 15.5±4.7 vs. 20.3±5.3, MODS score： 4.6±1.4 vs. 7.3±2.2, Murray score： 1.4±0.5 vs. 1.7±0.6, SIRS score： 2.9±0.8 vs. 3.7±1.0, WBC （×109/L）： 1.1±0.5 vs. 1.6±0.5, PCT （μg/L）： 26.7±12.0 vs. 32.4±14.1, Lac （mmol/L）： 7.6±2.2 vs. 9.3±2.8, TNF-α （μg/L）： 96.3±17.4 vs. 153.4±24.2, IL-6 （μg/L）： 146.8±20.6 vs. 213.8±29.2, IL-8 （μg/L）： 287.1±43.6 vs. 354.5±56.2, endotoxin （kEU/L）： 1.4±0.5 vs. 2.6±0.8, BUN （mmol/L）： 8.7±3.6 vs. 18.5±6.4, SCr （μmol/L）： 143±39 vs. 197±42, ALT （U/L）： 141±27 vs. 183±34, PaO2/FiO2 （mmHg, 1 mmHg = 0.133 kPa）： 150.3±45.4 vs. 124.7±32.1, all P 〈 0.05], and the difference was significant up to 72 hours. In the treatment group, TNF-α, IL-6, IL-8, and endotoxin could be decreased in the filtrate 24 hours and 48 hours after treatment and they correlated with the lowering tendency of their plasma levels. Compared with the control group, CVVH based on conventional treatment of severe sepsis could significantly reduce the incidence of MODS （10.8% vs. 29.7%, χ2 = 4.423, P = 0.038） and mortality （5.4% vs. 13.5%, χ2 = 4.674, P = 0.032）, and remarkably shortened the duration of mechanical ventilation （days： 3.1±0.6 vs. 5.3±1.7, t = 2.103, P = 0.045）, and the length of intensive care unit （ICU） stay （days： 8.5±1.7 vs. 13.2±2.4, t = 2.245, P = 0.042）. Conclusion Early CBP can decrease the level of pro-inflammatory cytokines, prevent MODS, and remarkably improve the prognosis of patients with severe sepsis.