中华急诊医学杂志  2017, Vol. 26 Issue (8): 919-923
配对血浆吸附滤过治疗重症脓毒症并发多器官功能障碍综合征的研究
李小丽, 刘鲁沂, 初静, 梁亚凤, 李梅凤, 田行瀚, 王希锋, 于清霞, 刘佳     
264000 山东省烟台,青岛大学附属烟台毓璜顶医院重症医学科
摘要: 目的 观察配对血浆吸附滤过(coupled plasma filtration adsorption,CPFA)治疗对重症脓毒症并发多器官功能障碍综合征(MODS)患者血浆部分细胞因子(TNF-α、IL-1β、IL-6) 浓度、细胞免疫、血乳酸水平、血液有形成分、心率、呼吸频率、氧合指数、血流动力学及预后等方面的影响。方法 选择符合重症脓毒症并发MODS患者随机(随机数字法)分为三组:CVVH组,血液灌流+CVVH(HP+CVVH)组和CPFA组。三组患者记录临床一般资料、APACHEⅡ评分、器官衰竭数目及上述相关指标。每天血液净化治疗前后采血,分离血浆标本-60 ℃冰箱冻存,分批检测标本TNF-α、IL-1β、IL-6浓度。所有计量数据以均数±标准差x ± s表示。应用SPSS 13.0统计软件对资料进行分析,组内不同时间点进行配对t检验,组间资料行t检验。以P < 0.05差异有统计学意义。存活率比较行卡方检验中fisher检验。结果 CPFA治疗血浆分离吸附2 h后血浆TNF-α、IL-6、IL-1β浓度均较前下降,P < 0.01,继续CVVH治疗10 h后血浆IL-6浓度较吸附后下降,P < 0.05,血浆TNF-α、IL-1β较吸附后下降有下降趋势,但P>0.05,差异无统计学意义。HP+CVVH治疗对血浆TNF-α、IL-6、IL-1β浓度的影响与CPFA治疗组相似,组间比较差异无统计学意义。CVVH组:CVVH治疗12 h血浆TNF-α、IL-6、IL-β浓度均较治疗前下降,P < 0.05。对比三种血液净化方式HP+CVVH、CPFA治疗对TNF-α、IL-6、IL-1β三种炎性介质的清除差异无统计学意义,与CVVH治疗相比较,HP+CVVH、CPFA治疗组患者血清IL-6浓度明显降低,P < 0.05,而TNF-α水平有降低趋势,但P>0.05,而IL-1β水平三组治疗间差异无统计学意义。HP+CVVH、CPFA、CVVH三组治疗的患者均观察到血乳酸、心率、呼吸频率、氧合指数等临床指标的明显改善,血管活性药物的用量明显减少,T淋巴细胞亚群的CD3+、CD4+、CD8+、CD4+/CD8+比值与治疗前相比上升。CPFA、CVVH两种血液净化方式治疗前后红细胞、白细胞、血小板水平未见明显变化,两组相比差异无统计学意义。HP+CVVH治疗后血小板水平有下降趋势,统计学(P<0.05)。CPFA组与CVVH治疗组治疗后血小板水平明显高于HP+CVVH治疗组,(P<0.05)。CVVH+HP、CPFA及CVVH治疗组28 d病死率分别为6/15(40.0%)、5/15(33.3%)、5/15(33.3%),在28 d病死率,三组患者比较差异无统计学意义。结论 CVVH+HP、CPFA及CVVH三种血液净化模式比较,CPFA较CVVH具有更强的炎性介质清除能力,较HP+CVVH对血液有形成分损伤更小,尤其对血小板,是目前MODS患者治疗有效、安全的血液净化模式。
关键词: 血液灌流树脂吸附     配对血浆吸附滤过     CVVH     多器官功能障碍综合征     细胞因子    
Study of coupled plasma filtration adsorption therapy for patients with severe infection and multiple organ dysfunction syndromes
Li Xiaoli, iu Luyi, hu Jing, Liang Yafeng, Li Meifeng, Tian Xinghan, Wang Xifeng, Yu Qingxia, Liu Jia     
Department of Critical Care Medicine, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai 264000, China
Corresponding author: Liu Luyi, Email: luyi65166@126.com
Abstract: Objective To investigate the effect of coupled plasma filtration adsorption (CPFA) on plasma cytokines: TNF-α, IL-1β, IL-6, cellular immunity, blood lactate acid concentration, heart rate, respiration rate, oxygenation index, hemodynamics, blood cells counts, and prognosis in patients with multiple organ dysfunction syndromes (MODS). Methods This was a prospective, randomized clinical trial in 45 patients diagnosed as MODS. Patients were randomly assigned to hemoperfution with resin adsorption (HP)+continuous venous-venous hemofiltration (CVVH) group, CPFA group and CVVH group. The general clinical data, APACHE Ⅱ score, number of failure organ and previous mentioned biomarkers were documented. Blood samples were collected before and after blood filtration with any one of these procedures. The plasma samples were isolated and stored with frozen at -60 ℃. Data were statistically analyzed with SPSS 13.0 version software. Results In CPFA group, plasma cytokines, TNF-α、IL-1β、IL-6, decreased markedly after plasma adsorption for two hours (P < 0.01); and plasma concentrations of IL-6 were further descended after subsequent CVVH for 10 hours (P < 0.05). In HP+CVVH group, plasma cytokines, TNF-α、IL-1β、IL-6, decreased markedly after HP (P < 0.01), and plasma concentrations of IL-6 were further descended after subsequent CVVH for 10 hours (P < 0.05). In CVVH group, plasma cytokines, TNF-α、IL-1β、IL-6, decreased after CVVH for 12 hours (P < 0.05). Blood lactate acid concentration, heart rate, respiration rate, oxygenation index, T-lymphocytes subgroups (CD3+, CD4+, CD8+, CD4+/CD8+ ratio), clinical symptoms were improved and dose of vasoactive agent was reduced in the patients of three groups without differences among them. The counts of red blood cells, white blood cells and platelets after CPFA and CVVH showed no significant changes. There was no significant difference in blood cell counts between CPFA and CVVH groups. After HP+CVVH, there was a trend of decrease in platelet count (P < 0.05). Platelet counts were significantly higher in patients treated with CPFA and CVVH group than those in patients treated with HP+CVVH group (P < 0.05).There were 6 patients died in HP + CVVH group, 6 patients died in CPFA group and 5 patients died in CVVH group within 28days. Conclusions The comparison of efficacy of blood filtration among 3 modalities of HP+CVVH, CPFA and CVVH showed CPFA had higher capacity of Inflammatory medium scavenging than CVVH, and had less damage effect on blood visible component, especially on platelet compared with HP+CVVH. CPFA was an effective and safety modality in the treatment of the patients with multiple organ dysfunction syndrome.
Key words: Hemoperfusion with resin adsorption     Coupled plasma filtration adsorption     Continuous venous-venous hemofiltration     Multiple organ dysfunction syndromes; Cytokines    

配对血浆吸附滤过(coupled plasma filtration adsorption,CPFA)是近年来应用于重症脓毒症救治的一种新型的血液净化技术,它综合了血浆分离、血浆吸附、血液滤过(或血液透析)几种血液净化模式,大大提高了大中小分子炎性介质及毒素的清除范围及数量,不良反应更小,展现出更多的优势[1-2]。本研究以目前较为成熟的血液净化技术为基础,应用连续性静-静脉血液滤过(CVVH)、血液灌流吸附联合连续性静-静脉血液滤过(HP+CVVH)及CPFA三种血液净化模式,治疗重症脓毒症导致的MODS患者,观察治疗前后三种主要的细胞因子(TNF-α、IL-6、IL-1β)、血液有形成分、血流动力学、细胞免疫功能、危重病评分、各器官功能障碍、血乳酸水平、心率、呼吸频率、氧合指数及最终转归等指标的变化。

1 资料与方法 1.1 一般资料

选择2013年3月至2015年12月入住青岛大学附属烟台毓璜顶医院ICU的患者,年龄>18岁、性别不限、各种原因导致重症脓毒症所诱发的MODS患者。除外预后恶劣,影响生存的基础(原发)疾病,如特重型颅脑损伤及脑卒中、心肺复苏术后、恶性肿瘤晚期、血液病、脑血管疾病致长期卧床、老年痴呆及HIV等患者。入组前1月内应用糖皮质激素以及其他免疫抑制药物的患者排除。终剔除标准:治疗未超过72 h死亡、出院者及未能坚持系统治疗者(只能是因患者原因)。MODS诊断采用北京MODS课题组制定的2008标准, 脓毒症诊断采用2001年华盛顿国际脓毒症定义会议推荐的标准。本研究获本院伦理委员会审核通过。

1.2 方法

纳入患者45例,按随机数字表法分为3组。CVVH组:常规治疗+CVVH;血液灌流+CVVH(HP+CVVH)组:常规治疗+血液灌流树脂吸附串联CVVH;CPFA组:常规治疗+CPFA。

C VVH组15例:男9例,女6例,年龄39~85岁, (64.5±18.8) 岁,伴肾功不全12例,少尿无尿4例,机械通气14例,APACHEⅡ(26.3±8.7)。HP+CVVH组15例:男10例,女5例,年龄26~78岁(60.2±21.4) 岁, 伴肾功不全11例,少尿无尿5例,机械通气13例,APACHEⅡ(25.1±10.3)。CPFA组15例:男11例,女4例,年龄35~77岁, (62.3±20.7) 岁, 伴肾功不全12例,少尿无尿5例,机械通气15例,APACHEⅡ(27.1±12.3)。

凡符合入选标准的患者进行以下研究:无论有无肾功衰竭,CVVH组每天给予单纯CVVH治疗12 h以上,每天更换滤器,连续治疗3~5 d;HP +CVVH均给予血液灌流树脂吸附同时串联CVVH治疗,血液灌流树脂吸附治疗2~2.5 h后取下血液灌流器,继续行CVVH治疗10 h以上,连续3~5 d,之后患者有肾功能衰竭根据需要行CVVH治疗;CPFA组患者每天给予单纯血浆分离吸附串联CVVH治疗2.5 h后,继续CVVH治疗10 h以上,连续3~5 d。患者经上述治疗之后,有肾功能衰竭的根据需要行间断行血滤治疗。

患者于入室24 h行APACHEⅡ评分,分别于第1天治疗前(0 h)、树脂灌流吸附后或者血浆分离吸附后(2~2.5 h)、CVVH治疗后(12 h)、第2天治疗前(24 h)、血液灌流树脂吸附后或者血浆分离吸附后(26 h)、CVVH治疗后(36 h)、第3天治疗前(48 h)、树脂灌流吸附后或者血浆分离吸附后(50 h)、CVVH治疗后(60 h)采血,分离血清标本,留取样本-60 ℃冰箱冻存待检。TNF-α、IL-6、IL-1β检测使用北京北方生物技术研究所提供的试剂盒,按照使用说明书使用放射免疫法检测。疗前采用血透单针双腔管股静脉置管建立血管通路。血滤机使用爱德华生命科学有限公司AQUARIUS;滤器使用百特HF-1200,聚砜膜,最大截留相对分子质量5 500~6 500;血浆分离器使用意大利贝尔克有限公司的MPS05血浆分离器;吸附器采用珠海丽珠生产的HA330-Ⅰ、HA330-Ⅱ、BS330吸附器(根据治疗目的选择)。置换液配方:A液NS 3 000 mL+灭菌注射用水820 mL+5%GS 170 mL+25%硫酸镁注射液3.2 mL,另根据患者监测血钾及血钙水平给予加用氯化钙注射液及氯化钾注射液。B液:5% NaHCO3200~250 mL。置换量3~4 L/h[(治疗剂量40~65 mL/(kg·h)]。抗凝方法:视患者有无出血倾向,选用普通肝素、枸橼酸和无肝素抗凝法。

1.3 观察指标

记录患者临床一般资料,观察APACHEⅡ评分、器官功能障碍数目、T淋巴细胞亚群分类、其他相关指标(血乳酸、心率、呼吸频率、氧合指数、血流动力学、血常规)及三种细胞因子(TNF-α、IL-6、IL-1β)等治疗前后的变化,记录患者28 d总病死率。

1.4 统计学方法

所有计量数据以均数±标准差(x ± s)表示。应用SPSS 13.0统计软件对资料进行分析,组内不同时间点进行配对t检验,组间资料行LSD-t检验。以P < 0.05为差异有统计学意义。存活率比较精确fisher检验。

2 结果 2.1 一般情况比较

三组患者入组时病因、年龄、性别方面相似,APCHEⅡ评分差异无统计学意义。

表 1 三组患者一般资料 Table 1 The physical condition of three group patients before blood purification therapy
指标CVVH组HP+CVVH组CPFA组
年龄64.5±18.360.4±21.262.3±20.7
性别(n,%)
  男9(60)10(66.7)11
  女6(40)5(33.3)4
内科疾病(n,%)9(60)87
  呼吸系统感染(n)342
  消化系统感染(n)644
  泌尿系统感染(n)101
外科疾病(n)568
  大手术后(n)344
  多发创伤(n)224
慢性疾病史(%)87.689.280
  高血压(n)655
  冠心病(n)764
  糖尿病(n)564
APACHEⅡ(x ± s)24.3±8.725.1±10.325.7±12.3
28 d死亡(n,%)5(33.3)6(40.0)5(33.3)
2.2 炎症介质变化

CVVH、HP+CVVH、CPFA三种血液净化方式均具有清除血液中炎症介质的作用。HP+CVVH、CPFA治疗对TNF-α、IL-6、IL-1β三种炎症介质的清除差异无统计学意义,HP+CVVH、CPFA治疗患者血清IL-6浓度明显低于CVVH治疗患者,P < 0.05,而TNF-α水平有降低趋势,但P>0.05,而IL-1β水平三组治疗间差异无统计学意义。见表 2

表 2 三组患者治疗前后血浆TNF-α、IL-6、IL-1β浓度变化(x ± s) Table 2 Plasm concentrations of TNF-α、IL-1β and IL-6 before and after blood purification therapy(x ± s)
指标组别02 h12 h24 h26 h36 h48 h50 h60 h
TNF-aHP+CVVH组20.30±8.7315.98±5.1116.05±6.3318.52±8.5815.62±6.6713.31±4.5315.41±6.5212.89±6.1915.59±9.18
(fmol/L)CPFA组26.04±10.2221.04±9.3523.45±7.7722.16±8.9918.37±10.33a20.1±8.1116.75±7.8914.32±9.32a15.23±8.51
CVVH组27.04±4.6319.70±4.5125.25±6.3922.19±4.7720.13±5.8118.27±6.44
IL-6HP+CVVH组358.23±99.34302.65±93.10a226.32±81.57229.27±180.65216.23±174.31178.03±169.56168.45±156.14164.13±161.10128.12±138.14
(ng/L)CPFA组418.65±269.23325±165.30238±166.27258±197.22272±169.12171±123.87172±155.37162±120.30132±135.28
CVVH组401.58±178.80327.74±150.31289.73±161.80266.05±149.79242.89±143.58244.58±121.83
IL-1βHP+CVVH组0.15±0.060.11±0.050.09±0.050.13±0.050.10±0.050.12±0.050.12±0.050.09±0.030.09±0.03
(ng/L)CPFA组0.15±0.070.11±0.050.12±0.060.14±0.030.11±0.04a0.12±0.030.13±0.050.10±0.060.11±0.04
CVVH0.13±0.070.10±0.040.14±0.050.09±0.040.13±0.060.08±0.05
2.3 T淋巴细胞分类比较

三组患者治疗后,T淋巴细胞分类CD3+、CD4+、CD8+、CD4+/CD8+比值均上升,三组之间差异无统计学意义。

2.4 血乳酸、心率、呼吸频率、氧合指数比较

三组患者乳酸、心率、呼吸频率、氧合指数等指标的改善,但三组差异无统计学意义。

2.5 红细胞、白细胞、血小板水平比较

CPFA、CVVH两种血液净化方式治疗前后红细胞、白细胞、血小板水平未见明显变化。HP+CVVH治疗后血小板水平有下降趋势,P<0.05。CPFA组与CVVH治疗组治疗后血小板水平明显高于HP+CVVH治疗组,P<0.05。

表 3 三组患者治疗后对T淋巴细胞分类的影响(x ± s) Table 3 The influence on T-lymphocytes subpopulations through HP +CVVH, CPFA and CVVH(x ± s)
组别时间CD3+CD4+CD8+CD4+/CD8+
HP+CVVH组045.01±27.0126.68±12.5821.32±7.351.76±0.95
第5天51.03±15.01a30.23±8.64a26.46±9.32a1.95±0.98a
CPFA组042.45±17.2621.31±6.4819.87±6.771.63±1.27
第5天53.26±16.31a32.64±9.25a19.54±7.64a1.97±1.03a
CVVH组046.65±10.3527.23±6.4820.89±6.811.56±1.11
第5天50.26±14.42a30.64±8.23a24.68±7.28a1.89±1.22a
注:与治疗前相比,aP < 0.05

表 4 三组患者治疗第5天、第10天的血乳酸、心率、呼吸频率、氧合指数等指标的变化比较(x ± s) Table 4 Blood lactate acid concentration, heart rate, breath rare, oxygenation index on 5th day and 10th day(x ± s)
组别时间去甲肾上腺素
(μg/min)
血乳酸
(mmol/L)
心率
(次/min)
氧合指数
(mmHg)
呼吸频率
(次/min)
HP+CVVH组028.31±11.753.31±3.61121.53±20.45100.56±42.3135.21±9.43
第5天10.64±8.722.14±1.6594.25±18.73151.3±32.3727.24±6.74
第10天8.93±8.251.35±1.5292.14±16.26187.4±55.1624.12±8.75
CPFA组032.12±16.685.21±3.78123.8±30.75110.23±42.3132.74±10.35
第5天11.27±10.362.75±2.11100.51±20.14157.39±36.2826.71±10.25
第10天5.97±5.161.84±1.558823±20.14200.15±60.1325.14±9.36
CVVH组031.26±15.674.02±2.10130.5±28.14105.2±45.2433.62±10.57
第5天9.36±7.942.45±1.5491.33±19.21172.1±53.2626.41±9.38
第10天7.81±6.291.51±2.6189.45±36.15183.3±66.2323.54±7.11
注:P>0.05

表 5 三组患者治疗红细胞、血小板、白细胞等指标的变化比较(x ± s) Table 5 Blood RBC, PLT, WBC level during HP+CVVH, CPFA and CVVH treatment(x ± s)
组别02 h12 h24 h26 h36 h48 h50 h60 h
红细胞HP+CVVH组3.15±0.893.21±1.012.95±1.133.05±1.092.93±1.023.02±1.152.98±0.973.19±1.233.07±1.01
(×1012L-1)CPFA组3.29±1.133.12±2.113.33±0.983.15±1.343.17±1.093.24±1.323.19±1.523.00±1.483.22±1.09
CVVH组3.42±0.983.54±1.213.48±1.263.21±1.093.43±1.383.29±1.063.21±1.383.19±1.323.11±1.40
血小板HP+CVVH组150.23±50.34131.67±46.21135.57±55.24145.51±51.76118.23±62.77128.58±44.61126.92±57.25131.27±62.92123.56±49.21
(×109L-1)CPFA组147.11±51.95171.02±45.36a156.21±40.56165.62±69.21150.24±70.15a154.69±65.23a165.13±51.27a153.94±38.23a171.91±60.74a
CVVH组168.23±45.26182.01±80.34a162.69±77.29173.22±69.15170.16±60.53a159.57±66.1a158.18±69.24a163.47±55.16a168.35±47.66a
白细胞HP+CVVH组15.13±4.5713.12±6.1414.63±3.9214.20±5.8113.72±3.2814.09±5.3512.73±5.5712.05±3.8112.33±4.75
(×109L-1)CPFA组14.92±5.3514.18±6.1913.32±5.8513.736±4.9311.16±6.9412.92±5.5612.14±4.6513.23±4.8612.39±3.91
CVVH组16.16±5.9816.07±8.1116.48±6.7915.42±6.3513.05±5.1514.82±5.4713.92±6.7113.95±5.8412.78±4.32
注:CPFA组、CVVH组分别与HP+CVVH治疗组相比,aP<0.05
2.6 病死率比较

CVVH+HP、CPFA及CVVH治疗组28 d病死率比较,三组病死率分别为6/15(40.0%)、5/15(33.3%)、5/15(33.3%),差异无统计学意义(P>0.05)。

3 讨论

MODS本质上是由于感染或非感染因素导致炎症细胞在不同层面上被激活,经过传导、瀑布样放大,产生并释放大量炎性介质,导致机体远隔各器官功能的损伤或衰竭[3]。脓毒症患者病情越重, 相关细胞因子质量浓度越高[4]。在2016年Sepsis3.0指南强调了机体对于感染的应答的具有个体差异,导致部分患者出现危及生命的器官功能障碍[5]。血液净化辅助治疗脓毒症通过阻断或降低炎性介质的过度释放,从而减轻炎症反应导致的组织器官损伤,进行器官支持,对重症脓毒症诱发MODS的治疗及预后有重要意义[6-8]

CPFA作为一种新型的血液净化技术,组合了血液净化治疗的多种模式,强化了血浆吸附的作用。CPFA治疗模式的主要优势是,能够清除循环中通过血滤或血透模式无法清除的大分子内毒素及胆酸、胆红素、硫醇、酚类等物质,并增强了清除炎性介质、细胞因子、活化补体等效果,较全血吸附减少了血液有形成分破坏,可调节机体致炎、抗炎及免疫功能平衡,同时维持水、电及酸碱平衡等内环境稳定;可降低或避免血浆置换时大量外源血浆进入体内、导致过敏反应及血源性感染等风险,同时避免了体内有用物质丢失、血细胞与吸附剂接触而引起粒细胞和补体的活化,两者联合应用已逐渐成为MODS血液净化治疗的有效方法[9-10]

本研究发现CVVH、HP+CVVH、CPFA三种血液净化模式均具有清除循环血液中炎性介质的作用,与研究[2, 10-13]相吻合。HP+CVVH、CPFA治疗模式对TNF-α、IL-6、IL-1β三种炎症介质的清除效果差异无统计学意义,但二者与CVVH治疗模式相比较,患者血清IL-6浓度明显降低,P < 0.05,TNF-α水平有降低趋势,但P>0.05,IL-1β水平三组治疗间未见明显差别。这些结果证明通过吸附联合血滤的治疗模式较单纯CVVH具有更强的炎性介质清除能力,是目前重症脓毒症诱发MODS患者有效、安全的血液净化治疗模式。CPFA、CVVH两种血液净化方式治疗前后红细胞、白细胞、血小板水平未见明显变化。HP+CVVH治疗后血小板水平有下降趋势,CPFA组与CVVH治疗组治疗后血小板水平明显高于HP+CVVH治疗组,与HP+CVVH治疗比较,CPFA治疗模式对血液有形成分的保护更具优越性,尤其对血小板。

在治疗过程中,HP+CVVH、CPFA、CVVH三组治疗的患者均观察到血乳酸、心率、呼吸频率、氧合指数等指标的明显改善,血管活性药物的用量逐渐减少,血流动力学渐趋于稳定,T淋巴细胞亚群的CD4+、CD4+/CD8+比值与治疗前相比上升。以上观察结果说明,三种血液净化模式均可通过稳定机体内环境、降低或部分清除各种炎性介质、调节机体免疫功能平衡、改善血流动力学、减轻机体应激反应及组织器官损伤等诸多方面的有益作用,可能改善MODS患者的预后。未发现CVVH、CVVH+HP、CPFA三组组患者28 d病死率差异无统计学意义,考虑与研究样本数偏少、入选患者原发疾病不同、部分患者转入ICU时机偏晚、血液净化介入时机有差异等因素相关,需要进一步研究证实。

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