血液净化技术治疗脓毒症的基础与临床研究
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摘要
脓毒症是重症病人死亡的主要原因,是目前重症医学的重点研究领域,腹腔感染是最常见的引起脓毒症的原因。脓毒症的病理生理非常复杂,目前仍未完全了解。过度的促炎或抗炎反应均能导致细胞和器官功能障碍,严重时导致死亡。脓毒症干预的目标是恢复循环介质的动态平衡,而不是选择性的抑制促炎和抗炎介质。很多研究报道血液净化可以广泛的清除炎性介质,这种影响是广谱的,自动调节的,并且也能通过提高抗原递呈能力,调节白细胞募集,氧化爆发和吞噬能力,提供白细胞反应性,恢复免疫功能。为了找到优化的最佳的体外循环治疗脓毒症的方案,还需要做大量的工作。针对这些新的发病机制,提出了很多新技术、新材料。高容量血液滤过,血液吸附,配对血浆滤过吸附,高截留分子量膜等正对脓毒症患者开展研究。初步的研究数据表明,这些新技术方案具有可行性。但是仍然需要通过大规模随机临床试验证明这些新的技术方法及材料对病人的预后影响。最新的理论表明,脓毒症可以诱导免疫抑制,这也为体外血液净化治疗脓毒症的发展,提供了额外的理论依据。虽然对脓毒症的发病机制的认识已经取得重大进展,但目前脓毒症死亡率仍没有多少改善。体外血液净化作为一种辅助治疗脓毒症,已经应用了十几年,但对其疗效的评估仍然是有争议的。在最近几年,我们对其技术能力,及其使用的基本原理的理解已经有了相当大的进展。虽然目前仍然缺乏大规模的随机临床试验数据,但一些技术在动物实验和小规模的临床观察中看到了应用的前景。然而,在过去十年中对脓毒症发病机制的理解取得了很大的进步。所以,也需要我们根据这些新的研究结果,重新评估血液净化的效果。
为探讨血液净化技术在脓毒症中的治疗效果,以找到和优化最佳血液净化治疗策略,本研究主要分为如下几部分：(1)脓毒症大鼠模型的建立(2)脓毒症大鼠静-静脉血液净化模型建立及安全性评估；(3)血液吸附治疗脓毒症的实验研究；(4)高吸附血液滤过治疗脓毒症的实验研究：(5)高容量血液滤过治疗脓毒症的临床研究。美国匹兹堡大学CRISMA实验室为本研究提供了全方位的技术支持。
第一部分脓毒症大鼠模型的建立
研究目的：为了更好地开展血液净化治疗脓毒症的研究,探讨建立稳定的不同严重程度的脓毒症模型方法,以适应不同研究目的血液净化治疗研究。
方法：应用成年雄性Sprague-Dawley大鼠30只,随机分为三组,每组10只。第一组(CLP1)结扎盲肠1/4,穿孔两个；第二组(CLP2)结扎盲肠1/3,穿刺三个；对照组,打开腹腔,暴露盲肠,但不结扎和穿孔。观察各组大鼠7天存活率,检测手术48小时后血乳酸和血糖水平,并观察肝肾脏器损伤情况。
结果：对照组大鼠全部存活,CLP1组7天存活率50%,CLP2组7天存活率为10%。CLP48小时后出现血乳酸增高,血糖下降,CLP后肝脏组织学显示肝细胞有局灶性坏死,肝细胞肿胀,肾脏组织学显示肾小管空泡形成。
结论：通过控制结扎盲肠的长度和穿孔数目能建立不同严重程度的腹腔感染脓毒症模型,与人类脓毒症病理生理过程相近,能引起组织灌注不足,代谢障碍及脏器功能损伤。
第二部分脓毒症大鼠静-静脉血液净化模型的建立及安全性研究
背景和研究目的：血液净化技术目前已被广泛应用在脓毒症病人中。但很难在啮齿类动物中开展实验研究,过去的实验研究主要应用于大动物,并且采用动静脉血管通路。为了探讨血液净化技术在脓毒症大鼠模型中应用的可能性,我们开展了建立脓毒症大鼠静-静脉血液净化模型的研究,并评估其安全性。
方法：应用成年Sprague-Dawley大鼠,采用p50导管在大鼠股动脉或静脉和颈静脉置管,建立动-静脉或静-静脉回路。动-静脉血液回路利用动-静脉间压力差驱动,静-静脉血液回路需要应用微量蠕动泵驱动。观察血白介素-6(IL-6)、直肠温度和7天的存活率的变化,评估此血管回路的安全性,实验动物分为三组,体外循环血液净化治疗组,假血液净化治疗组(建立体外循环血管通路,但无滤器进行治疗),对照组(不建立血管回路),并且比较动-静脉回路和静-静脉回路主要并发症的发生率。
结果：体外循环治疗后IL-6,体温和存活率没有明显变化。静-静脉通路与动-静脉通路体外循环治疗相比,主要并发症发生率明显降低：大出血(2.5%比15%,P=0.04),血栓形成(2.5%比5%,P=0.04)。静-静脉体外循环技术目前已成功的应用于治疗脓毒症大鼠的各种血液净化技术中(如血液吸附和血液滤过)。
结论：静-静脉体外循环血液净化技术应用在大鼠模型中是有效安全的方法。
第三部分血液吸附治疗脓毒症的实验研究
目的：脓毒症患者血液和组织中会产生大量的细胞因子,导致全身炎症反应和多器官功能障碍。血液吸附可以通过清除血液中细胞因子减弱炎性反应,减轻脏器损伤,改善预后。本实验目的是研究应用CTP,一种新的吸附剂,血液净化治疗脓毒症,清除细胞因子的效果和对脏器功能的保护作用。
方法：将无菌CTR吸附颗粒填充到三种不同尺寸的柱子里,小(0.5ml),中(1m1),和大(2m1)。研究分为体外实验和体内实验部分。体外实验主要观察吸附柱对IL-6和TNF-α吸附效果。体内试验应用大鼠进行研究,采用盲肠结扎穿孔(cecal ligation and puncture, CLP)脓毒症模型,CLP手术后18小时,40只大鼠随机接受小,中,大吸附柱血液净化治疗(CTRO.5, CTR1, CTR2)或假血液净化治疗,分别在治疗前,治疗后0小时,4小时,24小时,48小时,留取血液标本,检测血浆内细胞因子水平(TNF-α, IL-1β, IL-6和IL-10),高迁移率族蛋白(high mobility group boxl, HMGB-1),肌酐,胱蛋白酶抑制剂C,并记录存活时间。
结果：体外实验表明,随着吸附柱尺寸的增加,对IL-6的清除率增加,并且对IL-6清除速度高于TNF-α。假治疗组,CTR0.5, CTR1, CTR2治疗组7天死亡率分别为50%,63.64%,62.5%,and72.72%。在治疗晚期(24小时和48小时),CTRO.5和CTR2治疗组,细胞因子浓度(TNF-α, IL-1β, IL-6, and IL-10)明显降低(p<0.05)。CTR2组在治疗两天后HMGB-1水平明显下降(p<0.05)。各组对于肌酐和ALT的影响没有明显的统计学意义,尽管治疗组似乎显示存在晚期肾脏保护的趋势。但是与假治疗组相比,CTR1和CTR2治疗组治疗后24小时胱蛋白酶抑制剂C明显降低。
结论：尽管采用CTR吸附柱血液净化治疗对于脓毒症大鼠细胞因子水平没有即刻的效果,但能提高CLP大鼠的存活率。CTR治疗组,尤其是CTR2组在治疗相对晚阶段确实能降低细胞因子和HMGB-1水平。CTR1和CTR2组在治疗后24小时能明显改善肾脏损伤。对于CTR的对细胞因子的吸附作用和治疗效果仍需进一步研究评估。
第四部分高吸附血液滤过治疗脓毒症的实验研究
研究目的：体外血液净化治疗严重脓毒症和脓毒性休克已经进行了很多的研究,随着血液净化治疗技术的进步,有很多新的技术被开发出来,特别是膜材料领域有很多最新进展。但是医学文献中很少有报道对比研究这些疗法。本研究的目的是在脓毒症大鼠中,比较高吸附血液滤过治疗的效果以及比较血液吸附的治疗效果的差别。
材料与方法：36只雄性Sprague-Dawley大鼠,CLP诱导严重脓毒症后18小时,被随机分为三组,建立体外循环血液净化,一组应用具有高度吸附内毒素能力的吸附剂(Oxiris(?),金宝),行高吸附血液滤过治疗(血液滤过组),一组应用有较强吸附细胞因子能力的吸附剂(CYTOSORB(?), CytoSorbents)行血液灌流治疗(血液吸附组),一组行体外循环无血液净化治疗(对照组),每组治疗均持续4小时。主要终点是7天生存率(log-rank检验)。在血液净化治疗开始和每次治疗结束后测量血液样本的细胞因子(TNF, GM-CSF, IFN-γ, IL-1α, IL-1β IL-2, IL-4, IL-6, IL-10, IL-12)
结果：血液滤过组12只大鼠,血液灌流组11只大鼠,对照组11只大鼠(2只大鼠随机分组前去世)。高吸附性血液滤过在7天的总生存率为66%,(8/12),血液灌流组总生存率45%(5/11),对照组18%(2/11)。高吸附血液滤过组死亡率相比对照组显著减少(p=0.011)。所有的细胞因子水平三组之间无显著性差异。
结论：高吸附血液滤过能够明显提高严重脓毒症大鼠的生存率,但对治疗后即时的细胞因子水平没有明显影响。
第五部分高容量血液滤过(HVHF)治疗脓毒症的临床研究
5.1高容量血液滤过(HVHF)治疗脓毒症引起的重度急性呼吸窘迫综合征的临床疗效
目的：探讨高容量血液滤过治疗脓毒症引起的重度急性呼吸窘迫综合征的临床疗效。
方法：对2007-2012年收治到我科的65例脓毒症引起的重度ARDS患者进行研究,有37例病人入选为治疗组,其余28例为对照组即常规治疗组,治疗组应用连续性高容量血液滤过治疗及其他常规治疗,对照组应用除血液滤过外的常规治疗。观察两组病人治疗前,治疗后6、24、48、72小时肺功能指标包括氧合指数、血管外肺水指数、PaC02的变化,及血流动力学参数指标包括心率、平均动脉压的变化,并观察机械通气的持续时间,成功撤机的百分率,28天存活率等指标。
结果：治疗组及对照组治疗后肺功能指标包括氧合指数、血管外肺水指数、PaC02较治疗前均有明显改善,治疗组较对照组改善明显,有统计学意义(p<0.05)。血流动力学指标包括心率及平均动脉压治疗后均有改善,但两组比较无统计学意义(p>0.05)。并且治疗组机械通气的持续时间、ICU治疗天数、成功撤机百分率、28天存活率等指标均明显好转。
结论：重度ARDS患者采用连续性高容量血液滤过治疗,能明显改善肺功能,缩短应用机械通气时间,提高机械通气撤机成功率,降低死亡率,对血流动力学无明显不利影响。
5.2高容量血液滤过(HVHF)对脓毒症引起的急性肺和肾损伤患者的影响
目的：探讨高容量血液滤过(HVHF)对脓毒症引起的急性肺损伤、急性肾损伤患者的影响。
方法：选取2007年8月至2011年12月收治到我科的108例脓毒症引起的急性肺损伤、急性肾损伤患者,随机分为常规治疗组(A组,68例)和HVHF组(B组,40例),均完成72h HVHF,比较两组治疗前后动脉血乳酸(Lac)、血清高敏C反应蛋白(hs-CRP)变化；比较反应急性肺损伤指标的肺泡氧分压与动脉氧分压的差值[P(A-a)D02].氧合指数[0I=Pa02/Fi02]的变化；比较反应急性肾损伤指标的血清胱抑素(Cyst C).血清肌酐清除率(CCR)的变化。
结果：①治疗后72h时,B组较A组血Lac、hs-CRP下降,分别为[2.7±1.5vs1.7±0.7(mmol/L),p<0.05和99.5±20.4vs35.8±18.8(mg/L) p<0.01],均具有统计学意义；②治疗后72h时,B组的P(A-a)D02、0I差异具有显著性,分别为155.4±27.4vs115.5±23.1,99.5±20.4vs295.2±38.8(P 结论：HVHF能改善脓毒症患者急性肺损伤、急性肾损伤患者的脏器功能,防治多脏器功能障碍综合征的发生。
结论
通过从基础到临床的系列应用研究表明血液净化技术是一种可行的治疗脓毒症的方法。
(1)首先采用最常用的CLP模型建立了脓毒症大鼠模型,通过控制结扎盲肠的长度和穿孔数目建立了两种严重程度不同的脓毒症模型,与人类脓毒症病理生理过程相近,能引起组织灌注不足,代谢障碍及脏器功能损伤。
(2)目前大部分血液净化治疗实验研究主要应用于大动物,应用大鼠行血液净化研究较少,我们成功的建立了脓毒症大鼠静-静脉体外循环血液净化模型,并评估了其安全性。研究结果表明静-静脉体外循环血液净化技术应用在大鼠模型中是有效安全的方法。
(3)利用含不同质量的新的吸附剂CTR制成的血液吸附装置,对腹腔感染引起的脓毒症大鼠进行血液灌流治疗,结果表明CTR似乎能够改善脓毒症大鼠的预后,有一定的脏器保护作用,特别是对肾脏,并与剂量相关。对炎性介质水平没有立即的影响,但可以引起晚期炎性介质水平的降低,这为进一步探讨血液净化的治疗机制提供了参考。
(4)利用新的吸附材料Oxiris对脓毒症大鼠行高吸附血液滤过治疗,结果表明高吸附血液滤过治疗能够改善预后,但对炎性介质水平没有即时的影响,并且似乎比单纯应用血液吸附治疗效果更好,尽管由于样本量较小,没有达到统计学意义,尽管如此,我们仍然相信结合了高吸附和高滤过技术的治疗策略可能比单一技术效果更好,这仍需要更进一步的研究。
(5)临床研究中我们应用高容量血液滤过技术治疗脓毒症引起的器官损伤,结果表明高容量血液净化技术可以改善脏器功能,改善预后。
总之血液净化技术为脓毒症的治疗提供了一种可行的方案,各种新的技术新的策略仍需要大规模的随机对照临床试验检验,对脓毒症的发病机制也需要进一步的研究。
Sepsis is one of the main causes of death in critically ill patients. The pathophysiology of sepsis is complex and not completely understood till now. The pro-inflammatory and anti-inflammatory response leads to cell and organ dysfunction and, in severe cases, death. Thus, the goal of the intervention is to restore the homeostasis of circulating mediators rather than to inhibit selectively the pro-inflammatory or anti-inflammatory mediators. The blood purification has been reported to remove a wide array of inflammatory mediators. The effects are broad-spectrum and auto-regulating. It is also demonstrated to restore immune function through improving antigen-presenting capability, adjusting leukocyte recruitment, oxidative burst and phagocytosis, and improving leukocyte responsiveness. A great deal of work has to be done in order to find and optimize the best extracorporeal blood purification therapy for sepsis. New devices specifically target the pathophysiological mechanisms involved in these conditions. High-volume hemofiltration, hemoadsorption, coupled plasma filtration adsorption, high cut-off membrane are now being trialed in septic patients. Preliminary data indicate the feasibility of these modified techniques in sepsis. Their impact on patient prognosis, however, still needs proof by large randomized clinical trials. Finally, the emerging paradigm of sepsis-induced immune suppression provides additional rationale for the development of extracorporeal blood purification therapy for sepsis.
To investigate the effect of blood purification on sepsis caused by abdominal infection, and to find the best blood purification methods and optimize treatment strategies, Our study was divided into the following sections:(1) establish a rat model of sepsis;(2) development of venovenous extracorporeal blood purification circuits in rodents for sepsis and Safety assessment;(3) Effects of hemoadsorption with a novel adsorbent in the treatment of sepsis:in vivo and in vitro study (4) Effect of high adsorption homofiltrationi in treatment of septic rats;(5) clinical studies of high-volume hemofiltration in treatment of sepsis. CRISMA Laboratory, University of Pittsburgh provided us a full range of technical support.
The First Part Establishment of sepsis model of rat
Objective:In order to access the effect of blood purification treatment in sepsis, we explored the approach to setup stable rat sepsis model of different severity for different blood purification therapy research purposes.
Methods:Adult male Sprague-Dawley rats(n=30) were randomly divided into three groups(n=10each group). Sepsis in the experimental groups was induced by CLP, whereas the control group underwent a sham operation neither ligated nor punctured. In CLP group1(CLP1), the cecum was ligated at the position of1/4, then punctured twice with a21-gauge needle and a small amount of the bowel contents was extruded through the puncture holes; in the CLP group2(CLP2), cecum was ligated at the position of1/3, puncture3times. Survival time of rats will be observed in7days, the blood was dawnd at48hours after surgery to detect blood lactate and glucose levels.The pathological changes of kidney and liver would be observed.
Results:All rats of control group survived in7day,50%rats survived in CLP1Group, only10%rats survived in CLP2group. The blood lactate level increased, blood glucose decreased at48hours after CLP. Liver histology slice after CLP showed swelling of hepatocytes with focal piecemeal necrosis. Kidney histology after CLP showed significant vacuolization in tubules
Conclusion:By controlling the ligation length and puncture numbers of cecum we can create different severity of sepsis model induced by abdominal infection, it was silmilar with the pathophysiology characters of human sepsis, which can cause tissue hypoperfusion, metabolic disorders and organ damage.
The Second Part Development of venovenous extracorporeal blood purification circuits in rodents for sepsis and safety assessment
Background/Aim:Unlike pharmacologic interventions in sepsis, extracorporeal blood purification, which is widely used in septic patients, is not typically studied in experimental rodents. Most of the previous studies have performed extracorporeal blood purification in larger animals and typically use arterio-venous (AV) vascular access. In order to explore the possibility of blood purification technology applied in a rat model of sepsis, we developed a veno-venous (VV) purification model in the rat as an adjunct for the treatment of sepsis.
Methods:Using adult male Sprague-Dawley rats, we cannulated the femoral artery or vein and the jugular vein with P50tubing and created an AV or VV circuit. Blood flow was maintained by arterial pressure in the AV circuit, whereas in the VV circuit the blood flow was regulated using a rotary pump. The safety of this circuit was evaluated using the changes of blood interleukin6, rectal temperature, and7-d survival with sham extracorporeal circulation (circuit connection without treatment) compared with the control (without circuit). The main side complications of this VV circuit were compared with those of the AV circuit.
Results:The differences in interleukin6, body temperature, and cumulative survival were not statistically significant after extracorporeal circulation. The main complications of extracorporeal circulation occurred less often with VV compared with AV therapy:massive bleeding (2.5%versus15%, P=0.04); clot formation (2.5% versus15%, P=0.04). This VV circuit has been successfully used in different septic rodent models with different techniques (such as hemoadsorption and hemofiltration).
Conclusions:VV blood purification in a rodent model appears to be effective and is safer than AV circuit.
The Third Part Effects of hemoadsorption with a novel adsorbent on sepsis: in vivo and in vitro study
Background/Aims:Sepsis is characterized by an overproduction of cytokines in the blood and tissues. Hemoadsorption may attenuate the dysfunctional inflammatory response and improve outcomes by removing cytokines from the circulating blood. We hypothesized that CTR, a new adsorbent, can remove cytokines and improve organ function.
Methods:The sterile CTR sorbent beads were filled into columns of three sizes: small (0.5ml), medium (1.0ml) and large (2.0ml). Each size of column was tested using IL-6capture in vitro. In vivo, rats were subjected to cecal ligation and puncture (CLP) and18hours later were randomly assigned to receive treatment with either0.5ml, lml, or2.0ml of CTR beads (CTR0.5, CTR1and CTR2respectively) or sham treatment (n=10each) for four hours. Blood was drawn at18hours (hrs) after CLP, at0hrs after the4hr treatment, and then again at24hrs and48hrs after treatment. Plasma cytokines (TNF-a, IL-1β, IL-6, and IL-10), high mobility group boxl (HMGB-1), alanine aminotransferase (ALT), creatinine and cystatin C were measured. Survival time was recorded.
Results:In vitro study showed that IL-6removal was accelerated with increasing bead mass. IL-6capture was faster than TNF-a capture. The mortality rates at7days after CLP were50%,63.64%,62.5%, and72.72%for the sham, CTR0.5, CTR1, CTR2respectively. At later time points (24hrs and48hrs) after intervention, the cytokine concentrations (TNF-α, IL-1β, IL-6, and IL-10) were significantly lower in the CTR0.5and CTR2bead treatment groups (p<0.05). CTR2groups showed a significant decrease in HMGB-1after two days (p<0.05). There were no statistically significant differences reached on ALT and creatinine, but the results show strong evidence for late renal protection. Additionally, cystatin C levels after24hr of treatments in CTR1and CTR2groups were significantly lower compared to the sham treatments.
Conclusion:CTR appeared to have a favorable effect on survival despite no immediate effects on cytokine removal. However, CTR, especially CTR2beads, did result in a late decrease cytokines and HMGB-1. CTR1andCTR2beads also significantly reduced kidney injury at24hrs after treatments. Further study is needed.
The Fouth Part Effect of high adsorption homofiltrationi in treatment of septic rats
Background/Aim:The extracorporeal blood purification is proposed as immunomodulatory adjuvant septic shock. Recent advances in the field of renal replacement therapy membranes have allowed the development of new techniques. These therapies are very low compared with one another in the medical literature. The objective of this study was to compare the mortality of septic shock in rats after high adsorption hemofiltration versus after hemoperfusion.
Materials and Methods:36rats were subjected to cecal ligation and puncture (CLP) Eighteen hours after induction of sepsis, they were randomized into three groups to receive a session4h high adsorption hemofiltration (adsorbent membrane hemofiltration endotoxins (Oxiris(?), Gambro)), or a session of4hours hemoperfusion (cartridge bearings adsorbent cytokines (CytoSorb(?), CytoSorbents)), or a session of4hours extracorporeal circulation without blood purification element (control group). The primary endpoint was survival to7days (log-rank test). Furthermore, assays of cytokines (TNF, GMCSF, IFN-y, IL-la, IL-1p, IL-2, IL-4, IL-6, IL-10, IL-12) on blood samples were carried out at the beginning,2hours and4hours after each session.
Results:Twelve rats were included in the hemofiltration group,11in the hemoperfusion group and11in the control group (2rats died before randomization). Overall survival at day7was66%in group high adsorption hemofiltration (8/12),45%in the hemoperfusion group (5/11) and18%in the control group (2/11). Mortality was significantly reduced in the high adsorption hemofiltration group compared to control group (P=0.011). All cytokine assays showed no significant difference between the3groups.
Conclusion:In this animal model of septic shock, high adsorption hemofitrtion seemed improve survival. But there were no significant difference in all cytokine level before and after treatment, no difference between the3group.
The Fifth Part5.1Effect of Continuous high volume hemofiltration on patients with severe acute respiratory distress syndrome
OBJECTIVE:To investigate the effect of continuous high-volume hemofiltration (HVHF) on patients with severe acute respiratory distress syndrome.
METHODS:Sixty-five patients with severe ARDS from2007to2012were divided into control group (28patients) and HVHF treatment group (37patients). The patients in HVHF treatment group were treated with HVHF (45ml/kg/h) and the other normal treatment.28patients of control group was received the normal treatment except hemofiltration therapy. We compared the oxygenation index (PaO2/FiO2). extravascular lung water index (EVLWI), PaCO2, heart rate, mean arterial pressure between control group and treatment group before and after treatment. The duration of mechanical ventilation,ICU stay time and percentage of withdraw from ventilation also were compared.
RESULTS:The oxygenation index (PaO2/FiO2),extravascular lung water index (EVLWI), PaCO2,we compared,were improved after the treatment in both the HVHF treatment group and the control group(p<0.05), but improvement in the HVHF treatment group is more obvious than control group(p<0.05). The heart rate and mean arterial pressure were improved after the treatment in both groups(p<0.05), but no obvious difference compared between the treatment group to the control group (p>0.05). The duration of mechanical ventilation,ICU stay time and percentage of withdraw from ventilation were showed obvious improvement in the HVHF treatment group(p<0.05).
Conclusion:HVHF is an effective assistant treatment for severe ARDS. It can improve the lung function,shorten the duration of mechanical ventilation, percentage of withdraw from ventilation and the survival rate, but no obvious hemodynamics influence to patients.
5.2Study the effects of high-volume hemofiltration on acute lung injury and acute kidney injury patients induced by sepsis
Objective:To evaluate the effects of high-volume hemofiltration(HVHF) on the organ function in patients with acute lung injury(ALI) and acute kidney injury(AKI).
Methods:108cases septic patients with ALI and AKI underwent HVHF were enrolled our Department between August2007and December2011. All the patients were randomly divided in two groups(routine treatment, group A,68cases) and (high-volume hemofiltration, group B,40cases).The artery lactate level were checked by arterial blood gas analysis(ABGA) at first and at72hour in two groups; serum high sensitivity reactive protein(hs-CRP) was detected by immunity-cross muddy method on admission and comparison before treatment and after72hour in two groups; Alveolar-arterial oxygen pressure difference P(A-a)DO2and oxygenation index(OI) was checked. The serum Cystatin C (Cyst c) and serum creatinine clearance rate (CCR) levels was checked by at first and after72hour in two groups. Data were expressed as mean±standard deviation and the analysis of variance was done with Spss12.0software. Two group average comparison was conducted with t-test and the ratio by chi-square test. The change were considered as statistically significant if P value was less than0.05.
Results:(①The difference of artery lactate、hs-CRP in two groups[2.7±1.5vs1.7±0.7(mmol/L), P<0.05and99.5±20.4vs35.8±18.8(mg/L), P<0.05] in two groups after72hours was significant (P<0.01);②The levels of P(A-a)DO2in HVHF group were reduced more significantly than routine treatment [155.4±27.4vs115.5±23.1(mmHg), P<0.05], but the level of OI was increased [99.5±20.4vs295.2±38.8,P<0.01];③The Cystatin C (Cyst C) level in B groups was reduced gradually after72hour treatment [3.95±2.06vs2.06±1.12(mg/L), P<0.05], but the creatinine clearance rate (CCR) at72th hour in group B were higher than group A[90.21±30.35vs108.71±31.33, P<0.01].
Conclusions:HVHF could improve the organ function in patients with ALI and AKI, at the same time take precaution multiple organ dysfunction syndrome(MODS), so it could improve the survival rate of patients.
Our study from basic to clinical showed that blood purification technology is a feasible approach to the treatment of sepsis.
(1) Sepsis model in rats were established by CLP, which was the most commonly sepsis model. By controlling the ligation length and puncture numbers of cecum we established two kind of different severity of sepsis model, it was silmilar with the pathophysiology characters of human sepsis, which can cause tissue hypoperfusion, metabolic disorders and organ damage.
(2) We developed the VV extracorporeal blood purification in a rodent model IT appears to be effective and is safer than AV circuit.
(3) CTR appeared to have a favorable effect on survival despite no immediate effects on cytokine removal. However, CTR, especially CTR2beads, did result in a late decrease cytokines and HMGB-1. CTR1and CTR2beads also significantly reduced kidney injury at24hrs after treatments. Further study is needed.
(4) In this animal model of septic shock, high adsorption hemofitrtion seemed improve survival. But there were no significant difference in all cytokine level before and a fter treatment, no difference between the3group.
(5) In clinical research, we observed the effect of high volume hemofiltration in treatment of sepsis, the results showed that the HVHF technology can improve organ function and improve the prognosis.The research provides much useful iinformation about blood purification technique for the treatment of sepsis and can help us to manage the treatment of blood purification.Various new techniques and new strategy still need large-scale randomized controlled clinical trials to test, the pathogenesis of sepsis also need further study.
为探讨血液净化技术在脓毒症中的治疗效果,以找到和优化最佳血液净化治疗策略,本研究主要分为如下几部分：(1)脓毒症大鼠模型的建立(2)脓毒症大鼠静-静脉血液净化模型建立及安全性评估；(3)血液吸附治疗脓毒症的实验研究；(4)高吸附血液滤过治疗脓毒症的实验研究：(5)高容量血液滤过治疗脓毒症的临床研究。美国匹兹堡大学CRISMA实验室为本研究提供了全方位的技术支持。
第一部分脓毒症大鼠模型的建立
研究目的：为了更好地开展血液净化治疗脓毒症的研究,探讨建立稳定的不同严重程度的脓毒症模型方法,以适应不同研究目的血液净化治疗研究。
方法：应用成年雄性Sprague-Dawley大鼠30只,随机分为三组,每组10只。第一组(CLP1)结扎盲肠1/4,穿孔两个；第二组(CLP2)结扎盲肠1/3,穿刺三个；对照组,打开腹腔,暴露盲肠,但不结扎和穿孔。观察各组大鼠7天存活率,检测手术48小时后血乳酸和血糖水平,并观察肝肾脏器损伤情况。
结果：对照组大鼠全部存活,CLP1组7天存活率50%,CLP2组7天存活率为10%。CLP48小时后出现血乳酸增高,血糖下降,CLP后肝脏组织学显示肝细胞有局灶性坏死,肝细胞肿胀,肾脏组织学显示肾小管空泡形成。
结论：通过控制结扎盲肠的长度和穿孔数目能建立不同严重程度的腹腔感染脓毒症模型,与人类脓毒症病理生理过程相近,能引起组织灌注不足,代谢障碍及脏器功能损伤。
第二部分脓毒症大鼠静-静脉血液净化模型的建立及安全性研究
背景和研究目的：血液净化技术目前已被广泛应用在脓毒症病人中。但很难在啮齿类动物中开展实验研究,过去的实验研究主要应用于大动物,并且采用动静脉血管通路。为了探讨血液净化技术在脓毒症大鼠模型中应用的可能性,我们开展了建立脓毒症大鼠静-静脉血液净化模型的研究,并评估其安全性。
方法：应用成年Sprague-Dawley大鼠,采用p50导管在大鼠股动脉或静脉和颈静脉置管,建立动-静脉或静-静脉回路。动-静脉血液回路利用动-静脉间压力差驱动,静-静脉血液回路需要应用微量蠕动泵驱动。观察血白介素-6(IL-6)、直肠温度和7天的存活率的变化,评估此血管回路的安全性,实验动物分为三组,体外循环血液净化治疗组,假血液净化治疗组(建立体外循环血管通路,但无滤器进行治疗),对照组(不建立血管回路),并且比较动-静脉回路和静-静脉回路主要并发症的发生率。
结果：体外循环治疗后IL-6,体温和存活率没有明显变化。静-静脉通路与动-静脉通路体外循环治疗相比,主要并发症发生率明显降低：大出血(2.5%比15%,P=0.04),血栓形成(2.5%比5%,P=0.04)。静-静脉体外循环技术目前已成功的应用于治疗脓毒症大鼠的各种血液净化技术中(如血液吸附和血液滤过)。
结论：静-静脉体外循环血液净化技术应用在大鼠模型中是有效安全的方法。
第三部分血液吸附治疗脓毒症的实验研究
目的：脓毒症患者血液和组织中会产生大量的细胞因子,导致全身炎症反应和多器官功能障碍。血液吸附可以通过清除血液中细胞因子减弱炎性反应,减轻脏器损伤,改善预后。本实验目的是研究应用CTP,一种新的吸附剂,血液净化治疗脓毒症,清除细胞因子的效果和对脏器功能的保护作用。
方法：将无菌CTR吸附颗粒填充到三种不同尺寸的柱子里,小(0.5ml),中(1m1),和大(2m1)。研究分为体外实验和体内实验部分。体外实验主要观察吸附柱对IL-6和TNF-α吸附效果。体内试验应用大鼠进行研究,采用盲肠结扎穿孔(cecal ligation and puncture, CLP)脓毒症模型,CLP手术后18小时,40只大鼠随机接受小,中,大吸附柱血液净化治疗(CTRO.5, CTR1, CTR2)或假血液净化治疗,分别在治疗前,治疗后0小时,4小时,24小时,48小时,留取血液标本,检测血浆内细胞因子水平(TNF-α, IL-1β, IL-6和IL-10),高迁移率族蛋白(high mobility group boxl, HMGB-1),肌酐,胱蛋白酶抑制剂C,并记录存活时间。
结果：体外实验表明,随着吸附柱尺寸的增加,对IL-6的清除率增加,并且对IL-6清除速度高于TNF-α。假治疗组,CTR0.5, CTR1, CTR2治疗组7天死亡率分别为50%,63.64%,62.5%,and72.72%。在治疗晚期(24小时和48小时),CTRO.5和CTR2治疗组,细胞因子浓度(TNF-α, IL-1β, IL-6, and IL-10)明显降低(p<0.05)。CTR2组在治疗两天后HMGB-1水平明显下降(p<0.05)。各组对于肌酐和ALT的影响没有明显的统计学意义,尽管治疗组似乎显示存在晚期肾脏保护的趋势。但是与假治疗组相比,CTR1和CTR2治疗组治疗后24小时胱蛋白酶抑制剂C明显降低。
结论：尽管采用CTR吸附柱血液净化治疗对于脓毒症大鼠细胞因子水平没有即刻的效果,但能提高CLP大鼠的存活率。CTR治疗组,尤其是CTR2组在治疗相对晚阶段确实能降低细胞因子和HMGB-1水平。CTR1和CTR2组在治疗后24小时能明显改善肾脏损伤。对于CTR的对细胞因子的吸附作用和治疗效果仍需进一步研究评估。
第四部分高吸附血液滤过治疗脓毒症的实验研究
研究目的：体外血液净化治疗严重脓毒症和脓毒性休克已经进行了很多的研究,随着血液净化治疗技术的进步,有很多新的技术被开发出来,特别是膜材料领域有很多最新进展。但是医学文献中很少有报道对比研究这些疗法。本研究的目的是在脓毒症大鼠中,比较高吸附血液滤过治疗的效果以及比较血液吸附的治疗效果的差别。
材料与方法：36只雄性Sprague-Dawley大鼠,CLP诱导严重脓毒症后18小时,被随机分为三组,建立体外循环血液净化,一组应用具有高度吸附内毒素能力的吸附剂(Oxiris(?),金宝),行高吸附血液滤过治疗(血液滤过组),一组应用有较强吸附细胞因子能力的吸附剂(CYTOSORB(?), CytoSorbents)行血液灌流治疗(血液吸附组),一组行体外循环无血液净化治疗(对照组),每组治疗均持续4小时。主要终点是7天生存率(log-rank检验)。在血液净化治疗开始和每次治疗结束后测量血液样本的细胞因子(TNF, GM-CSF, IFN-γ, IL-1α, IL-1β IL-2, IL-4, IL-6, IL-10, IL-12)
结果：血液滤过组12只大鼠,血液灌流组11只大鼠,对照组11只大鼠(2只大鼠随机分组前去世)。高吸附性血液滤过在7天的总生存率为66%,(8/12),血液灌流组总生存率45%(5/11),对照组18%(2/11)。高吸附血液滤过组死亡率相比对照组显著减少(p=0.011)。所有的细胞因子水平三组之间无显著性差异。
结论：高吸附血液滤过能够明显提高严重脓毒症大鼠的生存率,但对治疗后即时的细胞因子水平没有明显影响。
第五部分高容量血液滤过(HVHF)治疗脓毒症的临床研究
5.1高容量血液滤过(HVHF)治疗脓毒症引起的重度急性呼吸窘迫综合征的临床疗效
目的：探讨高容量血液滤过治疗脓毒症引起的重度急性呼吸窘迫综合征的临床疗效。
方法：对2007-2012年收治到我科的65例脓毒症引起的重度ARDS患者进行研究,有37例病人入选为治疗组,其余28例为对照组即常规治疗组,治疗组应用连续性高容量血液滤过治疗及其他常规治疗,对照组应用除血液滤过外的常规治疗。观察两组病人治疗前,治疗后6、24、48、72小时肺功能指标包括氧合指数、血管外肺水指数、PaC02的变化,及血流动力学参数指标包括心率、平均动脉压的变化,并观察机械通气的持续时间,成功撤机的百分率,28天存活率等指标。
结果：治疗组及对照组治疗后肺功能指标包括氧合指数、血管外肺水指数、PaC02较治疗前均有明显改善,治疗组较对照组改善明显,有统计学意义(p<0.05)。血流动力学指标包括心率及平均动脉压治疗后均有改善,但两组比较无统计学意义(p>0.05)。并且治疗组机械通气的持续时间、ICU治疗天数、成功撤机百分率、28天存活率等指标均明显好转。
结论：重度ARDS患者采用连续性高容量血液滤过治疗,能明显改善肺功能,缩短应用机械通气时间,提高机械通气撤机成功率,降低死亡率,对血流动力学无明显不利影响。
5.2高容量血液滤过(HVHF)对脓毒症引起的急性肺和肾损伤患者的影响
目的：探讨高容量血液滤过(HVHF)对脓毒症引起的急性肺损伤、急性肾损伤患者的影响。
方法：选取2007年8月至2011年12月收治到我科的108例脓毒症引起的急性肺损伤、急性肾损伤患者,随机分为常规治疗组(A组,68例)和HVHF组(B组,40例),均完成72h HVHF,比较两组治疗前后动脉血乳酸(Lac)、血清高敏C反应蛋白(hs-CRP)变化；比较反应急性肺损伤指标的肺泡氧分压与动脉氧分压的差值[P(A-a)D02].氧合指数[0I=Pa02/Fi02]的变化；比较反应急性肾损伤指标的血清胱抑素(Cyst C).血清肌酐清除率(CCR)的变化。
结果：①治疗后72h时,B组较A组血Lac、hs-CRP下降,分别为[2.7±1.5vs1.7±0.7(mmol/L),p<0.05和99.5±20.4vs35.8±18.8(mg/L) p<0.01],均具有统计学意义；②治疗后72h时,B组的P(A-a)D02、0I差异具有显著性,分别为155.4±27.4vs115.5±23.1,99.5±20.4vs295.2±38.8(P
结论
通过从基础到临床的系列应用研究表明血液净化技术是一种可行的治疗脓毒症的方法。
(1)首先采用最常用的CLP模型建立了脓毒症大鼠模型,通过控制结扎盲肠的长度和穿孔数目建立了两种严重程度不同的脓毒症模型,与人类脓毒症病理生理过程相近,能引起组织灌注不足,代谢障碍及脏器功能损伤。
(2)目前大部分血液净化治疗实验研究主要应用于大动物,应用大鼠行血液净化研究较少,我们成功的建立了脓毒症大鼠静-静脉体外循环血液净化模型,并评估了其安全性。研究结果表明静-静脉体外循环血液净化技术应用在大鼠模型中是有效安全的方法。
(3)利用含不同质量的新的吸附剂CTR制成的血液吸附装置,对腹腔感染引起的脓毒症大鼠进行血液灌流治疗,结果表明CTR似乎能够改善脓毒症大鼠的预后,有一定的脏器保护作用,特别是对肾脏,并与剂量相关。对炎性介质水平没有立即的影响,但可以引起晚期炎性介质水平的降低,这为进一步探讨血液净化的治疗机制提供了参考。
(4)利用新的吸附材料Oxiris对脓毒症大鼠行高吸附血液滤过治疗,结果表明高吸附血液滤过治疗能够改善预后,但对炎性介质水平没有即时的影响,并且似乎比单纯应用血液吸附治疗效果更好,尽管由于样本量较小,没有达到统计学意义,尽管如此,我们仍然相信结合了高吸附和高滤过技术的治疗策略可能比单一技术效果更好,这仍需要更进一步的研究。
(5)临床研究中我们应用高容量血液滤过技术治疗脓毒症引起的器官损伤,结果表明高容量血液净化技术可以改善脏器功能,改善预后。
总之血液净化技术为脓毒症的治疗提供了一种可行的方案,各种新的技术新的策略仍需要大规模的随机对照临床试验检验,对脓毒症的发病机制也需要进一步的研究。
Sepsis is one of the main causes of death in critically ill patients. The pathophysiology of sepsis is complex and not completely understood till now. The pro-inflammatory and anti-inflammatory response leads to cell and organ dysfunction and, in severe cases, death. Thus, the goal of the intervention is to restore the homeostasis of circulating mediators rather than to inhibit selectively the pro-inflammatory or anti-inflammatory mediators. The blood purification has been reported to remove a wide array of inflammatory mediators. The effects are broad-spectrum and auto-regulating. It is also demonstrated to restore immune function through improving antigen-presenting capability, adjusting leukocyte recruitment, oxidative burst and phagocytosis, and improving leukocyte responsiveness. A great deal of work has to be done in order to find and optimize the best extracorporeal blood purification therapy for sepsis. New devices specifically target the pathophysiological mechanisms involved in these conditions. High-volume hemofiltration, hemoadsorption, coupled plasma filtration adsorption, high cut-off membrane are now being trialed in septic patients. Preliminary data indicate the feasibility of these modified techniques in sepsis. Their impact on patient prognosis, however, still needs proof by large randomized clinical trials. Finally, the emerging paradigm of sepsis-induced immune suppression provides additional rationale for the development of extracorporeal blood purification therapy for sepsis.
To investigate the effect of blood purification on sepsis caused by abdominal infection, and to find the best blood purification methods and optimize treatment strategies, Our study was divided into the following sections:(1) establish a rat model of sepsis;(2) development of venovenous extracorporeal blood purification circuits in rodents for sepsis and Safety assessment;(3) Effects of hemoadsorption with a novel adsorbent in the treatment of sepsis:in vivo and in vitro study (4) Effect of high adsorption homofiltrationi in treatment of septic rats;(5) clinical studies of high-volume hemofiltration in treatment of sepsis. CRISMA Laboratory, University of Pittsburgh provided us a full range of technical support.
The First Part Establishment of sepsis model of rat
Objective:In order to access the effect of blood purification treatment in sepsis, we explored the approach to setup stable rat sepsis model of different severity for different blood purification therapy research purposes.
Methods:Adult male Sprague-Dawley rats(n=30) were randomly divided into three groups(n=10each group). Sepsis in the experimental groups was induced by CLP, whereas the control group underwent a sham operation neither ligated nor punctured. In CLP group1(CLP1), the cecum was ligated at the position of1/4, then punctured twice with a21-gauge needle and a small amount of the bowel contents was extruded through the puncture holes; in the CLP group2(CLP2), cecum was ligated at the position of1/3, puncture3times. Survival time of rats will be observed in7days, the blood was dawnd at48hours after surgery to detect blood lactate and glucose levels.The pathological changes of kidney and liver would be observed.
Results:All rats of control group survived in7day,50%rats survived in CLP1Group, only10%rats survived in CLP2group. The blood lactate level increased, blood glucose decreased at48hours after CLP. Liver histology slice after CLP showed swelling of hepatocytes with focal piecemeal necrosis. Kidney histology after CLP showed significant vacuolization in tubules
Conclusion:By controlling the ligation length and puncture numbers of cecum we can create different severity of sepsis model induced by abdominal infection, it was silmilar with the pathophysiology characters of human sepsis, which can cause tissue hypoperfusion, metabolic disorders and organ damage.
The Second Part Development of venovenous extracorporeal blood purification circuits in rodents for sepsis and safety assessment
Background/Aim:Unlike pharmacologic interventions in sepsis, extracorporeal blood purification, which is widely used in septic patients, is not typically studied in experimental rodents. Most of the previous studies have performed extracorporeal blood purification in larger animals and typically use arterio-venous (AV) vascular access. In order to explore the possibility of blood purification technology applied in a rat model of sepsis, we developed a veno-venous (VV) purification model in the rat as an adjunct for the treatment of sepsis.
Methods:Using adult male Sprague-Dawley rats, we cannulated the femoral artery or vein and the jugular vein with P50tubing and created an AV or VV circuit. Blood flow was maintained by arterial pressure in the AV circuit, whereas in the VV circuit the blood flow was regulated using a rotary pump. The safety of this circuit was evaluated using the changes of blood interleukin6, rectal temperature, and7-d survival with sham extracorporeal circulation (circuit connection without treatment) compared with the control (without circuit). The main side complications of this VV circuit were compared with those of the AV circuit.
Results:The differences in interleukin6, body temperature, and cumulative survival were not statistically significant after extracorporeal circulation. The main complications of extracorporeal circulation occurred less often with VV compared with AV therapy:massive bleeding (2.5%versus15%, P=0.04); clot formation (2.5% versus15%, P=0.04). This VV circuit has been successfully used in different septic rodent models with different techniques (such as hemoadsorption and hemofiltration).
Conclusions:VV blood purification in a rodent model appears to be effective and is safer than AV circuit.
The Third Part Effects of hemoadsorption with a novel adsorbent on sepsis: in vivo and in vitro study
Background/Aims:Sepsis is characterized by an overproduction of cytokines in the blood and tissues. Hemoadsorption may attenuate the dysfunctional inflammatory response and improve outcomes by removing cytokines from the circulating blood. We hypothesized that CTR, a new adsorbent, can remove cytokines and improve organ function.
Methods:The sterile CTR sorbent beads were filled into columns of three sizes: small (0.5ml), medium (1.0ml) and large (2.0ml). Each size of column was tested using IL-6capture in vitro. In vivo, rats were subjected to cecal ligation and puncture (CLP) and18hours later were randomly assigned to receive treatment with either0.5ml, lml, or2.0ml of CTR beads (CTR0.5, CTR1and CTR2respectively) or sham treatment (n=10each) for four hours. Blood was drawn at18hours (hrs) after CLP, at0hrs after the4hr treatment, and then again at24hrs and48hrs after treatment. Plasma cytokines (TNF-a, IL-1β, IL-6, and IL-10), high mobility group boxl (HMGB-1), alanine aminotransferase (ALT), creatinine and cystatin C were measured. Survival time was recorded.
Results:In vitro study showed that IL-6removal was accelerated with increasing bead mass. IL-6capture was faster than TNF-a capture. The mortality rates at7days after CLP were50%,63.64%,62.5%, and72.72%for the sham, CTR0.5, CTR1, CTR2respectively. At later time points (24hrs and48hrs) after intervention, the cytokine concentrations (TNF-α, IL-1β, IL-6, and IL-10) were significantly lower in the CTR0.5and CTR2bead treatment groups (p<0.05). CTR2groups showed a significant decrease in HMGB-1after two days (p<0.05). There were no statistically significant differences reached on ALT and creatinine, but the results show strong evidence for late renal protection. Additionally, cystatin C levels after24hr of treatments in CTR1and CTR2groups were significantly lower compared to the sham treatments.
Conclusion:CTR appeared to have a favorable effect on survival despite no immediate effects on cytokine removal. However, CTR, especially CTR2beads, did result in a late decrease cytokines and HMGB-1. CTR1andCTR2beads also significantly reduced kidney injury at24hrs after treatments. Further study is needed.
The Fouth Part Effect of high adsorption homofiltrationi in treatment of septic rats
Background/Aim:The extracorporeal blood purification is proposed as immunomodulatory adjuvant septic shock. Recent advances in the field of renal replacement therapy membranes have allowed the development of new techniques. These therapies are very low compared with one another in the medical literature. The objective of this study was to compare the mortality of septic shock in rats after high adsorption hemofiltration versus after hemoperfusion.
Materials and Methods:36rats were subjected to cecal ligation and puncture (CLP) Eighteen hours after induction of sepsis, they were randomized into three groups to receive a session4h high adsorption hemofiltration (adsorbent membrane hemofiltration endotoxins (Oxiris(?), Gambro)), or a session of4hours hemoperfusion (cartridge bearings adsorbent cytokines (CytoSorb(?), CytoSorbents)), or a session of4hours extracorporeal circulation without blood purification element (control group). The primary endpoint was survival to7days (log-rank test). Furthermore, assays of cytokines (TNF, GMCSF, IFN-y, IL-la, IL-1p, IL-2, IL-4, IL-6, IL-10, IL-12) on blood samples were carried out at the beginning,2hours and4hours after each session.
Results:Twelve rats were included in the hemofiltration group,11in the hemoperfusion group and11in the control group (2rats died before randomization). Overall survival at day7was66%in group high adsorption hemofiltration (8/12),45%in the hemoperfusion group (5/11) and18%in the control group (2/11). Mortality was significantly reduced in the high adsorption hemofiltration group compared to control group (P=0.011). All cytokine assays showed no significant difference between the3groups.
Conclusion:In this animal model of septic shock, high adsorption hemofitrtion seemed improve survival. But there were no significant difference in all cytokine level before and after treatment, no difference between the3group.
The Fifth Part5.1Effect of Continuous high volume hemofiltration on patients with severe acute respiratory distress syndrome
OBJECTIVE:To investigate the effect of continuous high-volume hemofiltration (HVHF) on patients with severe acute respiratory distress syndrome.
METHODS:Sixty-five patients with severe ARDS from2007to2012were divided into control group (28patients) and HVHF treatment group (37patients). The patients in HVHF treatment group were treated with HVHF (45ml/kg/h) and the other normal treatment.28patients of control group was received the normal treatment except hemofiltration therapy. We compared the oxygenation index (PaO2/FiO2). extravascular lung water index (EVLWI), PaCO2, heart rate, mean arterial pressure between control group and treatment group before and after treatment. The duration of mechanical ventilation,ICU stay time and percentage of withdraw from ventilation also were compared.
RESULTS:The oxygenation index (PaO2/FiO2),extravascular lung water index (EVLWI), PaCO2,we compared,were improved after the treatment in both the HVHF treatment group and the control group(p<0.05), but improvement in the HVHF treatment group is more obvious than control group(p<0.05). The heart rate and mean arterial pressure were improved after the treatment in both groups(p<0.05), but no obvious difference compared between the treatment group to the control group (p>0.05). The duration of mechanical ventilation,ICU stay time and percentage of withdraw from ventilation were showed obvious improvement in the HVHF treatment group(p<0.05).
Conclusion:HVHF is an effective assistant treatment for severe ARDS. It can improve the lung function,shorten the duration of mechanical ventilation, percentage of withdraw from ventilation and the survival rate, but no obvious hemodynamics influence to patients.
5.2Study the effects of high-volume hemofiltration on acute lung injury and acute kidney injury patients induced by sepsis
Objective:To evaluate the effects of high-volume hemofiltration(HVHF) on the organ function in patients with acute lung injury(ALI) and acute kidney injury(AKI).
Methods:108cases septic patients with ALI and AKI underwent HVHF were enrolled our Department between August2007and December2011. All the patients were randomly divided in two groups(routine treatment, group A,68cases) and (high-volume hemofiltration, group B,40cases).The artery lactate level were checked by arterial blood gas analysis(ABGA) at first and at72hour in two groups; serum high sensitivity reactive protein(hs-CRP) was detected by immunity-cross muddy method on admission and comparison before treatment and after72hour in two groups; Alveolar-arterial oxygen pressure difference P(A-a)DO2and oxygenation index(OI) was checked. The serum Cystatin C (Cyst c) and serum creatinine clearance rate (CCR) levels was checked by at first and after72hour in two groups. Data were expressed as mean±standard deviation and the analysis of variance was done with Spss12.0software. Two group average comparison was conducted with t-test and the ratio by chi-square test. The change were considered as statistically significant if P value was less than0.05.
Results:(①The difference of artery lactate、hs-CRP in two groups[2.7±1.5vs1.7±0.7(mmol/L), P<0.05and99.5±20.4vs35.8±18.8(mg/L), P<0.05] in two groups after72hours was significant (P<0.01);②The levels of P(A-a)DO2in HVHF group were reduced more significantly than routine treatment [155.4±27.4vs115.5±23.1(mmHg), P<0.05], but the level of OI was increased [99.5±20.4vs295.2±38.8,P<0.01];③The Cystatin C (Cyst C) level in B groups was reduced gradually after72hour treatment [3.95±2.06vs2.06±1.12(mg/L), P<0.05], but the creatinine clearance rate (CCR) at72th hour in group B were higher than group A[90.21±30.35vs108.71±31.33, P<0.01].
Conclusions:HVHF could improve the organ function in patients with ALI and AKI, at the same time take precaution multiple organ dysfunction syndrome(MODS), so it could improve the survival rate of patients.
Our study from basic to clinical showed that blood purification technology is a feasible approach to the treatment of sepsis.
(1) Sepsis model in rats were established by CLP, which was the most commonly sepsis model. By controlling the ligation length and puncture numbers of cecum we established two kind of different severity of sepsis model, it was silmilar with the pathophysiology characters of human sepsis, which can cause tissue hypoperfusion, metabolic disorders and organ damage.
(2) We developed the VV extracorporeal blood purification in a rodent model IT appears to be effective and is safer than AV circuit.
(3) CTR appeared to have a favorable effect on survival despite no immediate effects on cytokine removal. However, CTR, especially CTR2beads, did result in a late decrease cytokines and HMGB-1. CTR1and CTR2beads also significantly reduced kidney injury at24hrs after treatments. Further study is needed.
(4) In this animal model of septic shock, high adsorption hemofitrtion seemed improve survival. But there were no significant difference in all cytokine level before and a fter treatment, no difference between the3group.
(5) In clinical research, we observed the effect of high volume hemofiltration in treatment of sepsis, the results showed that the HVHF technology can improve organ function and improve the prognosis.The research provides much useful iinformation about blood purification technique for the treatment of sepsis and can help us to manage the treatment of blood purification.Various new techniques and new strategy still need large-scale randomized controlled clinical trials to test, the pathogenesis of sepsis also need further study.
引文
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