高容量血液滤过对脓毒症休克猪心肌线粒体功能影响的研究
|
摘要
脓毒症是重症病人死亡的主要原因之一。据美国最近统计,每年大约有75万例重症脓毒症发生,治疗费用高达近20亿,而一旦重症脓毒症发展至多脏器功能障碍(MODS),其死亡率高达50%。
由于脓毒症发展至MODS的机制尚不清楚,因此也缺乏特别有效的治疗措施。目前,治疗脓毒症的主要手段是早期发现并清除感染灶,积极的应用有效的抗生素进行抗感染,以及其他辅助支持治疗。其中,血液滤过是脓毒症治疗的一个重要的辅助治疗措施,它是基于物质清除的原理,对伴有肾功能衰竭的重症病人具有良好的治疗效果,并被逐渐应用于治疗不伴有肾功能衰竭的重症脓毒症和急性呼吸窘迫综合征(ARDS)的患者,并取得良好的临床效果。正如脓毒症的发生不单单是由于某种炎症介质的作用,血液滤过的治疗作用也不能单纯的由其清除作用解释。理论上,血液滤过在清除机体有害物质的同时也清除了相应分子量的对机体有益的物质;动物实验证明,血液滤过对脓毒症的治疗效果是基于其炎性介质清除作用之外的。因此,血液滤过在脓毒症治疗中的作用机制还需要我们进一步探讨。
近年来,越来越多的现象提示线粒体在脓毒症发生发展过程中发挥着重要的作用。首先,线粒体耗氧达机体耗氧总量的90%;其次,对脓毒症休克病人增加供氧并不能相应的增加机体氧耗,降低无氧酵解的发生;第三,研究发现脓毒症休克的病人组织氧压正常,但乳酸水平增高;第四,有证据表明脓毒症休克病人体内的炎症介质能够直接损伤线粒体功能。
那么,血液滤过对脓毒症的治疗是否是通过改善脓毒症病人细胞线粒体功能而发挥作用的呢?如果这一假设得到证实,那么对于血液滤过的临床应用及这一技术的改进都具有及其重要的理论指导意义。
目的
本研究采用自体盲肠内容物腹腔回输建立猪的脓毒症休克模型,观察造模后实验动物的血流动力学变化,以及器官功能损伤的情况。
方法
7只健康雄性Landrace猪随机分为正常对照组(Normal,n=3)和模型组(Peritonitis,n=4)。通过手术从猪的盲肠部位采集盲肠内容物约0.5g·kg~(-1)体重,术后1小时将采集的盲肠内容物回输腹腔,建立脓毒症休克模型。而正常对照组仅进行盲肠游离操作,不采集盲肠内容物。采用呼吸机进行机械通气,持续静脉输入复方林格氏液,维持肺动脉楔压于8-12 mmHg。连续监测血压、呼吸、心率、直肠温度等生命体征,动态监测平均动脉压、平均肺动脉压、肺动脉楔压、心排出量等血流动力学指标。在各时间点采集动脉血进行血气分析,采集静脉血检测血常规,并用全自动生化仪检测ALT、AST、Cr、BUN。造模后24小时将存活动物处死,动物死亡或处死时留取组织标本用于光镜检查。
结果
1.两组动物生存时间具有显著差异,模型组24小时死亡率100%,而正常对照组24小时内没有动物死亡;
2.血流动力学指标检测显示,盲肠内容物腹腔回输后动物早期出现心排出量增高,6小时达高峰,之后迅速下降。平均动脉压在早期没有明显改变,但后期进行性下降。而正常对照组的上述指标没有明显改变;
3.血气分析显示,模型组在造模6小时后开始出现pH值进行性降低,血乳酸水平增高。正常组的上述指标没有明显改变;
4.血生化指标显示,在造模12小时以后模型组出现BUN和Cr的增高,而ALT和AST没有明显改变。正常对照组的肝肾功能指标没有明显改变;
5.病理结果显示,心脏、肾脏、肝脏、肺脏等重要脏器均表现为非特异性炎症改变,光镜检查可以看到组织炎症细胞浸润,以及血细胞淤积等循环衰竭的表现。
结论
采用自体盲肠内容物腹腔回输能够成功建立脓毒症休克动物模型。该模型致伤因素、发病过程、临床表现与临床脓毒症休克表现相似。且该模型制备简单,表现稳定,重复性好。
目的
本研究旨在观察高容量血液滤过(HVHF)对脓毒症休克猪心肌线粒体功能的影响,并进一步探讨其可能的作用机制。
方法
16只健康雄性Landrace猪随机分为正常对照组(Normal,n=4),模型组(Peritonitis,n=6)和治疗组(HVHF,n=6)。与第一部分相同,采用自体盲肠内容物腹腔回输建立脓毒症休克模型。造模后1小时对治疗组进行HVHF干预治疗。支持治疗同第一部分。连续监测血压、呼吸、心率、直肠温度等生命体征,动态监测平均动脉压、平均肺动脉压、肺动脉楔压、心排出量等血流动力学指标,治疗12小时处死动物。在各时间点采集动脉血和混合静脉血进行血气分析,并进行血红蛋白定量监测,采集静脉血用于检测血浆一氧化氮(NO),肿瘤坏死因子(TNF)-α,白介素(IL)-6,10的水平。在动物处死时留取心肌组织标本,用于检测心肌组织线粒体呼吸链复合体的活性,检测心肌组织单磷酸腺苷(AMP),二磷酸腺苷(ADP)和三磷酸腺苷(ATP)的水平,检测心肌组织NO的水平。
结果
1.在模型组和治疗组,自体盲肠内容物腹腔回输后动物表现出典型的高动力循环状态,伴随低动力学休克。在开始的6个小时内,模型组和治疗组的血流动力学参数没有明显的差别。随着脓毒症休克的进展,心排出量和每搏输出量逐渐降低。与之相比,治疗组动物的心排出量和每搏输出量维持在较高的水平。这一心排出量的改善不伴有心室充盈压的变化,表现为两组动物的肺动脉楔压没有明显差别。伴随心室收缩功能的改善,治疗组体循环平均动脉压较模型组明显增高。治疗组实验动物上述血流动力学参数的改善仅出现在造模6小时以后。
2.在造模后3-7小时模型组动物氧供(DO_2)和氧耗(VO_2)出现增高的趋势,但与正常对照组比较差别没有统计学意义。而后DO_2和VO_2逐渐降低,在造模后13小时模型组DO_2明显低于正常对照组,与之相比,治疗组的DO_2维持在较高的水平。三组间,氧摄取分数(OER)没有明显差别。
3.盲肠内容物腹腔输注后血乳酸浓度进行性增加,与模型组相比,治疗组的血乳酸水平有所降低。模型组动脉血pH值进行性降低,HVHF治疗能够改善之。
4.与正常对照组相比,模型组线粒体呼吸链复合体1的活性降低37%,而HVHF治疗能够明显改善复合体I的活性,差别有统计学意义(P＜0.05)。三组间复合体Ⅱ,Ⅲ,Ⅳ的活性没有明显差别。
5.与正常对照组比较,盲肠内容物腹腔回输后13小时模型组动物心肌组织AMP浓度增加(P＜0.05),而ATP浓度明显降低(P＜0.05),ATP/ADP比值降低(P＜0.01)。HVHF治疗组心肌ATP维持在较高的水平,且能够逆转ATP/ADP比值的改变,差别有统计学意义(P＜0.05)。
6.在治疗开始,即造模1小时,三组间血浆NO水平没有明显差别。在造模13小时,模型组血浆NO水平明显增高,而HVHF治疗组与正常对照组水平相近。三组间心肌组织NO水平没有明显差别。
7.正常情况下,TNF-α表达水平较低,造模后迅速达到高峰,后逐渐降低,在造模后13小时基本降至正常水平;IL-6表达水平在造模后也增高,但高峰出现较晚,出现在造模后7小时,其后维持在较高的水平;IL-10的水平在模型组有增高的趋势,但差别没有统计学意义。与模型组相比,HVHF治疗组IL-6水平有所降低,差别有统计学意义,但TNF-α和IL-10的水平没有明显差别。
结论
1.HVHF治疗能够明显改善脓毒症休克猪心脏收缩功能以及血流动力学,表现为心排出量的改善,平均动脉压的增加,以及外周血管阻力的下降;
2.HVHF治疗能够改善脓毒症休克猪心肌线粒体呼吸链复合体的活性,改善心肌的能量储备;
4.HVHF对脓毒症休克猪心脏功能的改善可能是由于HVHF改善了心肌线粒体呼吸链复合体的活性,增加了心肌的能量储备而发挥作用的。
Background
Sepsis is the leading cause of mortality in the critically ill.Its incidence is increasing;over 750,000 episodes are reported annually in the United States, carrying an estimated annual healthcare cost in excess of $17 billion.
Mechanisims by which sepsis leads to organ dysfunction remain to be established and the treatment needs further study.Despite new insights,the cornerstone of therapy continues to be early recognition,prompt initiation of effective antibiotic therapy,and eliminating the source of infection.To date,the adjuvant treatment of sepsis remains a major therapeutic challenge.Hemofiltration,based on the humoral theory of sepsis,is a safe and well-established treatment in critically patients with renal failure,and has also been used in the treatment of severe sepsis.The mechanisms of hemofiltration in sepsis remain obscure.There is substantial disagressment whether the beneficial clinical effects observed during treatment with hemofiltration can be attributed to removal of specific inflammatory mediators.To date,no specific inflammatory mediators solely responsible for sepsis-induced organ injury have been identified.Moreover,as hemofiltration is a nonspecific blood purification technique,anti-inflammatory and beneficial mediators may be removed as well.Therefore,the mechanism of hemofiltration in sepsis needs further study.
Recently,increasing evidence indicates that mitochondrial dysfunction play an important role in modulating the development of manifestations of septic shock in patients with bacterial infection.First,increasing oxygen delivery in patients with septic shock does not consistently increase oxygen consumption and decrease the level of anaerobic metabolism as measured by arterial lactate concentration.Second, normal levels of tissue oxygen tension and elevated arterial lactate concentrations have been reported in patients with septic shock.Third,a number of the mediators implicated in septic shock have been demonstrated to directly impair mitochondrial function.Finally,measures intended to protect myocardial mitochondria have been confirmed effective.
However,it remains unknown whether treatment with hemofiltration exerts a specific effect on the mitochondrial dysfunction.If the hypothesis was confirmed,we could find the valuable theory evidence of hemofiltration in preventing and treating septic shock.
PartⅠ
Set up of septic shock in porcine
Objective
In the study,we set up peritonitis and septic shock model by infusion of autologous feces and observed the hemodynamics parameters and the severity of organ dysfunction.
Methods
Seven pigs were randomly divided into two groups which were subjected to normal group(Normal,n=6)and model group(Peritonitis,n=4).About 0.5g·kg~(-1) weight autologous feces was collected by operation and was infused into abdominal cavity 1 hour later.In normal group,the cecum was also disassociated,however feces was not collected.Their tracheas were intubated,and respiration was supported by breathing machine.All animals received 2L lactated Ringer's solution during the surgical procedure and 10-15 ml·kg~(-1)·h~(-1)during the rest of the experiment,with a rate adjusted to keep pulmonary artery occlusion pressure(PAOP)8-12mmHg.Blood pressure,breath,heart rate and temperature were monitored continuously.Mean arterial pressure(MAP),central venous pressure(CVP),mean pulmonary artery pressure(MPAP)and PAOP were recorded with quartz pressure transducers.Arterial blood samples were collected at every time points for blood gas and serum was collected for ALT,AST,Cr,BUN.Alive animals were sacrified in 24 hours and tissue of vital organ was collected for lighr microscope.
Results
1.There is significant difference of live time between the two groups.The mortality of model group is 100%in 24 hours.However,there is no death in normal group.
2.Hemodynamics parameters showed that cardic output of peritonitis animal increased in the early phase,and followed by decrease.MAP was normal in early phase,and decreased in the following time.There was no significant change in the normal group.
3.Arterial Ph decreased progressively in peritonitis animals,and was significantly lower than that in normal animals.At the same time,the level of lactate was increased.
Conclusions
The septic shock model could be successfully reproduced by infusion of autologous feces.The model reproduces characteristic features of sepsis,such as causative factors of injury,progression of illness and clinical presentation. Furthermore,the model is stable and reproduced better.
PartⅡ
Hemofiltration with high-volume attenuates myocardial mitochondrial dysfunction in porcine septic shock
Objective
In the study,we observed the impact of high-volume hemofiltration(HVHF)on myocardial mitochondrial respiratory chain complex activities in peritonitis-induced septic shock and further investigated the possible mechanism.
Methods
Sixteen pigs were randomly divided into three groups which were subjected to normal group(Normal,n=4),model group(Peritonitis,n=6)and HVHF group (HVHF,n=6).As the partⅠ,septic shock model was reproduced by infusion of autologous feces.HVHF was applied 1 hour after induction of peritonitis and the support therapy was employed as the partⅠ.Blood pressure,breath,heart rate and temperature were monitored continuously.Mean arterial pressure(MAP),central venous pressure(CVP),mean pulmonary artery pressure(MPAP)and PAOP were recorded with quartz pressure transducers.Arterial blood samples were collected at every time points for blood gas and plasm was collected for NO,IL-6,IL-10,TNF-α. Alive animals were sacrified at 13 hours after induction of peritonitis and cardiac tissue was collected for further investigation,such as ATP,ADP,AMP and NO.
Results
1.In both peritonitis groups,fluid resuscitation provoked a typical hyperdynamic septic shock followed by hypodynamic shock.During the first 6h,hemodynamic parameters were similar in two peritonitis groups.With the progression of septic shock,cardiac output declined.Compared with animals without CVVH,cardiac output and stroke volume were substantially better maintained in the CVVH-treatment animals throughout the entire experiment period.This improvement of cardiac output was not associated with differences in ventricular filling pressures,as reflected by comparable PAOP in both groups.With the improved cardiac contractility,systolic MAP was significantly higher in animals with CVVH versus without CVVH.The divergence of this physiologic parameter was apparent only after 6h of the experimental protocol.
2.3-7 hours after induction of peritonitis,DO2 and VO2 slightly increased and then declined.However,there is no significant difference between normal group and peritonitis group.Compared with peritonitis group,DO2 in HVHF group was better kept.There was no difference among the three groups.
3.Compared with normal animals,arterial lactate was progressively increased and Ph was dcreased in peritonitis animals.HVHF could prevent the decline of Ph and decreased the level of lactate.
4.Compared with normal control,the activity of respiratory-chain complexⅠin myocardium was 37%lower for peritonitis animals.However,the activity of complexⅠwas better maintained in animals with CVVH(P＜0.05).No significant differences were found for complexⅡ,ⅢandⅣ.
5.Compared with normal group,the level of cardiac ATP and ATP/ADP in peritonitis animals was significantly decreased and AMP increased(P＜0.05).However, HVHF could prevent the decline of ATP and keep the ATP/ADP better(P＜0.05).
6.At the start of hemofiltration,1h after peritonitis challenge,plasma nitrite-nitrite concentrations did not differ between groups.However,plasma nitrate-nitrite increased in peritonitis-challenge animals,but was about normal in animals receiving CVVH at 13h after peritonitis induction.As for concentration of nitrate-nitrite in myocardial homogenate,there was no difference between groups.
7.Low-level expression of TNF-α,IL-6 and IL-10 was found in normal pigs.After induction of peritonitis,TNF-αwas increased sharply and then decreased to normal when the animals were killed.IL-6 was also increased and kept at high level during the procedure.There was no significant change of IL-10 during the disease.HVHF could decrease the expression of IL-6,but not influence the level of TNF-α.
Conclusions
1.HVHF improves cardiac dysfunction and hemodynamics in peritonitis-induced septic shock.
2.HVHF could ameliorate myocardial mitochondrial respiratory chain complex activities and improve the bioenergetics metabolism,which may be attributed to the decrease of plasma NO.
3.HVHF could decrease the level of IL-6 in peritonitis animals.
4.The improvement of cardiac dysfunction by HVHF in septic shock may be attributed to the amelioration of myocardial mitochondrial respiratory chain complex activities.
由于脓毒症发展至MODS的机制尚不清楚,因此也缺乏特别有效的治疗措施。目前,治疗脓毒症的主要手段是早期发现并清除感染灶,积极的应用有效的抗生素进行抗感染,以及其他辅助支持治疗。其中,血液滤过是脓毒症治疗的一个重要的辅助治疗措施,它是基于物质清除的原理,对伴有肾功能衰竭的重症病人具有良好的治疗效果,并被逐渐应用于治疗不伴有肾功能衰竭的重症脓毒症和急性呼吸窘迫综合征(ARDS)的患者,并取得良好的临床效果。正如脓毒症的发生不单单是由于某种炎症介质的作用,血液滤过的治疗作用也不能单纯的由其清除作用解释。理论上,血液滤过在清除机体有害物质的同时也清除了相应分子量的对机体有益的物质;动物实验证明,血液滤过对脓毒症的治疗效果是基于其炎性介质清除作用之外的。因此,血液滤过在脓毒症治疗中的作用机制还需要我们进一步探讨。
近年来,越来越多的现象提示线粒体在脓毒症发生发展过程中发挥着重要的作用。首先,线粒体耗氧达机体耗氧总量的90%;其次,对脓毒症休克病人增加供氧并不能相应的增加机体氧耗,降低无氧酵解的发生;第三,研究发现脓毒症休克的病人组织氧压正常,但乳酸水平增高;第四,有证据表明脓毒症休克病人体内的炎症介质能够直接损伤线粒体功能。
那么,血液滤过对脓毒症的治疗是否是通过改善脓毒症病人细胞线粒体功能而发挥作用的呢?如果这一假设得到证实,那么对于血液滤过的临床应用及这一技术的改进都具有及其重要的理论指导意义。
目的
本研究采用自体盲肠内容物腹腔回输建立猪的脓毒症休克模型,观察造模后实验动物的血流动力学变化,以及器官功能损伤的情况。
方法
7只健康雄性Landrace猪随机分为正常对照组(Normal,n=3)和模型组(Peritonitis,n=4)。通过手术从猪的盲肠部位采集盲肠内容物约0.5g·kg~(-1)体重,术后1小时将采集的盲肠内容物回输腹腔,建立脓毒症休克模型。而正常对照组仅进行盲肠游离操作,不采集盲肠内容物。采用呼吸机进行机械通气,持续静脉输入复方林格氏液,维持肺动脉楔压于8-12 mmHg。连续监测血压、呼吸、心率、直肠温度等生命体征,动态监测平均动脉压、平均肺动脉压、肺动脉楔压、心排出量等血流动力学指标。在各时间点采集动脉血进行血气分析,采集静脉血检测血常规,并用全自动生化仪检测ALT、AST、Cr、BUN。造模后24小时将存活动物处死,动物死亡或处死时留取组织标本用于光镜检查。
结果
1.两组动物生存时间具有显著差异,模型组24小时死亡率100%,而正常对照组24小时内没有动物死亡;
2.血流动力学指标检测显示,盲肠内容物腹腔回输后动物早期出现心排出量增高,6小时达高峰,之后迅速下降。平均动脉压在早期没有明显改变,但后期进行性下降。而正常对照组的上述指标没有明显改变;
3.血气分析显示,模型组在造模6小时后开始出现pH值进行性降低,血乳酸水平增高。正常组的上述指标没有明显改变;
4.血生化指标显示,在造模12小时以后模型组出现BUN和Cr的增高,而ALT和AST没有明显改变。正常对照组的肝肾功能指标没有明显改变;
5.病理结果显示,心脏、肾脏、肝脏、肺脏等重要脏器均表现为非特异性炎症改变,光镜检查可以看到组织炎症细胞浸润,以及血细胞淤积等循环衰竭的表现。
结论
采用自体盲肠内容物腹腔回输能够成功建立脓毒症休克动物模型。该模型致伤因素、发病过程、临床表现与临床脓毒症休克表现相似。且该模型制备简单,表现稳定,重复性好。
目的
本研究旨在观察高容量血液滤过(HVHF)对脓毒症休克猪心肌线粒体功能的影响,并进一步探讨其可能的作用机制。
方法
16只健康雄性Landrace猪随机分为正常对照组(Normal,n=4),模型组(Peritonitis,n=6)和治疗组(HVHF,n=6)。与第一部分相同,采用自体盲肠内容物腹腔回输建立脓毒症休克模型。造模后1小时对治疗组进行HVHF干预治疗。支持治疗同第一部分。连续监测血压、呼吸、心率、直肠温度等生命体征,动态监测平均动脉压、平均肺动脉压、肺动脉楔压、心排出量等血流动力学指标,治疗12小时处死动物。在各时间点采集动脉血和混合静脉血进行血气分析,并进行血红蛋白定量监测,采集静脉血用于检测血浆一氧化氮(NO),肿瘤坏死因子(TNF)-α,白介素(IL)-6,10的水平。在动物处死时留取心肌组织标本,用于检测心肌组织线粒体呼吸链复合体的活性,检测心肌组织单磷酸腺苷(AMP),二磷酸腺苷(ADP)和三磷酸腺苷(ATP)的水平,检测心肌组织NO的水平。
结果
1.在模型组和治疗组,自体盲肠内容物腹腔回输后动物表现出典型的高动力循环状态,伴随低动力学休克。在开始的6个小时内,模型组和治疗组的血流动力学参数没有明显的差别。随着脓毒症休克的进展,心排出量和每搏输出量逐渐降低。与之相比,治疗组动物的心排出量和每搏输出量维持在较高的水平。这一心排出量的改善不伴有心室充盈压的变化,表现为两组动物的肺动脉楔压没有明显差别。伴随心室收缩功能的改善,治疗组体循环平均动脉压较模型组明显增高。治疗组实验动物上述血流动力学参数的改善仅出现在造模6小时以后。
2.在造模后3-7小时模型组动物氧供(DO_2)和氧耗(VO_2)出现增高的趋势,但与正常对照组比较差别没有统计学意义。而后DO_2和VO_2逐渐降低,在造模后13小时模型组DO_2明显低于正常对照组,与之相比,治疗组的DO_2维持在较高的水平。三组间,氧摄取分数(OER)没有明显差别。
3.盲肠内容物腹腔输注后血乳酸浓度进行性增加,与模型组相比,治疗组的血乳酸水平有所降低。模型组动脉血pH值进行性降低,HVHF治疗能够改善之。
4.与正常对照组相比,模型组线粒体呼吸链复合体1的活性降低37%,而HVHF治疗能够明显改善复合体I的活性,差别有统计学意义(P＜0.05)。三组间复合体Ⅱ,Ⅲ,Ⅳ的活性没有明显差别。
5.与正常对照组比较,盲肠内容物腹腔回输后13小时模型组动物心肌组织AMP浓度增加(P＜0.05),而ATP浓度明显降低(P＜0.05),ATP/ADP比值降低(P＜0.01)。HVHF治疗组心肌ATP维持在较高的水平,且能够逆转ATP/ADP比值的改变,差别有统计学意义(P＜0.05)。
6.在治疗开始,即造模1小时,三组间血浆NO水平没有明显差别。在造模13小时,模型组血浆NO水平明显增高,而HVHF治疗组与正常对照组水平相近。三组间心肌组织NO水平没有明显差别。
7.正常情况下,TNF-α表达水平较低,造模后迅速达到高峰,后逐渐降低,在造模后13小时基本降至正常水平;IL-6表达水平在造模后也增高,但高峰出现较晚,出现在造模后7小时,其后维持在较高的水平;IL-10的水平在模型组有增高的趋势,但差别没有统计学意义。与模型组相比,HVHF治疗组IL-6水平有所降低,差别有统计学意义,但TNF-α和IL-10的水平没有明显差别。
结论
1.HVHF治疗能够明显改善脓毒症休克猪心脏收缩功能以及血流动力学,表现为心排出量的改善,平均动脉压的增加,以及外周血管阻力的下降;
2.HVHF治疗能够改善脓毒症休克猪心肌线粒体呼吸链复合体的活性,改善心肌的能量储备;
4.HVHF对脓毒症休克猪心脏功能的改善可能是由于HVHF改善了心肌线粒体呼吸链复合体的活性,增加了心肌的能量储备而发挥作用的。
Background
Sepsis is the leading cause of mortality in the critically ill.Its incidence is increasing;over 750,000 episodes are reported annually in the United States, carrying an estimated annual healthcare cost in excess of $17 billion.
Mechanisims by which sepsis leads to organ dysfunction remain to be established and the treatment needs further study.Despite new insights,the cornerstone of therapy continues to be early recognition,prompt initiation of effective antibiotic therapy,and eliminating the source of infection.To date,the adjuvant treatment of sepsis remains a major therapeutic challenge.Hemofiltration,based on the humoral theory of sepsis,is a safe and well-established treatment in critically patients with renal failure,and has also been used in the treatment of severe sepsis.The mechanisms of hemofiltration in sepsis remain obscure.There is substantial disagressment whether the beneficial clinical effects observed during treatment with hemofiltration can be attributed to removal of specific inflammatory mediators.To date,no specific inflammatory mediators solely responsible for sepsis-induced organ injury have been identified.Moreover,as hemofiltration is a nonspecific blood purification technique,anti-inflammatory and beneficial mediators may be removed as well.Therefore,the mechanism of hemofiltration in sepsis needs further study.
Recently,increasing evidence indicates that mitochondrial dysfunction play an important role in modulating the development of manifestations of septic shock in patients with bacterial infection.First,increasing oxygen delivery in patients with septic shock does not consistently increase oxygen consumption and decrease the level of anaerobic metabolism as measured by arterial lactate concentration.Second, normal levels of tissue oxygen tension and elevated arterial lactate concentrations have been reported in patients with septic shock.Third,a number of the mediators implicated in septic shock have been demonstrated to directly impair mitochondrial function.Finally,measures intended to protect myocardial mitochondria have been confirmed effective.
However,it remains unknown whether treatment with hemofiltration exerts a specific effect on the mitochondrial dysfunction.If the hypothesis was confirmed,we could find the valuable theory evidence of hemofiltration in preventing and treating septic shock.
PartⅠ
Set up of septic shock in porcine
Objective
In the study,we set up peritonitis and septic shock model by infusion of autologous feces and observed the hemodynamics parameters and the severity of organ dysfunction.
Methods
Seven pigs were randomly divided into two groups which were subjected to normal group(Normal,n=6)and model group(Peritonitis,n=4).About 0.5g·kg~(-1) weight autologous feces was collected by operation and was infused into abdominal cavity 1 hour later.In normal group,the cecum was also disassociated,however feces was not collected.Their tracheas were intubated,and respiration was supported by breathing machine.All animals received 2L lactated Ringer's solution during the surgical procedure and 10-15 ml·kg~(-1)·h~(-1)during the rest of the experiment,with a rate adjusted to keep pulmonary artery occlusion pressure(PAOP)8-12mmHg.Blood pressure,breath,heart rate and temperature were monitored continuously.Mean arterial pressure(MAP),central venous pressure(CVP),mean pulmonary artery pressure(MPAP)and PAOP were recorded with quartz pressure transducers.Arterial blood samples were collected at every time points for blood gas and serum was collected for ALT,AST,Cr,BUN.Alive animals were sacrified in 24 hours and tissue of vital organ was collected for lighr microscope.
Results
1.There is significant difference of live time between the two groups.The mortality of model group is 100%in 24 hours.However,there is no death in normal group.
2.Hemodynamics parameters showed that cardic output of peritonitis animal increased in the early phase,and followed by decrease.MAP was normal in early phase,and decreased in the following time.There was no significant change in the normal group.
3.Arterial Ph decreased progressively in peritonitis animals,and was significantly lower than that in normal animals.At the same time,the level of lactate was increased.
Conclusions
The septic shock model could be successfully reproduced by infusion of autologous feces.The model reproduces characteristic features of sepsis,such as causative factors of injury,progression of illness and clinical presentation. Furthermore,the model is stable and reproduced better.
PartⅡ
Hemofiltration with high-volume attenuates myocardial mitochondrial dysfunction in porcine septic shock
Objective
In the study,we observed the impact of high-volume hemofiltration(HVHF)on myocardial mitochondrial respiratory chain complex activities in peritonitis-induced septic shock and further investigated the possible mechanism.
Methods
Sixteen pigs were randomly divided into three groups which were subjected to normal group(Normal,n=4),model group(Peritonitis,n=6)and HVHF group (HVHF,n=6).As the partⅠ,septic shock model was reproduced by infusion of autologous feces.HVHF was applied 1 hour after induction of peritonitis and the support therapy was employed as the partⅠ.Blood pressure,breath,heart rate and temperature were monitored continuously.Mean arterial pressure(MAP),central venous pressure(CVP),mean pulmonary artery pressure(MPAP)and PAOP were recorded with quartz pressure transducers.Arterial blood samples were collected at every time points for blood gas and plasm was collected for NO,IL-6,IL-10,TNF-α. Alive animals were sacrified at 13 hours after induction of peritonitis and cardiac tissue was collected for further investigation,such as ATP,ADP,AMP and NO.
Results
1.In both peritonitis groups,fluid resuscitation provoked a typical hyperdynamic septic shock followed by hypodynamic shock.During the first 6h,hemodynamic parameters were similar in two peritonitis groups.With the progression of septic shock,cardiac output declined.Compared with animals without CVVH,cardiac output and stroke volume were substantially better maintained in the CVVH-treatment animals throughout the entire experiment period.This improvement of cardiac output was not associated with differences in ventricular filling pressures,as reflected by comparable PAOP in both groups.With the improved cardiac contractility,systolic MAP was significantly higher in animals with CVVH versus without CVVH.The divergence of this physiologic parameter was apparent only after 6h of the experimental protocol.
2.3-7 hours after induction of peritonitis,DO2 and VO2 slightly increased and then declined.However,there is no significant difference between normal group and peritonitis group.Compared with peritonitis group,DO2 in HVHF group was better kept.There was no difference among the three groups.
3.Compared with normal animals,arterial lactate was progressively increased and Ph was dcreased in peritonitis animals.HVHF could prevent the decline of Ph and decreased the level of lactate.
4.Compared with normal control,the activity of respiratory-chain complexⅠin myocardium was 37%lower for peritonitis animals.However,the activity of complexⅠwas better maintained in animals with CVVH(P＜0.05).No significant differences were found for complexⅡ,ⅢandⅣ.
5.Compared with normal group,the level of cardiac ATP and ATP/ADP in peritonitis animals was significantly decreased and AMP increased(P＜0.05).However, HVHF could prevent the decline of ATP and keep the ATP/ADP better(P＜0.05).
6.At the start of hemofiltration,1h after peritonitis challenge,plasma nitrite-nitrite concentrations did not differ between groups.However,plasma nitrate-nitrite increased in peritonitis-challenge animals,but was about normal in animals receiving CVVH at 13h after peritonitis induction.As for concentration of nitrate-nitrite in myocardial homogenate,there was no difference between groups.
7.Low-level expression of TNF-α,IL-6 and IL-10 was found in normal pigs.After induction of peritonitis,TNF-αwas increased sharply and then decreased to normal when the animals were killed.IL-6 was also increased and kept at high level during the procedure.There was no significant change of IL-10 during the disease.HVHF could decrease the expression of IL-6,but not influence the level of TNF-α.
Conclusions
1.HVHF improves cardiac dysfunction and hemodynamics in peritonitis-induced septic shock.
2.HVHF could ameliorate myocardial mitochondrial respiratory chain complex activities and improve the bioenergetics metabolism,which may be attributed to the decrease of plasma NO.
3.HVHF could decrease the level of IL-6 in peritonitis animals.
4.The improvement of cardiac dysfunction by HVHF in septic shock may be attributed to the amelioration of myocardial mitochondrial respiratory chain complex activities.
引文
1. Martin G S, Mannino D M, Eaton S, et al. The epidemiology of sepsis in the United State from 1979 through 2000. N Engl J Med 2003; 348: 1546-1554.
2. Angus D C, Linde-Zwirble W T, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303-1310.
3. Annane D, Aegerter P, Jars-Guincestre MC, et al. Current epidemiology of septic shock: the UCB-Rea Network. Am J Respir Crit Care Med 2003; 1687:165-172.
4. O'Reilly M, Newcomb D E, Remick D. Endotoxin, sepsis, and the primrosepath. Shock 1999; 12: 411-420.
5. Remick D G, Newcomb D E, Bolgos G L, et al. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide versus cecal ligation and puncture. Shock 2000; 13:110-116.
6. L ekkou A, Karakantza M, Mouzak i A, et al. Cytok ine p roduction and monocyte HLA DR expression as predictors of outcome for patients with communityacquired severe infections. Clin Diagn Lab Immunol, 2004; 11: 161-167.
7. Taniguchi T, Yamamoto K, Ohmoto N, et al. Effects of propofol on hemodynamic and inflammatory responses to endotoxemia in rats. Crit Care Med 2000; 28: 1101-1106.
8. Abraham E, Anzueto A, Gutierrez G, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 1998; 351: 929-933.
9. Deitch E A. Animal models of sepsis and shock: a review and lessons learned. Shock 1998; 9: 1-11.
10. Newcomb D, Bolgos G, Green L, et al. Antibiotic treatment influences outcome in murine sepsis: mediators of increased morbidity. Shock 1998; 10: 110-117.
11. Remick D G, Newcomb D E, Bolgos G, et al. Comparison of the mortality andinflammatory response of two models of sepsis:lipopo lysaccharide vs cecal ligation and puncture.Shock 2000;13:110-116.
[12].Remick D G,Manohar P,Bolgos G,et al.Block of tumor necrosis factor reduces lipopolysaccharide lethality,but not the lethality of cecal ligation and puncture.Shock 1995;4:89-95.
[13].王恒进,王笑云,应旭,等.猪多器官功能障碍综合征合并急性肾功能衰竭模型的制作.南京医科大学学报 2003:23:196-199.
[14].Luzius B H,Vladimir K,Gisli H S.Effects of dobutamine and dopexamine on microcirculatory blood flow in the gastrointestinal tract during sepsis and anesthesia.Anesthesiology 2004;100:1188-1197.
1. Angus D C, Linde-Zwirble W T, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1303-1310.
2. Ullrich R, Roeder G, Lorber C, et al. Continuous venovenous hemofiltration improves arterial oxygenation in endotoxin-induced lung injury in pigs. Anesthesiology 2001; 95:428-436.
3. Yekebas E F, Eisenberger C F, Ohnesorge H, et al. Attenuation of sepsis-related immunoparalysis by continuous venovenous hemofiltration in experimental porcine pancreatitis. Crit Care Med 2001; 29(7): 1423-1430.
4. Chen Z H, Liu Z H, Yu C, et al. Endothelial dysfunction in patients with severe acute pancreatitis: improved by continuous blood purification therapy. Int J Artif Organs 2007; 30 (5): 393-400.
5. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360(9328): 219-223.
6. Suematsu N, Tsutsui H, Wen J, et al.Oxidative stress mediates tumor necrosis factor-α-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2002; 26:1418-1423.
7. Crouser E D, Julian M W, Huff J E, et al. Abnormal permeability of immer and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia. Crit Care Med 2004; 32(2): 478-488.
8. Brealey D, Karyampudi S, Jacques T S, et al. Mytochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 2004; 286: R494-R497.
9. Lopez L C, Escames G, Tapias V, et al. Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice. Int J Biochem Cell Biol 2006; 38: 267-278.
10. Vanhorebeek I, De Vos R, Mesotten D, et al. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005; 365: 53-59.
11. Larche J, Lancel S, Hassoun S M, et al. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol 2006; 48(2): 377-385.
12. Supinske G S, Callahan L A. Hemin prevents cardiac and diaphragm mitochondrial dysfunction in sepsis. Free Radic Biol Med 2006; 40:127-137.
13. Martin G S, Mannino D M, Eaton S, et al. The epidemiology of sepsis in the United State from 1979 through 2000. N Engl J Med, 2003; 348 (16): 1546-1554.
14. YaoY M, Bahrami S, Leichtfried G, et al. Pathogenesis of hemorrhage-induced bacteria/endotoxin translocation in rats. Effect of recombinant bactericidal/permeability-increasing protein. Ann Surg 1995; 221 (4): 398-405.
15. Cavaillon J M, Adib-Conquy M, Fitting C, et al. Cytokine cascade in sepsis. Scand J Infect Dis 2003; 35: 535-544.
16. Pathan N, Hemingway C A, Alizadeh A A, et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet; 2004; 363: 203-209.
17. Aaroli J, FesslerM B, Abraham E. Genetic polymorphisms and sepsis. Shock 2005;24:300-312.
18. Bernard G R, Vincent J L, Laterre P F, et al. Efficacy and safety of recombinanthuman activated protein C for severe sepsis. N Engl J Med 2001; 344 (10): 699-709.
19. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341:586-592.
20. Cate H. Pathophysiology of disseminated intravascular coagulation in sepsis. Crit Care Med. 2000; 28:S9-S11.
21. Mela L, Bacalzo L V, Miller L D. Defective energy metabolism of rat liver mitochondrialin hemorrhagic and endotoxin shock. Am J Physiol 1971; 220: 571-577.
22. Tavakoli H, Mela L. Alterations of mitochondrial metabolism and protein concentrations in subacute septicemia. Infect Immun 1982; 38: 536-541.
23. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 2007; 35 (6): 1599-1608.
24. Trumbeckaite S, Poalka J R, Neuhof C, et al. Different sensitivity of rabbit heart and skeletal muscle to endotoxininduced impairment of mitochondrial function. Eur J Biochem 2001; 268: 1422- 1429.
25. Schenkman KA, Arakaki LS, Ciesielski WA, et al. Optical spectroscopy demonstrates elevated intracellular oxygenation in an endotoxic model of sepsis in the perfused heart. Shock 2007; 27 (6): 695-700.
26. Supinski G S, Callahan L A. Alterations in the mitochondrial electron transport chain in endotoxin-mediated sepsis. FASEB J 2001; 15: Al080.
27. Ronco C, Bellomo R, Homel P, et al. Effect of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomized trail. Lancet 2000; 356 (9223): 26-30.
28. Joannes-Boyau O, Rapaport S, Bazin R, et al. Impact of high volume hemofiltration on heodynamic disturbances and outcome during septic shock. ASAIO J 2004; 50: 102-109.
29. Bellomo R, Baldwin I, Ronco C. High volume hemofiltration. Contrib Nephrol 2001; 13: 375-382.
30. Honore P M, Jamez J, Wauthier M. Very high volume hemofiltration: A comprehensive review. International SYMPOSIUM ON critical Care Nephrology (ISCCN). Melbourne, 2001; Nov. 1-3.
31. Honore P M, Zydney A L, Matson J R. High volume and high permeability haemofiltration for sepsis: The evidence and the key issues. Care of the Critically III, 2003; 19: 1-7.
32. Acute Dialysis Quality intiative. [http://www.adqi.net]
33. Sun Q, Tu Z, Lobo S, et al. Optimal adrenergic support in septic shock due to peritonitis. Anesthesiology 2003; 98: 888-896.
34. Rokyta R Jr, Matejovic M, Krouzecky A, et al. Effects of continuous venovenous hemofiltration-induced cooling on global hemodynamics, splanchnic oxygen and energy balance in critically ill patients. Nephrol Dial Transplant 2004; 19: 623-630.
35. Silvester W. Mediator removal with CRRT: Complement and cytokines. Am J KidneyDis 1997;30:S38-43.
36. van Bommel EF. Should continuous renal replacement therapy be used for non-renal indications in critically ill patients with shock? Resuscitation 1997; 33: 257-270.
37. Grau G E, Maennel D N. TNF inhibition and sepsis: Sounding a cautionary note. NatMed 1997; 3: 1193-1195.
38. Watt J A, Kline J A, Thornton L R, et al. Metabolic dysfunction and depletion of mitochondria in hearts of septic rats. J Mol Cell Cardiol 2004; 36: 141-150.
39. Frost M T, Wang Q, Moncada S, et al. Hypoxia accelerates nitric oxide-dependent inhibition of mitochondrial complex I in activated macrophages. Am J Physiol Regul Integr Comp Physiol 2005; 288: R394-R400.
40. Brown GC, Borutaite. Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res 2007; 75 (2): 283-290.
41. Boekstegers P, Orsi A, Clementi E, et al. Oxidative stress and S-nitrosylation of proteins in cells. Br J Pharmacol 2000; 129: 953-960.
42. Riobo N A, Clementi E, Melani M, et al. Nitric oxide inhibits mitochondrial NADH: ubiquinone reductase activity through peroxynitrite formation. Biochem J 2001; 359: 139-145.
43. Brown G C, Cooper C E. Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 1994; 356: 295-298.
44. Gerald S S, Leigh A C. Hemin prevents cardiac and diaphragm mitochondrial dysfunction in sepsis. Free Radi Biol Med 2006; 40: 127-137.
45. Rogiers P, Zhang H, Smail N, et al. Continuous venovenous haemofiltration improves cardiac performance by mechanisms other than tumor necrosis factor-alpha attenuation during endotoxic shock. Crit Care Med 1999; 27 (9): 1848-1855.
46. Gomez A, Wang R, Unruh H, et al. Hemofiltration reverses left ventricular dysfunction during sepsis in dogs. Anesthesiology 1990; 73 (4): 671-685.
47. Nethery D, Callahan L, Stofan D, et al. PLA (2) dependence of diaphragm mitochondrial formation of reactive oxygen species. J Appl Physiol 2000; 89: 72-80.
48. Cooper C E, Davies N A, Psychoulis M, et al. Nitric oxide and peroxynitrite cause irreversible increases in the Km for oxygen of mitochondrial cytochrome oxidase: in vitro and in vivo studies. Biochim Biophys Acta 2003; 1607 (1): 27-34.
49. Khadour F H, Panas D, Ferdinandy P, et al. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol 2002; 283: H1108-H1115.
50. Rogiers P, Sun Q, Dimopoulos G, et al. Blood warming during haemofiltration can improve hemodynamics and outcome in ovine septic shock. Anesthesiology 2006; 104: 1216-1222.
51. Pereira Arias A M, Wester J P, Blankendaal M, et al. Multiple organ dysfunction syndrome induced by whole-body hyperthermia and polychemotherapy in a patient with disseminated leiomyosarcoma of the uterus. Intensive Care Med 1999; 25:1013-1016.
52. Bouchama A, Knochel J P. Heat stroke. N Engl J Med 2002; 346: 1978-1988
53. Hoffmann J N, Werdan K, Hartl W H, et al. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock 1999; 12 (3): 174-180.
1. Annane D, Bellissant, Cavaillon J M. Septic shock. Lancet 2005; 365(9453): 63-78.
2. Garcia-Fernandez N, Lavilla F J, Rocha E, et al. Haemostatic changes in systemic inflammatory response syndrome during continuous renal rep;acement therapy. J Nephrol 2000; 13: 282-289.
3. Yekebas E F, Strate T, Zolmajd S, et al. Impact of different modalities of continuous venovenous hemofiltration on sepsis-induced alterations in experimental pancreatitis. Kidney Int 2002; 62: 1806-1818.
4. Horner C, Schuster S, Plachky J, et al. Hemofiltration and immune response in severe sepsis. J Surg Res 2007; 142: 59-65.
5. Morgera S, Klonower D, Rocktaschel J, et al. TNF-alpha elimination with high cut-off haemofilters:a feasible clinical modality for septic patients?Nephrol Dial Transplant 2003; 18: 1361-1369.
6. Morgera S, Slowinski T, Melzer C, et al. Impact of convection and diffusion on cytokine clearances and protein status. Am J Kidney Dis 2004; 43:444-53.
7. Honore P M, Joannes-Boyau O, Gressens B. Blood and plasma treatments: high-volume hemofiltration-a global view. Contrib Nephrol 2007; 156: 371-386.
8. Toft P, Nilsen B U, Bollen P, et al. The impact of long-term haemofiltration (continuous veno-venous haemofiltration) on cell-mediated immunity during endotoxaemia. Acta Anaesthesiol Scand 2007; 51 (6): 679-686.
9. Joannes-Boyau O, Rapaport S, Bazin R, et al. Impact of high volume hemofiltration on hemodynamic disturbance and outcome during septic shock.ASAIO J 2004; 50: 102-109.
10. Cornejo R, Downey P, Castro R, et al. High-volume hemofiltration as salvage therapy in severe hyperdynamic septic shock. Intensive Care Med 2006; 32 (5): 713-722.
11. Honore P M, Jamez J, Wauthier M, et al. Very high volume hemofiltration: A comprehensive review.International SYMPOSIUM ON critical Care Nephrology(ISCCN). Melbourne 2001; Nov.1-3.
12. Ronco C, Bellomo R, Homel P, et al. Effect of different doses in continuous veno-venous haemofiltration in outcomes of acute renal failure:A prospective randomized trial.Lancet 2000; 355: 26-30.
13. Honore P M, Zydney A L, Matson J R. High volume and high permeability haemofiltration for sepsis: The evidence and the key issues. Care of The Critically III 2003; 19: 1-7.
14. Lee P A, Werger G, Pryor R W, et al. Effects of filter pore size on efficacy of continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine. Crit Care Med 1998; 26: 730-737.
15. Bordoni V, Bolgan I, Brendolan A, et al. Caspase-3 and -8 activation and cytokine removal with a novel cellulose triacetate super-permeable membrane in an vitro sepsos model. Int J Artif Organ 2003; 26: 897-905.
16. Morgera S, Haase M, Rocktaschel J, et al. High permeability haemofiltration improves peripheral blood mononuclear cell proliferation in septic patients with acute renal failure. Nephrol Dial Transplant 2003; 18: 2570-2576.
17. Morgera S, Haase M, Rocktaschel J, et al. Intermittent high-permeability hemofiltration modulates inflammatory response in septic patients with multiorgan failure. Nephron Clin Pract 2003; 94: 75-80.
18. Kellum J A, Dishart M K. Effect of hemofiltration filter adsorption on circulating IL-6 levels in septic rats.Crit Care 2002; 6: 429-433.
19. Kellum J A, Song M, Venkataraman R. Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves sort-term survival in lethal endotoxemia. Crit Care Med 2004;32:801-805.
20. Nakamura T, Ushiyama C, Suzuki S, et al. Polymyxin b-immobilized fiber reduces increased plasma endothelin-1 concentrations in hemodialysis patients with sepsis. Ren Fail 2000; 22: 225-234.
21. Kushi H, Nakahara J, Miki F, et al. Hemoperfusion with an immobilized polymyxin B fiber column inhibits activation of vascular endothelial cells.Ther Apher Dial 2005; 9: 303-307.
22. Tsujimoro H, Ono S, Hiraki S, et al. Hemoperfusion with polymyxin B-immobilized fibers reduced the number of CD16+CD14+ monocytes in patients with septic shock.J Endotoxin Res 2004; 10: 229-237.
23. Opal SM. Hemofiltration-absorption systems for the treatment of experimental sepsis: is it possible to remove the 'evil humors' responsible for septic shock? Crit Care Med 2000; 28:1681-1682.
24. Natanson C, Hoffman W D, Koev LA, et al. Plasma exchange does not improve survival in a canine model of human septic shock. Transfusion 1993; 33: 243-248
25. Bnegsch S, Boos K S, Nagel D, et al. Extracorporeal plasma treatment for the removal of endotoxin in patients with sepsis: clinical results of a pilot study. Shock 2005; 23 (6): 494-500.
26. Berlot G, Gullo A, Fasiolo S, et al. Hemodynamic effects of plasma exchange in septic patients: preliminary report. Blood Purif, 1997; 15: 45-53.
27. Carcillo J A, Kellum J A. Is there a role for plasma pheresis/p;asma exchange therapy in septic shock,MODS,and thrombocytopenia-associated multiple organ failure? We still do not know-but perhaps we are closer.Intensive Care Med 2002; 28:1373-1375.
28. MacKay S M, Funke A J, Buffington D A, et al. Tissue engineering of a bioartificial renal tubule.ASAIO J 1998; 44:179-183.
29. Humes H D, Buffington D A, MacKay S M, et al. Replacement of fenal function in uremic animals with a tissue-engineered kidney. Nat Biotechnol 1999; 17:451-455.
30. Fissel W H, Lou L, Abrishami S, et al. Bioartificial kidney ameliorates Gram-negative bacteria-induced septic shock in uremic animals. J Am Soc Nephrol 2003; 14: 454-461.
31. H.David, Deborah A, Buffington, et al. Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock. Crit Care Med 2003; 31: 2421-2428.
32. Huijuan M, Xiaoyun W, Xumin Y, et al. Effect of continuous bioartificial kidney therapy on porcine multiple organ dysfunction syndrome with acute renal failure. ASAIO J 2007; 53 (3): 329-334.
33. Ricci Z, Ronco C, D'Amico G,et al. Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Dephrol Dial Transplant 2006; 21 (3): 690-696.
34. John S, Eckardt K U. Renal replacement therapy in the treatment of acute renal failure-intermittent and continuous. Semin Dial 2006; 19 (6): 455-464.
1. DeBacker D, Creteur J, Preiser J C, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002; 166: 98-104.
2. Abraham E. Neutrophils and acute lung injury. Crit Care Med 2003; 31: S195-199.
3. Scaffidi P, Misteli T, Bianchi M E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418:191-195.
4. Czura C J, Tracey K J. Targeting high mobility box 1 as a late-acting mediator of inflammation. Crit Care Med 2003; 31: S46-S50.
5. Freedman B D, Natanson C. Anti-inflammatory therapies in sepsis and septic shock. Expert Opin Invest Drugs 2000; 9: 1651-1663.
6. Schenkman KA, Arakaki LS, Ciesielski WA, et al. Optical spectroscopy demonstrates elevated intracellular oxygenation in an endotoxic model of sepsis in the perfused heart. Shock 2007; 27 (6): 695-700.
7. Singer M. Mitochondrial function in sepsis: acute phase versus multiple organ failure. Crit Care Med 2007; 35 (9Supple): 441-448
8. Belikova I, Lukaszewicz A C, Faivre V, et al. Oxygen consumption of human peripheral blood mononuclear cells in severe human sepsis. Crit Care Med 2007; 35 (12): 2702-2708.
9. Mela L, Bacalzo L V, Miller L D. Defective energy metabolism of rat liver mitochondrialin hemorrhagic and endotoxin shock. Am J Physiol 1971; 220: 571-577.
10. Tavakoli H, Mela L. Alterations of mitochondrial metabolism and protein concentrations in subacute septicemia.Infect Immun 1982; 38: 536-541.
11. Bealey D, Karyampudi S, Jacques T S,et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure.Am J Physiol Regul Integr Comp Physiol 2004; 286: R491-R497.
12. Cowley R A, Mergner W J, Fisher R S, et al. The subcellular pathology of shock in trauma patients: studies using the immediate autopsy. Am Surg 1979; 45: 255-269.
13. Brealey D, Brand M, Hargreanes I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock.Lancet 2002; 360: 219-223.
14. Vanhorebeek I, De Vos R, Mesotten D, et al. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005; 365: 53-59.
15. Larche J, Lancel S, Hassoun S M, et al. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol 2006; 48(2): 377-385.
16. Supinske G S, Callahan L A. Hemin prevents cardiac and diaphragm mitochondrial dysfunction in sepsis. Free Radic Biol Med 2006; 40:127-137.
17. Schaefer C F, Lerner M R, Biber B. Dose-related reduction of intestinal cytochrome a,a3 induced by endotoxin in rats. Cric Shock 1991; 33: 17-25.
18. Hotchkiss R S, Morikawa S, Inubushi T, et al. Gluconeogenesis and phosphoenergetics in rat liver during endotoxemia. J Surg Res 1998; 74: 179-186.
19. Siskind L J, Kolesnick R N, Colombini M. Ceramaide channels increase the permeability of outer mitochondrial membrane to small proteins. J Biol Chem 2002; 277: 26796-26803.
20. Delogu G, Famularo G, Amati F, et al. Ceramide concentrations in septic patient: a possible marker of multiple organ dysfunction syndrome.Crit Care Med 1999; 27:2413-2417.
21. Kim B C, Kim H T, Mamura M, et al. Tumor necrosis factor induces apoptosis in hepatoma cells by increasing Ca2+ realse frome the endoplasmic reticulum and suppressing Bcl-2 expression. J Biol Chem 2002; 277: 31381-31389.
22. Crouser E D, Julian M W, Huff J E, et al. Abnormal permeability of inner and outer mitochondrial membranes contribute independently to mitochondrial dysfunction in the liver during acute endotoxemia. Crit Care Med 2004: 32: 478-488.
23. Coopersmith C M, Chang K C, Swanson P E. Overexpression of Bcl-2 in the intestinal epithlium improves survival in septic mice. Crit Care Med 2002; 30: 195-201.
24. Ritter C, Andrades M E, Frota M L C, et al. Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation. Int Care Med 2003; 29: 1782-1789.
25. Ritter C, Andrades M E, Reinke A, er al. Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis.Crit Care Med 2004; 32: 342-349.
26 Brown GC, Borutaite. Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res 2007; 75 (2): 283-290.
27. Barreiro E, Comtois A S, Gea J, et al. Protein tyrosine nitration in the ventilatory muscles:role of nitric oxide synthases. Am J Respir Cell Mol 2002; 26:438-446.
28. Boekstegers P, Orsi A, Clementi E, et al. Oxidative stress and S-nitrosylation of proteins in cells. Br J Pharmacol 2000; 129: 953-960.
29. Riobo N A, Clementi E, Melani M, et al. Nitric oxide inhibits mitochondrial NADH: ubiquinone reductase activity through peroxynitrite formation. Biochem J 2001; 359:139-145.
30. Nin N, Cassina A, Boggia J, et al. Septic diaphragmatic dysfunction is prevented by Mn(III)porphyrin therapy and inducible nitric oxide synthase inhibition.Intensive Care Med 2004; 30: 2271-2278.
31. Khan A U, Delude R L, Han Y Y, et al. Liposomal NAD(+) prevents diminished O(2) consumption by immunostimulated Caco-2 cells. Am J Physiol Lung Mol Physiol 2002; 282: 1082-1091.
32. Cobb J P. Nitric oxide synthase inhibition as therapy for sepsis: a decade of promise. Surg Infect 2001; 1: 93-100.
33. Sulliman H B, Carraway M S, Piantidose C A. Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am J Respir Crit Care Med 2003; 167: 570-579.
34. Callahan L A, Supinski G S. Downregulation of diaphragm electron transport chain and glycolytic enzyme gene expression in sepsis. J Appl Physiol 2005; 99: 1120-1126.
2. Angus D C, Linde-Zwirble W T, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303-1310.
3. Annane D, Aegerter P, Jars-Guincestre MC, et al. Current epidemiology of septic shock: the UCB-Rea Network. Am J Respir Crit Care Med 2003; 1687:165-172.
4. O'Reilly M, Newcomb D E, Remick D. Endotoxin, sepsis, and the primrosepath. Shock 1999; 12: 411-420.
5. Remick D G, Newcomb D E, Bolgos G L, et al. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide versus cecal ligation and puncture. Shock 2000; 13:110-116.
6. L ekkou A, Karakantza M, Mouzak i A, et al. Cytok ine p roduction and monocyte HLA DR expression as predictors of outcome for patients with communityacquired severe infections. Clin Diagn Lab Immunol, 2004; 11: 161-167.
7. Taniguchi T, Yamamoto K, Ohmoto N, et al. Effects of propofol on hemodynamic and inflammatory responses to endotoxemia in rats. Crit Care Med 2000; 28: 1101-1106.
8. Abraham E, Anzueto A, Gutierrez G, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 1998; 351: 929-933.
9. Deitch E A. Animal models of sepsis and shock: a review and lessons learned. Shock 1998; 9: 1-11.
10. Newcomb D, Bolgos G, Green L, et al. Antibiotic treatment influences outcome in murine sepsis: mediators of increased morbidity. Shock 1998; 10: 110-117.
11. Remick D G, Newcomb D E, Bolgos G, et al. Comparison of the mortality andinflammatory response of two models of sepsis:lipopo lysaccharide vs cecal ligation and puncture.Shock 2000;13:110-116.
[12].Remick D G,Manohar P,Bolgos G,et al.Block of tumor necrosis factor reduces lipopolysaccharide lethality,but not the lethality of cecal ligation and puncture.Shock 1995;4:89-95.
[13].王恒进,王笑云,应旭,等.猪多器官功能障碍综合征合并急性肾功能衰竭模型的制作.南京医科大学学报 2003:23:196-199.
[14].Luzius B H,Vladimir K,Gisli H S.Effects of dobutamine and dopexamine on microcirculatory blood flow in the gastrointestinal tract during sepsis and anesthesia.Anesthesiology 2004;100:1188-1197.
1. Angus D C, Linde-Zwirble W T, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1303-1310.
2. Ullrich R, Roeder G, Lorber C, et al. Continuous venovenous hemofiltration improves arterial oxygenation in endotoxin-induced lung injury in pigs. Anesthesiology 2001; 95:428-436.
3. Yekebas E F, Eisenberger C F, Ohnesorge H, et al. Attenuation of sepsis-related immunoparalysis by continuous venovenous hemofiltration in experimental porcine pancreatitis. Crit Care Med 2001; 29(7): 1423-1430.
4. Chen Z H, Liu Z H, Yu C, et al. Endothelial dysfunction in patients with severe acute pancreatitis: improved by continuous blood purification therapy. Int J Artif Organs 2007; 30 (5): 393-400.
5. Brealey D, Brand M, Hargreaves I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360(9328): 219-223.
6. Suematsu N, Tsutsui H, Wen J, et al.Oxidative stress mediates tumor necrosis factor-α-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2002; 26:1418-1423.
7. Crouser E D, Julian M W, Huff J E, et al. Abnormal permeability of immer and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia. Crit Care Med 2004; 32(2): 478-488.
8. Brealey D, Karyampudi S, Jacques T S, et al. Mytochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 2004; 286: R494-R497.
9. Lopez L C, Escames G, Tapias V, et al. Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice. Int J Biochem Cell Biol 2006; 38: 267-278.
10. Vanhorebeek I, De Vos R, Mesotten D, et al. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005; 365: 53-59.
11. Larche J, Lancel S, Hassoun S M, et al. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol 2006; 48(2): 377-385.
12. Supinske G S, Callahan L A. Hemin prevents cardiac and diaphragm mitochondrial dysfunction in sepsis. Free Radic Biol Med 2006; 40:127-137.
13. Martin G S, Mannino D M, Eaton S, et al. The epidemiology of sepsis in the United State from 1979 through 2000. N Engl J Med, 2003; 348 (16): 1546-1554.
14. YaoY M, Bahrami S, Leichtfried G, et al. Pathogenesis of hemorrhage-induced bacteria/endotoxin translocation in rats. Effect of recombinant bactericidal/permeability-increasing protein. Ann Surg 1995; 221 (4): 398-405.
15. Cavaillon J M, Adib-Conquy M, Fitting C, et al. Cytokine cascade in sepsis. Scand J Infect Dis 2003; 35: 535-544.
16. Pathan N, Hemingway C A, Alizadeh A A, et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet; 2004; 363: 203-209.
17. Aaroli J, FesslerM B, Abraham E. Genetic polymorphisms and sepsis. Shock 2005;24:300-312.
18. Bernard G R, Vincent J L, Laterre P F, et al. Efficacy and safety of recombinanthuman activated protein C for severe sepsis. N Engl J Med 2001; 344 (10): 699-709.
19. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341:586-592.
20. Cate H. Pathophysiology of disseminated intravascular coagulation in sepsis. Crit Care Med. 2000; 28:S9-S11.
21. Mela L, Bacalzo L V, Miller L D. Defective energy metabolism of rat liver mitochondrialin hemorrhagic and endotoxin shock. Am J Physiol 1971; 220: 571-577.
22. Tavakoli H, Mela L. Alterations of mitochondrial metabolism and protein concentrations in subacute septicemia. Infect Immun 1982; 38: 536-541.
23. Rudiger A, Singer M. Mechanisms of sepsis-induced cardiac dysfunction. Crit Care Med 2007; 35 (6): 1599-1608.
24. Trumbeckaite S, Poalka J R, Neuhof C, et al. Different sensitivity of rabbit heart and skeletal muscle to endotoxininduced impairment of mitochondrial function. Eur J Biochem 2001; 268: 1422- 1429.
25. Schenkman KA, Arakaki LS, Ciesielski WA, et al. Optical spectroscopy demonstrates elevated intracellular oxygenation in an endotoxic model of sepsis in the perfused heart. Shock 2007; 27 (6): 695-700.
26. Supinski G S, Callahan L A. Alterations in the mitochondrial electron transport chain in endotoxin-mediated sepsis. FASEB J 2001; 15: Al080.
27. Ronco C, Bellomo R, Homel P, et al. Effect of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomized trail. Lancet 2000; 356 (9223): 26-30.
28. Joannes-Boyau O, Rapaport S, Bazin R, et al. Impact of high volume hemofiltration on heodynamic disturbances and outcome during septic shock. ASAIO J 2004; 50: 102-109.
29. Bellomo R, Baldwin I, Ronco C. High volume hemofiltration. Contrib Nephrol 2001; 13: 375-382.
30. Honore P M, Jamez J, Wauthier M. Very high volume hemofiltration: A comprehensive review. International SYMPOSIUM ON critical Care Nephrology (ISCCN). Melbourne, 2001; Nov. 1-3.
31. Honore P M, Zydney A L, Matson J R. High volume and high permeability haemofiltration for sepsis: The evidence and the key issues. Care of the Critically III, 2003; 19: 1-7.
32. Acute Dialysis Quality intiative. [http://www.adqi.net]
33. Sun Q, Tu Z, Lobo S, et al. Optimal adrenergic support in septic shock due to peritonitis. Anesthesiology 2003; 98: 888-896.
34. Rokyta R Jr, Matejovic M, Krouzecky A, et al. Effects of continuous venovenous hemofiltration-induced cooling on global hemodynamics, splanchnic oxygen and energy balance in critically ill patients. Nephrol Dial Transplant 2004; 19: 623-630.
35. Silvester W. Mediator removal with CRRT: Complement and cytokines. Am J KidneyDis 1997;30:S38-43.
36. van Bommel EF. Should continuous renal replacement therapy be used for non-renal indications in critically ill patients with shock? Resuscitation 1997; 33: 257-270.
37. Grau G E, Maennel D N. TNF inhibition and sepsis: Sounding a cautionary note. NatMed 1997; 3: 1193-1195.
38. Watt J A, Kline J A, Thornton L R, et al. Metabolic dysfunction and depletion of mitochondria in hearts of septic rats. J Mol Cell Cardiol 2004; 36: 141-150.
39. Frost M T, Wang Q, Moncada S, et al. Hypoxia accelerates nitric oxide-dependent inhibition of mitochondrial complex I in activated macrophages. Am J Physiol Regul Integr Comp Physiol 2005; 288: R394-R400.
40. Brown GC, Borutaite. Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res 2007; 75 (2): 283-290.
41. Boekstegers P, Orsi A, Clementi E, et al. Oxidative stress and S-nitrosylation of proteins in cells. Br J Pharmacol 2000; 129: 953-960.
42. Riobo N A, Clementi E, Melani M, et al. Nitric oxide inhibits mitochondrial NADH: ubiquinone reductase activity through peroxynitrite formation. Biochem J 2001; 359: 139-145.
43. Brown G C, Cooper C E. Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 1994; 356: 295-298.
44. Gerald S S, Leigh A C. Hemin prevents cardiac and diaphragm mitochondrial dysfunction in sepsis. Free Radi Biol Med 2006; 40: 127-137.
45. Rogiers P, Zhang H, Smail N, et al. Continuous venovenous haemofiltration improves cardiac performance by mechanisms other than tumor necrosis factor-alpha attenuation during endotoxic shock. Crit Care Med 1999; 27 (9): 1848-1855.
46. Gomez A, Wang R, Unruh H, et al. Hemofiltration reverses left ventricular dysfunction during sepsis in dogs. Anesthesiology 1990; 73 (4): 671-685.
47. Nethery D, Callahan L, Stofan D, et al. PLA (2) dependence of diaphragm mitochondrial formation of reactive oxygen species. J Appl Physiol 2000; 89: 72-80.
48. Cooper C E, Davies N A, Psychoulis M, et al. Nitric oxide and peroxynitrite cause irreversible increases in the Km for oxygen of mitochondrial cytochrome oxidase: in vitro and in vivo studies. Biochim Biophys Acta 2003; 1607 (1): 27-34.
49. Khadour F H, Panas D, Ferdinandy P, et al. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol 2002; 283: H1108-H1115.
50. Rogiers P, Sun Q, Dimopoulos G, et al. Blood warming during haemofiltration can improve hemodynamics and outcome in ovine septic shock. Anesthesiology 2006; 104: 1216-1222.
51. Pereira Arias A M, Wester J P, Blankendaal M, et al. Multiple organ dysfunction syndrome induced by whole-body hyperthermia and polychemotherapy in a patient with disseminated leiomyosarcoma of the uterus. Intensive Care Med 1999; 25:1013-1016.
52. Bouchama A, Knochel J P. Heat stroke. N Engl J Med 2002; 346: 1978-1988
53. Hoffmann J N, Werdan K, Hartl W H, et al. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock 1999; 12 (3): 174-180.
1. Annane D, Bellissant, Cavaillon J M. Septic shock. Lancet 2005; 365(9453): 63-78.
2. Garcia-Fernandez N, Lavilla F J, Rocha E, et al. Haemostatic changes in systemic inflammatory response syndrome during continuous renal rep;acement therapy. J Nephrol 2000; 13: 282-289.
3. Yekebas E F, Strate T, Zolmajd S, et al. Impact of different modalities of continuous venovenous hemofiltration on sepsis-induced alterations in experimental pancreatitis. Kidney Int 2002; 62: 1806-1818.
4. Horner C, Schuster S, Plachky J, et al. Hemofiltration and immune response in severe sepsis. J Surg Res 2007; 142: 59-65.
5. Morgera S, Klonower D, Rocktaschel J, et al. TNF-alpha elimination with high cut-off haemofilters:a feasible clinical modality for septic patients?Nephrol Dial Transplant 2003; 18: 1361-1369.
6. Morgera S, Slowinski T, Melzer C, et al. Impact of convection and diffusion on cytokine clearances and protein status. Am J Kidney Dis 2004; 43:444-53.
7. Honore P M, Joannes-Boyau O, Gressens B. Blood and plasma treatments: high-volume hemofiltration-a global view. Contrib Nephrol 2007; 156: 371-386.
8. Toft P, Nilsen B U, Bollen P, et al. The impact of long-term haemofiltration (continuous veno-venous haemofiltration) on cell-mediated immunity during endotoxaemia. Acta Anaesthesiol Scand 2007; 51 (6): 679-686.
9. Joannes-Boyau O, Rapaport S, Bazin R, et al. Impact of high volume hemofiltration on hemodynamic disturbance and outcome during septic shock.ASAIO J 2004; 50: 102-109.
10. Cornejo R, Downey P, Castro R, et al. High-volume hemofiltration as salvage therapy in severe hyperdynamic septic shock. Intensive Care Med 2006; 32 (5): 713-722.
11. Honore P M, Jamez J, Wauthier M, et al. Very high volume hemofiltration: A comprehensive review.International SYMPOSIUM ON critical Care Nephrology(ISCCN). Melbourne 2001; Nov.1-3.
12. Ronco C, Bellomo R, Homel P, et al. Effect of different doses in continuous veno-venous haemofiltration in outcomes of acute renal failure:A prospective randomized trial.Lancet 2000; 355: 26-30.
13. Honore P M, Zydney A L, Matson J R. High volume and high permeability haemofiltration for sepsis: The evidence and the key issues. Care of The Critically III 2003; 19: 1-7.
14. Lee P A, Werger G, Pryor R W, et al. Effects of filter pore size on efficacy of continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine. Crit Care Med 1998; 26: 730-737.
15. Bordoni V, Bolgan I, Brendolan A, et al. Caspase-3 and -8 activation and cytokine removal with a novel cellulose triacetate super-permeable membrane in an vitro sepsos model. Int J Artif Organ 2003; 26: 897-905.
16. Morgera S, Haase M, Rocktaschel J, et al. High permeability haemofiltration improves peripheral blood mononuclear cell proliferation in septic patients with acute renal failure. Nephrol Dial Transplant 2003; 18: 2570-2576.
17. Morgera S, Haase M, Rocktaschel J, et al. Intermittent high-permeability hemofiltration modulates inflammatory response in septic patients with multiorgan failure. Nephron Clin Pract 2003; 94: 75-80.
18. Kellum J A, Dishart M K. Effect of hemofiltration filter adsorption on circulating IL-6 levels in septic rats.Crit Care 2002; 6: 429-433.
19. Kellum J A, Song M, Venkataraman R. Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves sort-term survival in lethal endotoxemia. Crit Care Med 2004;32:801-805.
20. Nakamura T, Ushiyama C, Suzuki S, et al. Polymyxin b-immobilized fiber reduces increased plasma endothelin-1 concentrations in hemodialysis patients with sepsis. Ren Fail 2000; 22: 225-234.
21. Kushi H, Nakahara J, Miki F, et al. Hemoperfusion with an immobilized polymyxin B fiber column inhibits activation of vascular endothelial cells.Ther Apher Dial 2005; 9: 303-307.
22. Tsujimoro H, Ono S, Hiraki S, et al. Hemoperfusion with polymyxin B-immobilized fibers reduced the number of CD16+CD14+ monocytes in patients with septic shock.J Endotoxin Res 2004; 10: 229-237.
23. Opal SM. Hemofiltration-absorption systems for the treatment of experimental sepsis: is it possible to remove the 'evil humors' responsible for septic shock? Crit Care Med 2000; 28:1681-1682.
24. Natanson C, Hoffman W D, Koev LA, et al. Plasma exchange does not improve survival in a canine model of human septic shock. Transfusion 1993; 33: 243-248
25. Bnegsch S, Boos K S, Nagel D, et al. Extracorporeal plasma treatment for the removal of endotoxin in patients with sepsis: clinical results of a pilot study. Shock 2005; 23 (6): 494-500.
26. Berlot G, Gullo A, Fasiolo S, et al. Hemodynamic effects of plasma exchange in septic patients: preliminary report. Blood Purif, 1997; 15: 45-53.
27. Carcillo J A, Kellum J A. Is there a role for plasma pheresis/p;asma exchange therapy in septic shock,MODS,and thrombocytopenia-associated multiple organ failure? We still do not know-but perhaps we are closer.Intensive Care Med 2002; 28:1373-1375.
28. MacKay S M, Funke A J, Buffington D A, et al. Tissue engineering of a bioartificial renal tubule.ASAIO J 1998; 44:179-183.
29. Humes H D, Buffington D A, MacKay S M, et al. Replacement of fenal function in uremic animals with a tissue-engineered kidney. Nat Biotechnol 1999; 17:451-455.
30. Fissel W H, Lou L, Abrishami S, et al. Bioartificial kidney ameliorates Gram-negative bacteria-induced septic shock in uremic animals. J Am Soc Nephrol 2003; 14: 454-461.
31. H.David, Deborah A, Buffington, et al. Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock. Crit Care Med 2003; 31: 2421-2428.
32. Huijuan M, Xiaoyun W, Xumin Y, et al. Effect of continuous bioartificial kidney therapy on porcine multiple organ dysfunction syndrome with acute renal failure. ASAIO J 2007; 53 (3): 329-334.
33. Ricci Z, Ronco C, D'Amico G,et al. Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Dephrol Dial Transplant 2006; 21 (3): 690-696.
34. John S, Eckardt K U. Renal replacement therapy in the treatment of acute renal failure-intermittent and continuous. Semin Dial 2006; 19 (6): 455-464.
1. DeBacker D, Creteur J, Preiser J C, et al. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 2002; 166: 98-104.
2. Abraham E. Neutrophils and acute lung injury. Crit Care Med 2003; 31: S195-199.
3. Scaffidi P, Misteli T, Bianchi M E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418:191-195.
4. Czura C J, Tracey K J. Targeting high mobility box 1 as a late-acting mediator of inflammation. Crit Care Med 2003; 31: S46-S50.
5. Freedman B D, Natanson C. Anti-inflammatory therapies in sepsis and septic shock. Expert Opin Invest Drugs 2000; 9: 1651-1663.
6. Schenkman KA, Arakaki LS, Ciesielski WA, et al. Optical spectroscopy demonstrates elevated intracellular oxygenation in an endotoxic model of sepsis in the perfused heart. Shock 2007; 27 (6): 695-700.
7. Singer M. Mitochondrial function in sepsis: acute phase versus multiple organ failure. Crit Care Med 2007; 35 (9Supple): 441-448
8. Belikova I, Lukaszewicz A C, Faivre V, et al. Oxygen consumption of human peripheral blood mononuclear cells in severe human sepsis. Crit Care Med 2007; 35 (12): 2702-2708.
9. Mela L, Bacalzo L V, Miller L D. Defective energy metabolism of rat liver mitochondrialin hemorrhagic and endotoxin shock. Am J Physiol 1971; 220: 571-577.
10. Tavakoli H, Mela L. Alterations of mitochondrial metabolism and protein concentrations in subacute septicemia.Infect Immun 1982; 38: 536-541.
11. Bealey D, Karyampudi S, Jacques T S,et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure.Am J Physiol Regul Integr Comp Physiol 2004; 286: R491-R497.
12. Cowley R A, Mergner W J, Fisher R S, et al. The subcellular pathology of shock in trauma patients: studies using the immediate autopsy. Am Surg 1979; 45: 255-269.
13. Brealey D, Brand M, Hargreanes I, et al. Association between mitochondrial dysfunction and severity and outcome of septic shock.Lancet 2002; 360: 219-223.
14. Vanhorebeek I, De Vos R, Mesotten D, et al. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005; 365: 53-59.
15. Larche J, Lancel S, Hassoun S M, et al. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol 2006; 48(2): 377-385.
16. Supinske G S, Callahan L A. Hemin prevents cardiac and diaphragm mitochondrial dysfunction in sepsis. Free Radic Biol Med 2006; 40:127-137.
17. Schaefer C F, Lerner M R, Biber B. Dose-related reduction of intestinal cytochrome a,a3 induced by endotoxin in rats. Cric Shock 1991; 33: 17-25.
18. Hotchkiss R S, Morikawa S, Inubushi T, et al. Gluconeogenesis and phosphoenergetics in rat liver during endotoxemia. J Surg Res 1998; 74: 179-186.
19. Siskind L J, Kolesnick R N, Colombini M. Ceramaide channels increase the permeability of outer mitochondrial membrane to small proteins. J Biol Chem 2002; 277: 26796-26803.
20. Delogu G, Famularo G, Amati F, et al. Ceramide concentrations in septic patient: a possible marker of multiple organ dysfunction syndrome.Crit Care Med 1999; 27:2413-2417.
21. Kim B C, Kim H T, Mamura M, et al. Tumor necrosis factor induces apoptosis in hepatoma cells by increasing Ca2+ realse frome the endoplasmic reticulum and suppressing Bcl-2 expression. J Biol Chem 2002; 277: 31381-31389.
22. Crouser E D, Julian M W, Huff J E, et al. Abnormal permeability of inner and outer mitochondrial membranes contribute independently to mitochondrial dysfunction in the liver during acute endotoxemia. Crit Care Med 2004: 32: 478-488.
23. Coopersmith C M, Chang K C, Swanson P E. Overexpression of Bcl-2 in the intestinal epithlium improves survival in septic mice. Crit Care Med 2002; 30: 195-201.
24. Ritter C, Andrades M E, Frota M L C, et al. Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation. Int Care Med 2003; 29: 1782-1789.
25. Ritter C, Andrades M E, Reinke A, er al. Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis.Crit Care Med 2004; 32: 342-349.
26 Brown GC, Borutaite. Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res 2007; 75 (2): 283-290.
27. Barreiro E, Comtois A S, Gea J, et al. Protein tyrosine nitration in the ventilatory muscles:role of nitric oxide synthases. Am J Respir Cell Mol 2002; 26:438-446.
28. Boekstegers P, Orsi A, Clementi E, et al. Oxidative stress and S-nitrosylation of proteins in cells. Br J Pharmacol 2000; 129: 953-960.
29. Riobo N A, Clementi E, Melani M, et al. Nitric oxide inhibits mitochondrial NADH: ubiquinone reductase activity through peroxynitrite formation. Biochem J 2001; 359:139-145.
30. Nin N, Cassina A, Boggia J, et al. Septic diaphragmatic dysfunction is prevented by Mn(III)porphyrin therapy and inducible nitric oxide synthase inhibition.Intensive Care Med 2004; 30: 2271-2278.
31. Khan A U, Delude R L, Han Y Y, et al. Liposomal NAD(+) prevents diminished O(2) consumption by immunostimulated Caco-2 cells. Am J Physiol Lung Mol Physiol 2002; 282: 1082-1091.
32. Cobb J P. Nitric oxide synthase inhibition as therapy for sepsis: a decade of promise. Surg Infect 2001; 1: 93-100.
33. Sulliman H B, Carraway M S, Piantidose C A. Postlipopolysaccharide oxidative damage of mitochondrial DNA. Am J Respir Crit Care Med 2003; 167: 570-579.
34. Callahan L A, Supinski G S. Downregulation of diaphragm electron transport chain and glycolytic enzyme gene expression in sepsis. J Appl Physiol 2005; 99: 1120-1126.