Liver support in fulminant liver failure after hemorrhagic shock

Acute liver failure (ALF) is a rare clinical syndrome associated with a mortality of up to 80% and its management remains an interdisciplinary challenge. Despite recent improvements in intensive care management, the mortality of patients with ALF remains high and is related to complications such as cerebral edema, sepsis and multiple organ failure. Emergency orthotopic liver transplantation (OLT) is currently the only effective treatment for those patients who are unlikely to recover spontaneously. Nevertheless, OLT is not always possible because of the shortage of the organs and/or complications related to ALF. Newly introduced liver-assist devices can temporarily support the patient's liver until native liver recovers or can serve as a bridging device until a liver graft is available. The support devices use both cell-based and non-cell-based techniques. One of the latest non-cell-based extracorporeal hepatic support devices, the molecular adsorbent recycling system (MARS), is based on the concept of albumin dialysis. MARS utilises selective hemodiafiltration with countercurrent albumin dialysis aiming to selectively remove both water-soluble and albumin-bound toxins of the low and middle molecular-weight range. We report on a young patient who presented with clinical symptoms of ischemic hepatitis and multi-organ failure (APACHE II score 38-->predicted postoperative mortality 87%) due to prolonged hemorrhagic shock. OLT was contraindicated because of history of pancreas cancer with metastases. It was necessary to use aggressive conservative therapy and an extracorporeal liver-assist device until liver regeneration began and hemodynamic conditions were stable. The patient underwent five treatments with MARS. During the treatment, there were improvements of hemodynamics, respiratory function, acid-base disturbances and laboratory parameters. The plasma disappearance rate of indocyanine green, a parameter of dynamic liver function, improved during MARS treatment. Although repeated neurological examination predicted diffuse brain damage (brain oedema, decreased cerebral blood flow), the patient recovered without any neurological deficits. The patient survived and was discharged from the hospital in good condition. In this case MARS treatment was successful in supporting the patient through the most critical period of ALF.     

热休克蛋白70对严重创伤休克后肝脏的作用

目的 探讨热休克蛋白70（HSP70）对严重创伤休克后肝脏作用.方法 成年Wistar大鼠,采用双侧股骨骨折伴失血性休克致严重创伤模型,动态观察伤后8 h大鼠肝组织HSP70、血清肝功能生化指标、肝脏病理等变化.HSP70表达测定采用免疫印迹法,并进行计算机图像分析.结果 伤后HSP70在肝组织中表达迅速增加,6 h达到峰值,伤后8 h仍维持较高水平;创伤合并休克后,HSP70表达高峰提前至伤后4 h,持续表达至伤后6 h后逐渐下降,死亡前在肝组织中仍有少量表达.创伤休克后血清ALT、TB伤后4 h开始明显增高（P＜0.01）,白蛋白下降（P＜0.01）.肝脏镜下创伤休克后6 h肝窦内出现较多炎性细胞浸润.结论 在创伤休克早期,HSP70可能参与了肝组织细胞抗损伤机制的启动,但随着休克时间的延长,HSP70的过高持续表达,则可能对肝脏造成损害.HSP70在创伤休克后肝保护与肝损害过程中可能发挥双重作用.     

Kinetics of P-selectin expression in regional vascular beds after resuscitation of hemorrhagic shock: a clue to the mechanism of multiple system organ failure

Leukocyte-endothelial cell interactions play an important role in mediating organ dysfunctions observed after hemorrhagic shock. P-selectin is the first endothelial cell adhesion molecule to be upregulated after an ischemic insult. The objective of this study was to define kinetics of P-selectin expression in different regional vascular beds of mice exposed to hemorrhagic shock. In-vivo P-selectin expressions were determined using dual radiolabeled monoclonal antibody technique in lungs, heart, liver, kidneys, intestinal mesentery, stomach, small bowel, and colon 0.5, 1, 2, 5, 10, and 24 h after resuscitation of 40 mmHg hemorrhagic shock. In another group, P-selectin expression was determined in same organs 5 h after resuscitation of 30 mmHg hemorrhagic shock. Hemorrhagic shock of 40 mmHg caused significant upregulation of P-selectin in lungs and liver at 30 min after resuscitation (P < 0.001). There was a second and more pronounced upregulation of P-selectin in lungs and liver at 5 h after resuscitation (P < 0.001). In heart, intestinal mesentery, stomach, small bowel, and colon, P-selectin was not upregulated until 5 h after resuscitation from 40 mmHg hemorrhagic shock (P < 0.001). While hemorrhagic shock of 40 mmHg did not cause P-selectin upregulation in kidneys, hemorrhage to 30 mmHg did elicit a significant increase at 5 h after resuscitation (P < 0.001). We conclude that P-selectin is upregulated after resuscitation of hemorrhagic shock in lungs, liver, heart, stomach, and intestines. P-selectin upregulation in kidneys only takes place after more severe hemorrhagic shock.     

甲泼尼龙对失血性休克后肠屏障功能的影响

目的探讨应用甲泼尼龙对失血性休克后肠黏膜屏障功能的影响。方法新西兰大白兔30只,随机分为失血性休克组、甲泼尼龙组、对照组。失血性休克采用股动脉放血制做模型,休克持续2h后回输失血及等量林格氏液复苏;甲泼尼龙组在复苏时静注甲泼尼龙50mg/kg一次;对照组不行放血处理。复苏后2h,留取血浆检测D-乳酸水平;取小肠组织行常规病理学检查,并制备肠组织匀浆测定其肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)和丙二醛(malondialdehyde,MDA)水平。结果失血性休克组肠黏膜结构破坏,血浆D-乳酸显著升高,肠组织匀浆中TNF-α和MDA水平增加。甲泼尼龙组上述指标均低于失血性休克组,差异具有统计学意义(P<0.05)。结论早期大剂量使用甲泼尼龙对失血性休克后的肠屏障功能有保护作用。     

Septic shock and multiple organ failure

OBJECTIVE: To assess the frequency and mortality rates of septic shock in ICU patients and the clinical course of multiple organ failure associated with septic shock. DESIGN: Retrospective case survey. SETTING: Tertiary care center. PATIENTS: During a 2-yr period, 2,469 consecutive intensive care patients were studied regarding the frequency and hospital mortality rates of septic shock. A subset of 1,311 patients was further analyzed for the occurrence of organ system failures within 48 hrs of the onset of septic shock and again 4 to 7 days later. MEASUREMENTS AND MAIN RESULTS: The frequency rate of septic shock was 1.9% (n = 48), with a mortality rate of 72.9% (n = 35) in patients with septic shock. Deaths due to septic shock represented 14.6% of all deaths in the ICU during the study period. Eighteen patients died within 72 hrs of the onset of septic shock. Refractory hypotension was the cause of death in 15 of these 18 patients. Beyond 72 hrs, multiple organ failure accounted for eight of 17 deaths. The mean +/- SD number of organ systems failing at 48 hrs was 3.3 +/- 1.3 in survivors and 4.0 +/- 1.1 in nonsurvivors, and at 4 to 7 days was 2.1 +/- 1.5 in survivors and 4.0 +/- 1.5 in nonsurvivors (p less than .05). None of the specific organ system failures had prognostic value. The number of organ system failures was not related to the duration of hypotension, but had a weak correlation (r2 = .26, p less than .05) with the duration of vasoactive treatment at 4 to 7 days. The prolonged need for norepinephrine therapy was associated with an increased occurrence of renal failure. Thirty (62.5%) patients had positive blood cultures and a mortality rate similar to the mortality rate of patients with negative blood cultures. Patients with negative blood cultures died more often with hypotension (p less than .02). CONCLUSIONS: Septic shock is a major cause of death in intensive care patients. Refractory hypotension is a main cause of early deaths. Later on, multiple organ failure becomes the primary clinical problem and cause of mortality.     

Hematopoietic failure after hemorrhagic shock is mediated partially through mesenteric lymph

OBJECTIVE: To determine whether hemorrhagic shock-induced bone marrow failure is mediated by the gut through the production of toxic mesenteric lymph and whether shock-induced bone marrow failure could be prevented by division of the mesenteric lymphatics. DESIGN: Prospective, controlled study. SETTING: University surgical research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats were divided into five groups: unmanipulated controls (n = 12), hemorrhagic shock with laparotomy (n = 8), hemorrhagic shock with mesenteric lymph duct ligation (n = 10), sham shock with laparotomy (n = 6), and sham shock with mesenteric lymph duct ligation (n = 7). At either 3 or 6 hrs after resuscitation, bone marrow was obtained for determination of early (cobblestone forming cells) and late (granulocyte-macrophage colony forming unit and erythroid burst forming unit) hematopoietic progenitor cell growth. Parallel cultures were plated with plasma (1% and 2% v/v) from all groups to determine the effect of lymphatic ligation on hematopoiesis. MEASUREMENTS AND MAIN RESULTS: Bone marrow cellularity, cobblestone forming cells, granulocyte-macrophage colony forming unit, and erythroid burst forming unit growth in rats subjected to hemorrhagic with lymph duct ligation were similar to those observed in sham-treated animals and significantly greater than in rats subjected to shock and laparotomy without lymphatic duct ligation. Plasma from rats subjected to shock without lymph ligation was inhibitory to hematopoietic progenitor cell growth. In contrast, this shock-induced inhibition was not observed with plasma obtained from shocked rats that underwent mesenteric lymph ligation. CONCLUSIONS: Hemorrhagic shock suppresses bone marrow hematopoiesis as measured by a decrease in early and late progenitor cell growth. This suppression appears mediated through mesenteric lymph as the effect is abrogated by mesenteric lymph duct ligation. These data clearly demonstrate a link between the gut and bone marrow failure after hemorrhagic shock     

失血致低血容量性休克大鼠心脏G蛋白表达及纳络酮的影响

目的：探讨纳络酮对失血致低血容量性休克大鼠的治疗作用及其对休克大鼠心脏组织Ｇ蛋白含量的影响。方法：颈总动脉放血,使平均动脉压降至６ｋＰａ（１ｋＰａ＝７．５ｍｍＨｇ）稳定１小时完成失血致低血容量性休克大鼠模型。２１只大鼠随机均分为：休克组（ＨＳ组）、纳络酮治疗组（ＮＡＬ组）和正常对照组（ＮＳ组）。在观察动脉血压、血气等指标的同时,采用Ｗｅｓｔｅｒｎ ｂｌｏｔ技术测定大鼠伤后６小时心脏组织中Ｇｓａ、Ｇ     

Pediatric septic shock and multiple organ failure

In the last 5 years, the understanding of the epidemiology and pathogenesis of pediatric sepsis, septic shock, and multiple organ failure has expanded greatly. There has also been a substantial increase in the number of successful randomized trials in which success has been measured as reduction in mortality in adults, children, and newborns. This article discusses these advances, updating the 1997 article on septic shock written by the author and by Dr. Robert E. Cunnion and following the format of the 1997 article.     

低体温对创伤失血性休克病人的影响

[目的]通过病例回顾性分析,研究低体温对创伤失血性休克病人的影响及护理。[方法]选择2003年5月—2013年1月我院救治的创伤失血性休克诊断病人100例,根据创伤后体温记录是否出现低温分为低温组33例和无低温组67例。分析两组创伤严重度评分(ISS)、乳酸、pH、凝血酶原时间、失血量、补液量及24h尿量、体温、血压监测及保暖措施等状况。[结果]两组ISS评分、院内出血量、6h输血量、24h补液量、24h尿量和死亡率比较差异有统计学意义(P0.05);对创伤病人体温监测频次明显低于血压的监测频次;保暖措施中95%病历记录采用了棉被保暖,其中15%合并采用了保温毯保温。[结论]临床护理工作中对创伤失血性休克病人的体温观察缺乏规范,易出现护士对创伤失血性休克病人低体温认识不足、监测力度不够、未能及时发现处理的情况,而且保暖方式单一,保温效果不理想。加强对护理工作流程的规范对于创伤失血性休克病人低温的预防、护理具有重要意义。     

地塞米松对创伤休克大鼠肝脏热休克蛋白70表达的影响

目的 探讨地塞米松对创伤休克肝组织中热休克蛋白70(HSP70)的表达变化以及对肝脏结构和功能的影响.方法 雄性健康Wistar大鼠72只,采用双侧股骨骨折伴失血性休克创伤模型,随机分成止常对照组12只,创伤休克组30只,创伤休克地塞米松组30只,地塞米松采用腹腔注射给药.动态观察伤后0.5、2、4、6、8 h大鼠肝组织HSP70、肝脏病理、肝功能、TNF-α、IL-6等变化.HSP70采用免疫印迹法测定其蛋白含量,并进行计算机图像分析.结果 HSP70伤后2h较正常对照相比差异有统计学意义,伤后6 h达到高峰,伤后8 h仍持续在较高水平.TNF-α、IL-6伤后逐渐升高,并于伤后6 h达到高峰,和正常组相比,差异有统计学意义.光镜下伤后4 h肝窦内淤血明显,有大量炎性细胞浸润;血清ALT、TB伤后4 h开始增高,8 h达到峰值.腹腔注射地塞米松后,HSP70在伤后各个时相点的表达均较创伤休克组明显增强,峰值仍然在伤后6 h.TNF-α、IL-6伤后各个时相点均迅速回落.肝脏大体淤血、肿胀明显减轻;光镜下伤后4 h肝细胞变性明显好转,肝窦内见淤血减轻,仅见少许淋巴细胞及中性粒细胞浸润;血清ALT、TB明显下降.结论 地塞米松可增强HSP70在创伤失血性休克后肝组织中的表达,可减轻创伤失血性休克后肝脏的继发性损害,表明地塞米松对创伤休克后肝脏的保护作用与HSP70密切相关.     

三种胶体对失血性休克组织代谢的影响

目的　探讨 3种不同液体对失血性休克大鼠组织氧代谢的影响。方法　将 2 1只Wistar大鼠均在麻醉下经股动脉放血 ,使平均动脉压维持在 4 0mmHg ,并根据输入的胶体不同随机分为 3组 ,每组 7只。A组 :6 %贺斯 (5 0mL·kg-1 ·h-1 ) ;B组 :5 %白蛋白 (5 0mL·kg-1 ·h-1 ) ;C组 :血定安 (5 0mL·kg-1 ·h-1 )。各组输液时间均为 6 0min。观察平均动脉压、动脉血气分析值以及动脉乳酸盐的浓度变化。结果　A组的动脉血氧分压 (PaO2 )在实验过程中未见明显变化 ,维持在 4 0 0mmHg左右 ,而其它 2组逐渐下降 ,在分组后 6 0、1 2 0、1 5 0min与A组比较明显降低 (P <0 .0 5 )。pH、PaCO2 、平均动脉压以及动脉乳酸盐浓度也呈现出A组改善明显好于其它 2组。结论　羟乙基淀粉可明显改善并维持失血性休克所致的低血压、肺通气及组织代谢     

Role of p38 mitogen-activated protein kinase on renal dysfunction after hemorrhagic shock in rats

Hemorrhagic shock has been reported to induce renal dysfunction as a consequence of different kinds of local inflammatory response. p38 mitogen-activated protein kinase (MAPK) is a key mediator in organ dysfunction relating to the inflammatory states, and acts as an important mediator in the intracellular signal pathway for proliferation, differentiation, and production of proinflammatory cytokines such as TNF-alpha and IL-1beta. The effect of p38 MAPK on the hemorrhagic damage has not been clearly estimated as yet. In this study, our aim was to evaluate the role of p38 MAPK on the renal damage during the first 5 h after a hemorrhage using a specific inhibitor of p38 MAPK activation, FR167653. p38 MAPK activation increased immediately after a hemorrhage and decreased with time. renal mRNA expression of TNF-alpha and IL-1beta increased, renal dysfunction continued to progress, and histological inflammatory injuries were confirmed after hemorrhagic shock. With the pretreatment of FR167653, all of these hemorrhagic changes were attenuated, although the induction of the primary hypotensive state was confirmed. This study demonstrated that renal p38 MAPK is activated in hemorrhagic shock, promotes the expression of proinflammatory cytokines in the kidney, and consequently develops renal dysfunction. We concluded that p38 MAPK activation is essential in causing renal damage and that the inhibition of p38 MAPK activation blocks the development of the renal dysfunction after hemorrhagic shock.     

N-乙酰半胱氨酸对休克鼠肠屏障的保护作用

目的通过大鼠失血性休克模型,研究探讨抗氧化剂N-乙酰半胱氨酸(NAC)是否具有减轻肠缺血-再灌注损伤(IRS)及保护肠屏障的作用。方法SD大鼠56只,分正常组、NAC干预组(休克 NAC)和对照组(休克 生理盐水),后两组又分为休克复苏后1h、3h和6h小组,每小组大鼠8只;动物实验前30min尾静脉注入NAC250mg/kg或5%葡萄糖;颈动脉和颈静脉插管,通过放血使大鼠的平均动脉压降至40mmHg,持续60min后回输血和生理盐水使动物复苏,血压平稳后分别以各时点取血和回肠标本进行组织学、肠黏膜损伤度检查和D-乳酸(D-LAC)、二胺氧化酶(DAO)活性及肠源性内毒素(LPS)测定。结果(1)对照组:大鼠失血性休克后,肠黏膜明显受损,组织学检查主要为黏膜的水肿、灶性坏死、绒毛脱落及炎性细胞浸润,复苏后1h、3h、6h肠黏膜损伤指数分别达3.0、2.4、1.6;外周血及肠DAO活性、门静脉LPS明显升高(与正常组相比,1h、3h和6h组P均<0.05);D-LAC于复苏后1h后显著升高(与对照组相比,P<0.05)。(2)NAC干预组:肠黏膜的损伤程度较对照组明显减轻,肠黏膜损伤指数分别为2.2、1.6、1.2;DAO活性、门静脉LPS及D-LAC均明显低于NAC非干预组(P<0.05),但部分仍高于正常组。结论NAC可减轻鼠肠IRS,并可抑制由于肠黏膜损伤后的肠渗透性增加。     

Role of p38 mitogen-activated protein kinase on cardiac dysfunction after hemorrhagic shock in rats

Cardiac dysfunction is a well-known complication of hemorrhagic shock as a consequence of local inflammatory response. Several studies have indicated that p38 mitogen-activated protein kinase (MAPK) is a key mediator in organ dysfunction that is associated with the inflammatory state through the activation of proinflammatory cytokines such as TNF-alpha and IL-1beta. Whether the same applies to cardiac dysfunction after hemorrhagic shock has not been clearly determined. Therefore, in this study, the role of p38 MAPK on cardiac dysfunction after hemorrhagic shock was studied up to 5 h after a hemorrhage using FR167653, a specific inhibitor of p38 MAPK phosphorylation. The p38 MAPK phosphorylation, the cardiac mRNA expressions of TNF-alpha and IL-1beta, and intracardiac serum concentrations of each cytokine and creatine phosphokinase-MB isozyme increased after a hemorrhage. Activated neutrophil accumulation in the heart, histological inflammation-related injuries, and frequent ventricular arrhythmia were observed in the late phase after hemorrhagic shock. FR167653 inhibited these hemorrhagic changes except the induction of the primary hypotensive state. These results demonstrate that p38 MAPK phosphorylation in hemorrhagic shock plays an important role in the cardiac expression of the proinflammatory cytokines and in the development of cardiac dysfunction relative to the inflammatory responses.     

Effect of naloxone on immune responses after hemorrhagic shock

OBJECTIVE: To determine whether naloxone administration after hemorrhagic shock has any beneficial or deleterious effect on immune responses. BACKGROUND DATA: Hemorrhagic shock is known to produce immunodepression in both humans and experimental animals. Although studies suggest that endogenous opioids play a role in immune regulation in adverse circulatory conditions, it remains controversial whether these opioids exert beneficial or detrimental effects on immunity after shock. Moreover, little information is available concerning the effects of opioid receptor blockade using naloxone on cell-mediated immunity and endocrine responses after shock. METHODS: Male C3H/HeN mice (25 g) were bled to and maintained at a mean arterial blood pressure of 35+/-5 mm Hg for 1 hr. The shed blood was then returned along with lactated Ringer's solution (two times the shed blood volume) to provide fluid resuscitation. The animals were randomized to receive either naloxone (1 mg/kg i.v.) or an equal volume of vehicle (saline) after the shed blood was returned, i.e., immediately before crystalloid resuscitation, and were killed at 2 hrs after resuscitation to obtain splenocytes, macrophages (peritoneal and splenic), and blood. MEASUREMENTS AND MAIN RESULTS: Bioassays revealed significantly decreased release of all studied interleukins (interleukins-1, -2, -3, and -6) by peritoneal and splenic macrophages as well as significantly decreased splenocyte proliferative capacity after shock in vehicle-treated mice. Naloxone administration after hemorrhage resulted in either similar or even more decreased levels of interleukin release compared with vehicle-treated hemorrhaged mice. Significantly increased plasma corticosterone concentrations were observed in vehicle-treated animals compared with control animals. Naloxone administration did not have any significant effects on corticosterone plasma concentrations after hemorrhage. CONCLUSIONS: These findings indicate the importance of the endogenous opioid system for the maintenance of immunity in adverse circulatory conditions, i.e., hemorrhage. Although additional studies involving different doses and/or times of naloxone administration may provide different results, the present findings raise the concern that naloxone administration in the traumatized host may have deleterious effects because it decreases peritoneal macrophage and splenic immune functions.     

Pulmonary pressure-flow relation after trauma and hemorrhagic shock

The significance of pulmonary pressure-flow relation and its correlation to alveolar dead space and histological lesions of the lung were evaluated in ten mongrel dogs, which were subjected to standardized bone trauma and hemorrhagic hypotension at 40 mm Hg for 3h. These results were compared with those of 5 control dogs without trauma and shock. Two different pressure-flow curves were obtained by consecutive measurements of cardiac output and mean pulmonary artery pressure during stepwise arterial hemorrhage and reinfusion. In each experiment, the difference between the two curves at CO of 100 ml/kg min was obtained and represents an increase in pulmonary artery pressure (delta MPP). This increase in pulmonary artery pressure is flow-independent and, therefore, can be used as a quantitative indicator of pulmonary vasoconstriction or vascular obstruction. Severity of shock (uptake) as well as grade of early histological lesions of the lung (microthrombi, edema, hemorrhage) and increased alveolar dead space after reinfusion were associated with a more pronounced shift of the pulmonary pressure-flow curve. In severe experimental shock, therefore, a consistent pattern of pulmonary hemodynamics, lung histology, and respiratory function was demonstrated by the pulmonary pressure-flow relation. This approach permits estimation of the effects of therapeutic interventions and may be suitable for assessing postshock pulmonary impairment.     

Attenuation of leukocyte adhesion by recombinant TNF-binding protein after hemorrhagic shock in the rat

Ischemia/reperfusion injury involves a large number of humoral and cellular mediators that activate leukocytes that subsequently migrate to local tissues. Tumor necrosis factor (TNF)-alpha may be one of the most important mediators of this post-shock inflammatory response. In this study, we investigated the influence of a recombinant Type I (55 kDa) TNF-binding protein (TNF-BP) on leukocyte-endothelial interactions in the liver after hemorrhagic shock. Hemorrhagic shock was induced in female Sprague-Dawley rats (40 mmHg for 90 min) and a standardized resuscitation regimen was applied. At the time of resuscitation, animals were treated intravenously with either TNF-BP 4 mg/kg or placebo. The liver microcirculation was investigated using intravital fluorescence microscopy and immunohistochemistry at 5 h and 48 h after reperfusion. At 5 h, treatment with TNF-BP significantly reduced temporary leukocyte adhesion in the liver sinusoids as well as mean adhesion time of leukocytes in the hepatic central vein. In contrast, after 48 h, permanent leukocyte adhesion in the central hepatic vein was significantly reduced in the group receiving TNF-BP, whereas temporary leukocyte adhesion and mean adhesion time did not differ between the two groups. Both types of leukocyte adhesion, rolling adhesion after 5 h and firm adhesion after 48 h, were reduced in the group treated with TNF-BP, thereby suggesting a long-lasting anti-inflammatory effect.