Endotoxemia in human obstructive jaundice. Effect of polymyxin B

A clinical trial was undertaken to study endotoxemia in 14 patients with obstructive jaundice given the antiendotoxin polymyxin B, 13 patients with obstructive jaundice who were not given the antiendotoxin , and 13 nonjaundiced control patients undergoing comparable surgery. Endotoxins were detected by the limulus assay. Endotoxemia did not occur in the nonjaundiced patients but was common before (68 percent), during (70 percent), and after (81 percent) surgery in the jaundice patients. Thirty-six percent of the jaundiced patients had postoperative oliguria. Endotoxemia before surgery was associated with death after surgery, all deaths occurring in patients who were endotoxemic before operation (p less than 0.05). Polymyxin B infusion had no effect on endotoxemia or outcome. Measurement of indicators of fibrinolysis, soluble fibrin, and fibrin degradation products showed no prognostic significance. We conclude that preoperative endotoxemia is an important predictor of outcome in patients who undergo surgery for jaundice.     

THE IDENTIFICATION OF RISK FACTORS AND THEIR APPLICATION TO THE MANAGEMENT OF OBSTRUCTIVE JAUNDICE

In the presence of obstructive jaundice, surgical procedures are associated with high rates of mortality and morbidity. In an endeavour to identify risk factors associated with a poor outcome, a detailed prospective study of 28 jaundiced patients has been performed. Factors associated with a fatal outcome of operation were serum bilirubin level> 300 µmol/1, glomerular filtration rate <50 ml/min, the presence of an abnormal level of fibrin degradation products (FDP) in serum, and the presence of endotoxaemia. Postoperative deep venous thrombosis was associated with low serum albumin, normal liver enzymes and rapid kaolin clotting time. Postoperative haemorrhage occurred in patients with FDP or endotoxaemia. Patients with normal renal function or elevated levels of liver enzymes were protected from sepsis. Based on the identification of these risk factors and of those patients with inoperable disease, a plan for management is proposed.     

The perioperative changes in glomerular filtration and renal blood flow in patients with obstructive jaundice

Experimental alterations in renal haemodynamics have been observed in obstructive jaundice and these may be the pathophysiological mechanism of increased renal susceptibility to injury in obstructive jaundice. Dynamic 99mTc-DTPA renal scintigraphy was done before and eight weeks after elective hepatobiliary surgery in six patients with obstructive jaundice (bilirubin greater than 100 mumol/l) and in six non-jaundiced control patients to assess changes in glomerular filtration and renal blood flow. Glomerular filtration was lower preoperatively in the jaundiced patients than in the control patients. Glomerular filtration increased postoperatively in jaundiced patients, but decreased in control patients. Renal blood flow was reduced postoperatively in control patients, but not in jaundiced patients. The changes in renal blood flow were different for each group of patients. These results provide clinical evidence of altered renal haemodynamics and a reversible impairment of glomerular filtration in obstructive jaundice. The changes seen in renal blood flow may be the underlying mechanism of increased renal susceptibility to injury.     

Acute gastric ulcerations in rats with obstructive jaundice--with special reference to gastric mucosal blood flow

The mechanism of acute gastric ulcerations in rats with obstructive jaundice was investigated in terms of the changes in the gastric mucosal blood flow. Further, the effect of vagotomy with or without obstructive jaundice was examined. One hundred and eighty-eight Sprague-Dawley rats weighing about 250 g were prepared and divided into 4 groups as follows; sham operation (control group), ligation of the bile duct (jaundiced group), vagotomy with pyloroplasty (vagotomized group), ligation of the bile duct and vagotomy with pyloroplasty (jaundiced and vagotomized group). After two weeks, water immersion and restraint stress procedures were performed in these 4 groups. The gravity of the gastric ulcerations was calculated by ulcer index. The gastric mucosal blood flow was measured by hydrogen clearance technique. The following results were obtained. The control group showed increased ulcer index and decreased gastric mucosal blood flow after the stress procedures. The jaundiced group showed significantly higher ulcer index and early, significant decrease of gastric mucosal blood flow compared to the control group after the stress procedures. The vagotomized group showed significantly decreased ulcer index after stress procedures compared to the control group, however, the gastric mucosal blood flow were unchanged between both groups before and after the stress procedures. The jaundiced and vagotomized group showed significant decrease of ulcer index and improvement of decrease of gastric mucosal blood flow compared to the jaundiced group. These data suggested that the significant decrease of gastric mucosal blood flow during the stress procedures was one of exacerbating factors of the acute gastric ulcerations in rats with obstructive jaundice, and vagotomy might prevent them by maintaining the gastric mucosal blood flow in obstructive jaundice.     

Renal function and other factors in obstructive jaundice.

Renal function and other factors that possibly affect the outcome of operation were measured in 24 patients with obstructive jaundice and in 15 non-jaundiced controls. The preoperative features that were associated with a poor postoperative recovery from obstructive jaundice were a raised serum fibrinogen/fibrin degradation product concentration, infection, hypoalbuminaemia and a low glomerular filtration rate. Preoperative serum fibrinogen/fibrin degradation product concentrations were raised in 4 of the 6 jaundiced patients who died after surgery but in none of the controls, in whom there was no mortality. In the jaundiced patients there was a greater incidence of postoperative renal impairment than in the controls. All patients were given mannitol during operation. Further mannitol was required after surgery in 13 of the 24 jaundiced patients in order to maintain urine flow rate despite adequate intravenous fluids being given. In contrast, only 1 of the 15 control patients required post operative mannitol. It is emphasized that repeated doses of mannitol can lead to a profound natriuresis and adequate intravenous saline should be given.     

Prevention of postoperative renal failure in patients with obstructive jaundice--the role of bile salts

Preoperative administration of the simple bile salt sodium deoxycholate has been shown in this study to prevent postoperative endotoxaemia and renal failure in patients with obstructive jaundice. Fifty-four per cent of jaundiced patients not given the salt were found to have systemic endotoxaemia, associated with renal impairment in two-thirds of the cases. No patient given sodium deoxycholate 500 mg 8 hourly for 48 hours before operation had portal or systemic endotoxaemia, and none had evidence of renal impairment (P less than 0 X 02, X2 with Yates' correction). The incidence of endotoxaemia in untreated jaundiced patients was very significantly greater than in non-jaundiced patients undergoing elective upper abdominal surgery (P less than 0 X 005), but this difference is abolished by the prophylactic administration of the oral bile salt. The mechanism of action of bile salts in preventing endotoxin absorption from the small bowel has been investigated, and the lack of any significant alteration in the small bowel microbial flora in obstructive jaundice suggests that a direct effect on the endotoxin molecule is involved. Nearly 20 per cent of patients with obstructive jaundice still develop postoperative renal insufficiency, but preoperative prophylactic use of sodium deoxycholate should reduce this very significantly.     

氨基胍对梗阻性黄疸大鼠治疗作用的实验研究

目的 探讨诱导型一氧化氮合酶(iNOS)抑制剂氨基胍(AG)对梗阻性黄疸大鼠的治疗作用及作用机制.方法 雄性Wistar大鼠40只,随机分为正常对照组、假手术组、黄疸组、氨基胍治疗组4组,每组10只.通过测定治疗前后肝功、血胆红素、内毒素、乳酸、肝组织丙二醛水平,以及通过对肝脏、小肠的形态学分析来探讨氨基胍对梗阻性黄疽大鼠的治疗作用.结果 血浆内毒素和血清乳酸、肝组织丙二醛随着胆道梗阻时间的延长逐步升高,并伴随着肝脏小肠病理形态学的改变.氨基胍治疗组各项指标显著低于对照组,并能改善肝组织及小肠病理形态.结论 氨基胍(AG)可通过减轻脂质过氧化与内毒素血症发挥保护肝脏及小肠的作用,为治疗梗阻性黄疸患者提供了一种新的思路和方法.     

Effects of biliary drainage in obstructive jaundice on microcirculation,phagocytic activity,and ultrastructure of the liver in rats

Background/Purpose: Biliary drainage before surgery for obstructive jaundice has been thought to be indispensable, because these patients tend to develop various complications after the surgery. We developed jaundiced rat models, and studied the effects of biliary drainage on the hepatic blood flow rate, portal pressure, and phagocytic activity. Methods: We generated rats with obstructive jaundice by surgical ligation followed by cutting of the common bile duct; some jaundiced rats then underwent biliary drainage. Lipopolysaccharide (LPS) was intraperitoneally administered to some rats. Control rats underwent open abdominal surgery alone. Ultrastructural changes of the liver sinusoidal endothelial cells were examined by scanning electron microscopy. Results: The hepatic blood flow rate and phagocytic activity in the jaundiced rats and the LPS-treated jaundiced rats were lower than those in the control rats. Biliary drainage improved the hepatic blood flow rate in both the jaundiced rats and the LPS-treated jaundiced rats to the control levels. Scanning electron microscopic observation of the liver sinusoids showed that, in the jaundiced rats, the endothelial cells were hypertrophic and there was a reduced number of fenestrae. In jaundiced rats that underwent biliary drainage, the hypertrophy was reduced, and the number of fenestrae was increased in comparison with those in the jaundiced rats without the drainage. Conclusions: These findings indicate that biliary drainage was effective in jaundiced and LPS-treated jaundiced rats. Received: November 16, 2001 / Accepted: February 11, 2002     

重组人生长激素在梗阻性黄疸的临床应用

目的　观察重组人生长激素 (rhGH)应用于梗阻性黄疸术后的治疗作用。方法　将 48例患者随机分为对照组 3 0例和rhGH组 18例 ,从术后第 1天开始 ,rhGH组皮下注射rhGH ,8U/d ,连续 7d ,与此同时对照组注射相同剂量的生理盐水。两组患者都给予肠道外营养支持治疗到能进食、水为止。并分别于术前、术后 1d、7d及 14d测定患者的生化全套、内毒素、肿瘤坏死因子及可溶性白细胞介素 2受体水平 ,并观察患者营养状况的改变。结果　术后 4drhGH组体重开始增加 ,术后 7d ,对照组体重也开始增加 ,但rhGH组比对照组体重增加明显。术后 7d ,rhGH组比对照组血糖升高 (P<0 .0 5 )。术后 7d ,rhGH组的血清白蛋白、转铁蛋白、前白蛋白比对照组升高 (P<0 .0 5 ) ;总胆汁酸、血清总胆固醇及低密度脂蛋白、血清谷草转氨酶、γ 谷氨酰转移酶、总胆红素、内毒素、肿瘤坏死因子及可溶性白细胞介素 2受体水平比对照组明显降低 (P<0 .0 1)。肾功能以及电解质两组变化无明显差异。结论　rhGH应用于梗阻性黄疸术后能改善机体的营养状况以及免疫功能。     

氨基胍对梗阻性黄疸大鼠治疗作用的实验研究

目的 探讨诱导型一氧化氮合酶(iNOS)抑制剂氨基胍(AG)对梗阻性黄疸大鼠的治疗作用及作用机制.方法 雄性Wistar大鼠40只,随机分为正常对照组、假手术组、黄疸组、氨基胍治疗组4组,每组10只.通过测定治疗前后肝功、血胆红素、内毒素、乳酸、肝组织丙二醛水平,以及通过对肝脏、小肠的形态学分析来探讨氨基胍对梗阻性黄疽大鼠的治疗作用.结果 血浆内毒素和血清乳酸、肝组织丙二醛随着胆道梗阻时间的延长逐步升高,并伴随着肝脏小肠病理形态学的改变.氨基胍治疗组各项指标显著低于对照组,并能改善肝组织及小肠病理形态.结论 氨基胍(AG)可通过减轻脂质过氧化与内毒素血症发挥保护肝脏及小肠的作用,为治疗梗阻性黄疸患者提供了一种新的思路和方法.

Abstract：

Objective To evaluate the therapeutic effect and mechanism of specific inducible nitric oxide synthase(iNOS)aminoguanidine(AG)in rats with obstructive jaundice.Methods Forty male Wistar rats were divided randomly into four groups: normal control group, sham operation group, obstructive jaundice group and aminoguanidine therapeutic group.Each group had 10 rats.We assayed levels of liver function,hemobilirubin, endotoxin,lactic acid and malondialdehyde before and after therapy, and we also analyzed pathology of the liver and small intestine.Then we could explore the therapeutic effect of AG in rats with obstructive jaundice.Results The levels of endotoxin,lactic acid and malondialdehyde in blood increased progressively along with the pathological changes of the liver and small intestine.Each of the AG group parameters was significantly lower, and the pathological changes of liver and small intestine were improved.Conclusion AG could protect liver and small intestine by attenuating lipid peroxidative and endotoxemia,and provide a new way to cure obstructive jaundice.     

A randomized trial on the effect of mannitol on postoperative renal function in patients with obstructive jaundice

A randomized trial was undertaken to reassess the effectiveness of mannitol in preventing postoperative renal impairment in patients with obstructive jaundice. The study included 31 patients with obstructive jaundice (bilirubin, 3 mg/dl or higher) randomly allocated in two groups to receive (n = 17) or not receive (n = 14) preoperative mannitol. Sixty-five percent of patients had a creatinine clearance below 70 ml/min before surgery. Serum bilirubin and bacteribilia had no relation with preoperative renal function. No relation was found between serum bilirubin value and the percentage fall in postoperative creatinine clearance. Compared with the preoperative values, the postoperative creatinine clearance was significantly impaired in the mannitol group (p = 0.03) and remained almost unaltered in the no-mannitol group. Three patients (9.7%) died of acute renal failure; two were in the mannitol group and one was in the no-mannitol group. Serum fibrin degradation products were not sensitive markers for impending renal failure. There was no significant difference in postoperative serum sodium concentration or in the urinary sodium excretion. Administration of mannitol did not improve the postoperative renal function of jaundiced patients, nor did it prove beneficial in preventing renal failure. Our results suggest that severe disturbances of body-fluid compartments may be the basic mechanism underlying kidney dysfunction in obstructive jaundice and that further water depletion induced by mannitol may indeed prove detrimental.     

精氨酸对梗阻性黄疸病人肾脏损害的保护作用

目的 观察精氨酸对梗阻性黄疸（梗黄）病人肾功能的保护效应。方法34例梗黄病人,随机分为两组,分别在术前给予一般治疗（梗黄组）和精氨酸治疗（治疗组）,连续治疗7d,观察手术前后血ET（内毒素）及Ccr（内生肌酥清除率）变化,并与20例无黄疸的慢性胆囊炎、胆囊结石病人（对照组）比较。结果（1）入院时梗黄组与治疗组外周血ET及Ccr水平比较,差别无显著意义（P>0.05）,但上述两组ET均显著高于对照组（P<0.01）,Ccr显著低于对照组（P<0.01）;（2）梗黄组术后第1天血ET较术前升高（P<0.05）,Ccr更趋下降（P<0.05）,7d后随血ET水平下降,Ccr逐渐升高,第14天ET和Ccr两项指标接近正常水平;ET与Ccr呈显著负相关（P<0.05）;（3）治疗组用药后血ET水平下降,术后保持较低水平,而Ccr用药后升高,第7天ET、Ccr两项指标已接近正常水平。结论 术前使用精氨酸可显著降低梗黄病人内毒素血症,提高内生肌酥清除率,对肾功能具有良好的保护作用。     

Kupffer cell blockade, tumour necrosis factor secretion and survival following endotoxin challenge in experimental biliary obstruction

BACKGROUND: Gram-negative sepsis and its sequelae frequently complicate invasive procedures in patients with obstructive jaundice. In response to endotoxin, Kupffer cells secrete tumour necrosis factor (TNF), a pivotal early mediator of sepsis. An investigation was carried out into the specific role of Kupffer cell TNF secretion following endotoxin challenge in obstructive jaundice. METHODS: Survival following intraperitoneal administration of endotoxin (2.0, 0.02 and 0.0002 mg per 100 g) was determined in rats following bile duct ligation (BDL) or sham operation. Plasma TNF concentration was quantified following endotoxin administration (0.0002 mg per 100 g) at 1, 2 and 6 h. Subsequently, the effect of Kupffer cell blockade by gadolinium chloride on survival and plasma TNF concentration was assessed. RESULTS: Jaundiced animals showed a significantly increased mortality rate following intraperitoneal injection of endotoxin 2.0 mg per 100 g (BDL 100 per cent versus sham 0 per cent) and 0.02 mg per 100 g (BDL 70 per cent versus sham 0 per cent; P = 0. 002, Fisher's exact test). Median plasma TNF concentration was significantly greater in jaundiced animals 1 h after endotoxin administration (BDL 943 (interquartile range (i.q.r.) 211-3900) pg/ml versus sham 64 (i.q.r. 47-127) pg/ml; P = 0.002, Mann-Whitney U test). Kupffer cell blockade with gadolinium chloride increased the survival rate following endotoxin administration in BDL animals (BDL-GdCl3 100 per cent versus BDL-saline 40 per cent; P = 0.0003, Fisher's exact test) and decreased median plasma levels of TNF (BDL-GdCl3 88 (i.q.r. 0-1065) pg/ml versus BDL-saline 16 550 (1255-29 360) pg/ml; P = 0.002, Mann-Whitney U test). CONCLUSION: Kupffer cell blockade improved survival and suppressed systemic TNF activity after endotoxin challenge. In obstructive jaundice, hypersecretion of TNF by Kupffer cells may supplement systemic cytokine production and be responsible for significant complications.     

Effect of jaundice and its resolution on wound re-epithelization, skin collagen synthesis, and serum collagen propeptide levels in patients with neoplastic pancreaticobiliary obstruction

BACKGROUND: Wound and anastomotic healing is considered to be delayed in patients with obstructive jaundice. The study was designed to find out whether the healing of experimental suction blister wounds, skin collagen synthesis, and serum procollagen levels are affected by obstructive jaundice, and if biliary drainage may cause any alterations in these processes. PATIENTS AND METHODS: Suction blisters were induced on 24 patients with obstructive jaundice caused by neoplastic pancreaticobiliary obstruction and 17 control patients with the corresponding condition without jaundice, to compare healing parameters and collagen synthesis between the groups. A second set of suction blisters were induced on 13 formerly jaundiced patients after the resolution of jaundice and on 14 control patients, to find out whether drainage or time modifies healing or collagen synthesis. By using this model, it is possible to evaluate the re-epithelization and inflammation on wound healing and to assess the baseline skin collagen synthesis. The healing of suction blisters was followed up by measuring water evaporation and blood flow in the wound. Blister fluids and serum samples were collected to study collagen propeptides. RESULTS: Healing of the blister wound was unaffected by obstructive jaundice. Drainage had no effect on healing. The baseline synthesis of type I and type III collagen in the skin was decreased in jaundiced patients. Biliary drainage improved the synthesis. Serum type III procollagen propeptide levels were elevated in jaundiced patients, but began to normalize after drainage. CONCLUSION: Healing of an experimental blister wound is not disturbed by obstructive jaundice. The decreased baseline skin collagen synthesis is partly restored by the resolution of jaundice. The results indicate that cell protein synthesis is disturbed earlier than cell dynamics in obstructive jaundice. The elevated serum PIIINP levels, which are most likely to be related to early fibrosis in liver, decreased after drainage.     

Prevention of postoperative complications in jaundiced rats. Internal biliary drainage versus oral lactulose.

In an experiment mimicking a severe surgical trauma by deliberate renal ischemia, the postoperative outcome in jaundiced rats was studied. Intervention studies were performed with preoperative oral lactulose (to reduce endotoxin toxicity) or preoperative internal biliary drainage. Compared to control, obstructive jaundice in rats significantly reduced survival time (p less than 0.001) and enhanced renal impairment (p less than 0.001) after renal ischemia. Preoperative supportive therapy of jaundiced rats with oral lactulose increased survival time (p less than 0.01) but did not reduce deterioration of renal function. Preoperative internal biliary drainage proved to be superior, with a significant reduction of renal impairment (p less than 0.001) and an improved survival time (p less than 0.001). Our experiments provide further evidence that obstructive jaundice increases the complication rate following major surgical procedures. Based on our results in rats, we suggest that in obstructive jaundice preoperative internal biliary drainage is the supportive therapy of choice. However, if adequate drainage is not possible, oral treatment with lactulose may help reduce postoperative complications.     

不同胆汁引流方式对梗阻性黄疸兔血清内毒素与免疫功能的影响

目的:探讨不同胆汁引流方式对梗阻性黄疸兔血清内毒素与免疫功能的影响。方法:将36只新西兰白兔随机均分为假手术组、外引流组、内引流组。外引流组与内引流组先建立可逆型梗阻性黄疸模型,7 d后解除梗阻,分别行胆汁外引流与内引流;假手术组按相同时间间隔行2次假手术。各组分别于造模前、造模后7 d、引流术后7 d采血,检测肝功能指标、血清内毒素水平、血中CD4+CD25+调节性T细胞的比例。结果:假手术组各时间点各项指标均无明显变化(均P0.05);造模后7 d,外引流组与内引流组血清胆红素、转氨酶、内毒素水平均较造模前明显升高,血CD4+CD25+调节性T细胞比例较造模前明显降低(均P0.05);行引流术7 d后,外引流组与内引流组肝功能指标、内毒素水平、CD4+CD25+调节性T细胞比例均较造模后7 d明显恢复,但内引流组后两项指标的恢复程度均明显优于外引流组(均P0.05)。结论:胆汁内引流较胆汁外引流更有利于梗阻性黄疸内毒素清除与机体免疫功能快速恢复。     

Pathophysiology of obstructive jaundice and its surgical problems

Mitochondrial respiratory function, ketogenesis, collagen metabolism of the liver in rats, dogs and patients with obstructive jaundice were investigated. In animal experiments, it was revealed that mitochondrial respiratory function and ketogenesis decreased significantly with prolongation of biliary obstruction. Hepatic collagen content and its synthesis significantly increased in biliary obstruction. After relief of biliary obstruction in these dogs and patients, these functions and contents improved or returned to near normal levels according to the duration of biliary obstruction and period after relief. By steroid hormone and CoQ administration to jaundiced rats, improvement of mitochondrial function was obtained to some extent. Cross circulation between the jaundiced rat and normal one was performed and it was found that mitochondrial function in normal rat was decreased and that of jaundiced rat improved, especially in renal mitochondria. When major surgery is required in patients of biliary obstruction with severe jaundice, biliary drainage should be carried out first 4 to 6 weeks before major operation. Steroid or CoQ therapy and plasma exchange are also useful for these patients.     

梗阻性黄疸患者手术前后血清C_3及血浆纤维蛋白含量的变化

作者对３０例梗阻性黄疸患者手术前后血清补体－３（Ｃ３）及血浆纤维结合蛋白（ＦＮ）水平进行了测定。结果显示，与无黄疸胆系疾病患者相比，梗阻性黄疸患者Ｃ３及ＦＮ增高（Ｐ＜０．０１），术后Ｃ３明显降低，持续两周，术后第２１天恢复术前水平；ＦＮ术后明显下降，低水平持续１周，第二周恢复术前水平。而无黄疸病人术后Ｃ３及ＦＮ无明显变化。作者认为梗阻性黄疸患者术前Ｃ３及ＦＮ高可能与潜在感染有关；术后Ｃ３和ＦＮ降低与炎症反应消耗及手术抑制非特异性防御系统功能有关。     

Experimental and clinical study of lactulose in obstructive jaundice

The role of lactulose in preventing endotoxaemia in obstructive jaundice has been investigated. A prospective study was performed on 24 consecutive patients with obstructive jaundice undergoing surgery. Twelve patients were given oral lactulose before operation and were compared with twelve controls. Endotoxaemia was reduced in peroperative portal (P less than 0.05) and postoperative systemic (P less than 0.05) blood samples in the lactulose treated group, and a significant fall (P less than 0.05) occurred in the postoperative 24 h creatinine clearances in controls compared with the lactulose treated group. Results from animal experiments in which oral lactulose reduced endotoxin related mortality in obstructive jaundice (P less than 0.05), and the in vitro demonstration of a direct anti-endotoxic action of lactulose suggest that its beneficial action is due in part to an inactivation of endotoxin.     

Endotoxin-induced lung hemorrhages in obstructive jaundiced rats

Endotoxemia in patients with biliary obstruction contributes to the high morbidity and mortality rates following surgery. We developed an animal model of disseminated intravascular coagulation (DIC) in rats on which bile duct ligation was performed following an injection of endotoxin (200 μg/kg bw). Macroscopic hemorrhages and microthrombi in the lung were found in jaundiced rats 6 hours after the injection of endotoxin and yet these phenomena were not found in non-jaundiced rats following an injection of the same amount of endotoxin. Coagulation studies also revealed characteristic findings of DIC in the jaundiced rats following the injection of endotoxin. This study confirms that obstructive jaundice is one of the main predisposing factors in the course of endotoxin-induced DIC.