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Background Systemic endotoxaemia is implicated in the development of complications associated with obstructive jaundice. The aims of these studies were to assess the systemic immune response to intervention in patients with jaundice and to compare the effects of surgical and non-surgical biliary drainage on host immune function and gut barrier function. Methods In the first study, 18 jaundiced and 12 control patients were studied to assess systemic immune responses before and after intervention. In the second study, immune responses and gut barrier function were assessed following surgical and non-operative biliary decompression in 45 patients with jaundice. Results Endotoxin antibody concentrations fell significantly in patients with jaundice immediately after surgical intervention, but not after non-operative biliary drainage. This decrease was associated with a significant increase in serum P55 soluble tumour necrosis factor (sTNF) receptor concentration (5·3 versus 10·5 ng/ml; P < 0·001), urinary excretion of P55 TNF receptors (21·4 versus 78·8 ng/ml; P = 0·002) and intestinal permeability (lactulose : mannitol ratio 0·032 versus 0·082; P = 0·048). Intestinal permeability was significantly increased in patients with jaundice compared with controls (0·033 versus 0·015; P = 0·002). Conclusion These data suggest that obstructive jaundice is associated with impaired gut barrier function and activation of host immune function that is exacerbated by intervention. Surgery causes an exaggerated pathophysiological disturbance not seen with non-operative biliary drainage procedures.

Background Complex limb trauma often involves combined arterial and venous injury, and the resultant ischaemia–reperfusion injury (IRI) causes both local and remote organ injury. This study assessed the influence of the timing of restoration of venous drainage on IRI. Methods Male New Zealand white rabbits (n = 36) were randomized into six groups: sham operation (group 1) and unilateral hind limb arterial and venous occlusion for 1 h followed by no reflow for 2 h (group 2), arterial and venous reflow for 2 h (group 3), arterial reflow alone for 2 h (group 4), arterial reflow alone for 1 h followed by arterial and venous (delayed) reflow for a further 1 h (group 5), and pretreatment with an enteral combination antioxidant before occlusion of both artery and vein and delayed venous reflow (group 6). Plasma hydroperoxide (HPO) and glutathione peroxidase concentration, hind limb skeletal muscle and lung tissue wet: dry weight ratios and myeloperoxidase (MPO) concentration were measured. Results The plasma HPO level in the femoral vein effluent was significantly greater after delayed venous reflow (mean(s.e.m.) 2·02(0·54) μmol/l) than in control animals (0·98(0·10) μmol/l) (P < 0·05). There was also a significantly greater tissue wet: dry weight ratio after delayed venous reflow than in controls, in skeletal muscle (mean(s.e.m.) 6·89(0·14) versus 5·34(0·54); P < 0·05) and lung (9·20(1·14) versus 7·23(0·38); P < 0·05) tissue. Lung tissue MPO activity was significantly greater after delayed venous reflow compared with controls (3·20(0·28) versus 1·86(0·14) units/g; P < 0·005), and also in comparison to simultaneous arterial and venous reflow (2·40(0·24) units/g; P < 0·05). In the antioxidant pretreatment group there was no significant increase in plasma HPO concentration, tissue MPO level or tissue wet: dry weight ratio compared with the control group. Conclusion In combined major arterial and venous injury of the limb, delayed restoration of venous drainage leads to significantly greater local skeletal muscle injury and remote neutrophil-mediated lung injury. These results support the clinical rationale for early restoration not only of arterial inflow but also venous drainage by means of intraluminal shunts.

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.

Background Sepsis and endotoxaemia occur frequently in biliary obstruction. Impaired Kupffer cell endocytosis is implicated in these events. Tumour necrosis factor and interleukin 6, secreted by Kupffer cells, are important mediators of sepsis. Kupffer cell clearance of endotoxin and secretion of cytokines in experimental obstructive jaundice were investigated. Methods Wistar rats were randomized to bile duct ligation, sham operation or control. Groups (n = 8) were studied 1 and 3 weeks after operation. Kupffer cell function was assessed using in situ hepatic perfusion. Results Clearance of endotoxin was significantly depressed 1 week (median (interquartile range) 20·3 (10·5–27·1) per cent) and 3 weeks (22·1 (20·2–23·2) per cent) after bile duct ligation compared with that in respective sham animals (35·5 (29·9–41·6) and 40·9 (37·7–47·0) per cent) and controls (39·5 (37·3–46·8) per cent). Secretion of tumour necrosis factor was significantly greater 1 week (1113·7 (706·5–1436·8) pg/ml) and 3 weeks (1118·2 (775·7–1484·1) pg/ml) following bile duct ligation compared with that in respective sham animals (114·3 (0–178·5) and 107·6 (63·7–166·4) pg/ml) and controls (0 (0–20·7) pg/ml). Interleukin 6 was not secreted by sham or control animals but was present in the perfusate from jaundiced animals at 1 and 3 weeks (52·5 (9·9–89·5) and 66·2 (60·2–193·1) pg/ml). Conclusion These data demonstrate simultaneous impairment of Kupffer cell clearance of endotoxin and increased secretion of proinflammatory cytokines in experimental obstructive jaundice. These diverse responses may contribute to the development of sepsis-related complications in biliary obstruction.

Background It has been suggested that bowel permeability is altered following abdominal aortic aneurysm surgery. The effect of ischaemia-reperfusion injury to the lower limb on the morphological structure, neutrophil infiltration and permeability of the bowel was investigated. Methods Histological assessment of the bowel was undertaken in five groups of Wistar rats: control, 3 h of bilateral hind limb ischaemia and 3 h of bilateral hind limb ischaemia followed by 1, 2 or 3 h of reperfusion. Using an everted gut sac model and 14 C-labelled polyethylene glycol, the effect of ischaemia-reperfusion on small bowel permeability was studied. Results The small bowel showed a significant decrease in mucosal thickness, villus height and crypt depth in animals subjected to ischaemia followed by 2-hr reperfusion (mean(s.e.m.) 420(15), 217(9) and 163(6) μm respectively) compared with controls (481(11), 245(6) and 195(6) μm) (P

Background Tumour necrosis factor (TNF) is a pleiotropic cytokine produced largely by macrophages and T lymphocytes. It has been implicated in the pathogenesis of numerous immunoinflammatory processes. Recently, a number of studies have indicated that anti-TNF antibodies may be of value in the treatment of inflammatory bowel disease. Method The literature is reviewed regarding the role of TNF in the pathogenesis of inflammatory bowel disease and the results of administering TNF inhibitors. Results and conclusions TNF may have a role in the pathogenesis of inflammatory bowel disease. The effects of TNF inhibitors are complex and incompletely understood. Anti-TNF antibody strategies may have a role in the treatment of acute exacerbations of the disease but are unlikely to be appropriate therapies for long-term management.

The effect of low-dose dopamine administration on intramucosal pH (pHi) of the sigmoid colon and on postoperative function of various organs in patients undergoing elective abdominal aortic aneurysm repair was examined. Nineteen patients were randomized to two groups; nine received dopamine at a rate of 3 μg per kg per min for 24 h from induction of anaesthesia and ten control patients received fluids without dopamine. pHi was measured with a silicone tonometer and daily samples of blood were taken for measurement of liver transaminase activity, arterial oxygen saturation and creatinine concentration. Mean(s.e.m.) pHi fell to a significantly lower minimum value in those receiving dopamine compared with control patients (6.86(0.10) versus 7.11(0.08), P

In 30 patients undergoing elective repair of abdominal aortic aneurysm the intramucosal pH (pHi) of the sigmoid colon was measured. Blood for endotoxin assay was taken at intervals before, during and after surgery. Daily measurements were made of liver transaminase activity and of arterial partial pressure of oxygen (PaO2). The mean(s.e.m.) peak systemic endotoxin concentration in those who developed intramucosal acidosis (pHi below 7·00) was 90(14) pg/ml, compared with 42(5) pg/ml in those who did not (P < 0·01). In the 14 patients whose pHi fell below 7·00, the mean(s.e.m.) postoperative rise in aspartate transaminase activity was 346(74) per cent, compared with 181(20) per cent in those whose pHi remained above this level (P < 0·05). The mean(s.e.m.) postoperative ratio of PaO2, to the fraction of inspired oxygen was 177(11) mmHg in those with intramucosal acidosis, compared with 260(24) mmHg in those whose pHi remained above 7·00 (P < 0·01). These results demonstrate a relationship between bowel ischaemia, endotoxaemia and organ impairment following elective aneurysm repair.

Jaundiced surgical patients have a high incidence of postoperative complications. Many causative factors have been identified including cachexia and immune suppression. The amino acid L-arginine has anabolic and immunostimulatory properties. It was hypothesized that dietary supplementation with L-arginine would diminish the weight loss and immune suppression of obstructive jaundice. Sixteen male Wistar rats rendered jaundiced by bile duct ligation were allocated to two groups. The test group (n = 8) received drinking water supplemented with 1·8 per cent L-arginine ad libitum and the control group (n = 8) received a solution of isonitrogenous glycine. Both groups had free access to standard chow. Body-weight, and fluid and food intake were recorded. After 21 days, delayed-type hypersensitivity to 2,4-dinitrofluorobenzene was assessed. Animals receiving L-arginine consumed more food than controls (mean(s.e.m.) 414(16) versus 360(13) g, P < 0·05) and lost less weight (mean(s.e.m.) proportion of initial body-weight lost 7·8(1·2) versus-14·8(1·4) per cent P < 0·05). The delayed-type hypersensitivity response was significantly greater in rats receiving L-arginine (mean(s.e.m.) increase in ear thickness 23·9(2·7) versus 9·4(2·1) per cent, P < 0·05). In this animal model of obstructive jaundice dietary supplementation with L-arginine diminished both weight loss and immune suppression.

Background: Clinical experience of the early use of intraluminal shunts in major limb trauma at this centre aimed at restoring arterial inflow and venous outflow has been shown to reduce amputation rates and morbidity. In a model of combined arterial and venous limb vessel trauma, ischaemia–reperfusion injury caused by delayed restoration of venous drainage locally on skeletal muscle and remotely on lung was studied. Furthermore, using antioxidant pretreatment the possibility of reversing these detrimental effects was investigated. Methods: New Zealand white rabbits (n = 36) were randomized into six groups: (1) sham operation; unilateral hind limb arterial and venous occlusion for 1 h followed by (2) no reflow for 2 h; (3) arterial and venous reflow for 2 h; (4) arterial reflow alone for 2 h; (5) arterial reflow for 1 h followed by arterial and venous (delayed) reflow for a further 1 h; (6) pretreatment with an enteral combination antioxidant before combined arterial and venous occlusion with delayed venous reflow. Plasma hydroperoxide (HPO) concentration in the femoral vein was a measure of lipid peroxidation. Hindlimb skeletal muscle and lung wet-to-dry weight ratio reflected tissue oedema, and myeloperoxidase (MPO) tissue levels estimated neutrophil sequestration. Plasma glutathione peroxidase (GPx) levels in systemic vein (SV) and femoral vein effluent (FV) reflected antioxidant status. Hindlimb skeletal muscle injury was graded histologically. Results: Femoral vein HPO (µmol l−1) GPx (units l−1) Lung MPO (units g−1) Skeletal muscle histological injury grade SV start SV end FV end Values are mean(s.e.m.). * P < 0·05 versus groups 1, 3 and 6 † P < 0·01 versus groups 1–5 ‡ P < 0·05 versus group 1 1 1·0(0·1) 414·9(31·7) 391·4(33·4) 440·1(47·2) 1·7(0·1) None 2 1·8(0·5) 291·7(10·9) 363·2(62·4) 488·6(45·6) 2·3(0·2) None 3 1·2(0·4) 423·1(68·3) 398·6(63·9) 409·1(63·9) 2·4(0·2) Mild 4 1·7(0·3) 408·8(26·4) 399·0(35·4) 397·3(26·4) 1·9(0·2) Moderate 5 2·0(0·5)* 468·0(40·8) 412·2(35·6) 358·4(22·0) 3·2(0·3)‡ Severe 6 0·9(0·2) 607·9(36·3)† 562·3(40·7)† 547·2(24·9)† 2·1(0·3) Mild Conclusion: In combined major arterial and venous vessel injury of the limb, delayed venous repair leads to significantly greater local skeletal muscle injury and remote neutrophil-mediated lung damage. Reversal of these detrimental effects with antioxidant pretreatment suggests that failure of antioxidant scavenging systems may be central to the injury accentuated by delayed venous drainage. These results support the clinical rationale for early restoration of not only arterial inflow but also venous drainage by intraluminal shunts. © 2000 British Journal of Surgery Society Ltd