Host immune responses and intestinal permeability in patients with jaundice.

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 P(55) soluble tumour necrosis factor (sTNF) receptor concentration (5.3 versus 10.5 ng/ml; P < 0.001), urinary excretion of P(55) 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.

Bactericidal/permeability-increasing protein attenuates systemic inflammation and acute lung injury in porcine lower limb ischemia-reperfusion injury.

OBJECTIVE: To investigate the role of recombinant bactericidal/permeability-increasing protein (rBPI21) in the attenuation of the sepsis syndrome and acute lung injury associated with lower limb ischemia-reperfusion (I/R) injury. SUMMARY BACKGROUND DATA: Gut-derived endotoxin has been implicated in the conversion of the sterile inflammatory response to a lethal sepsis syndrome after lower torso I/R injury. rBPI21 is a novel antiendotoxin therapy with proven benefit in sepsis. METHODS: Anesthetized ventilated swine underwent midline laparotomy and bilateral external iliac artery occlusion for 2 hours followed by 2.5 hours of reperfusion. Two groups (n = 6 per group) were randomized to receive, by intravenous infusion over 30 minutes, at the start of reperfusion, either thaumatin, a control-protein preparation, at 2 mg/kg body weight, or rBPI21 at 2 mg/kg body weight. A control group (n = 6) underwent laparotomy without further treatment and was administered thaumatin at 2 mg/kg body weight after 2 hours of anesthesia. Blood from a carotid artery cannula was taken every half-hour for arterial blood gas analysis. Plasma was separated and stored at -70 degrees C for later determination of plasma tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 by bioassay, and IL-8 by enzyme-linked immunosorbent assay (ELISA), as a markers of systemic inflammation. Plasma endotoxin concentration was measured using ELISA. Lung tissue wet-to-dry weight ratio and myeloperoxidase concentration were used as markers of edema and neutrophil sequestration, respectively. Bronchoalveolar lavage protein concentration was measured by the bicinclinoic acid method as a measure of capillary-alveolar protein leak. The alveolar-arterial gradient was measured; a large gradient indicated impaired oxygen transport and hence lung injury. RESULTS: Bilateral hind limb I/R injury increased significantly intestinal mucosal acidosis, intestinal permeability, portal endotoxemia, plasma IL-6 concentrations, circulating phagocytic cell priming and pulmonary leukosequestration, edema, capillary-alveolar protein leak, and impaired gas exchange. Conversely, pigs treated with rBPI21 2 mg/kg at the onset of reperfusion had significantly reduced intestinal mucosal acidosis, portal endotoxin concentrations, and circulating phagocytic cell priming and had significantly less pulmonary edema, leukosequestration, and respiratory failure. CONCLUSIONS: Endotoxin transmigration across a hyperpermeable gut barrier, phagocytic cell priming, and cytokinemia are key events of I/R injury, sepsis, and pulmonary dysfunction. This study shows that rBPI21 ameliorates these adverse effects and may provide a novel therapeutic approach for prevention of I/R-associated sepsis syndrome.

Circulating neutrophil priming and systemic inflammation in limb ischaemia-reperfusion injury.

BACKGROUND: Recruitment and activation of neutrophils is a key step in the development of local and systemic injury in lower limb ischaemia-reperfusion. We hypothesis that increased circulating neutrophil priming is responsible for systemic inflammation. METHODS: Anaesthetised ventilated swine (n = 6 per group) underwent mid-line laparotomy and were randomised to control group or bilateral external iliac artery occlusion for two hours followed by two and a half hours reperfusion (I/R group). Using luminol, respiratory burst activity was assayed with a BioOrbit Luminometer to detect whole blood chemiluminescence (CL) by stimulation with phorbol 1,2-myristate 1,3-acetate (PMA) in the absence or presence of tumour necrosis factor (TNF) respectively. PMN priming is expressed as the ratio of whole blood CL in the presence of TNF to that without. We measured plasma interleukin(IL)-6 and tumour necrosis factor alpha by bioassay as a measure of systemic inflammation. The alveolar-arterial (A-a) gradient was measured using the formula [(A-a)gradient = fraction inspired O2 x 710-(arterial pCO2/0.8)-arterial pO2], it is a measure of lung function, a large gradient being indicative of impaired oxygen transport and hence lung injury. RESULTS: Lower limb I/R caused significantly greater PMN priming, 0.83 +/- 0.14, compared to control group, 0.22 +/- 0.04, (p < 0.001). Plasma IL-6, a reliable indicator of systemic inflammation, was significantly increased in I/R group after two and a half hours of reperfusion, 1295.0 (833.9-2073.0) pg/L, compared to control, 382.9 (367.4-568.3) pg/L, (p < 0.005). Plasma tumour necrosis factor alpha was significantly elevated after one hour of reperfusion in the I/R group, 86.8 (48.7-106.6) pg/ml, compared to the control group, 32.7 (0.9-42.8) pg/ml, (p < 0.01). (A-a) gradient was significantly increased after IRI, 407.97 +/- 53.13, compared to the control, 183.19 +/- 45.75, (p < 0.005). Mean pulmonary artery pressure was significantly greater after IRI, 38.80 +/- 4.87 mmHg, compared to control, 27.86 +/- 1.92 mmHg, (p < 0.005). Data represents mean +/- standard error mean or median (interquartile range), statistical comparisons using one-way Anova with Student's "t"-test and Kruskall-Wallis Anova with the Mann-Whitney U test. CONCLUSIONS: Priming of neutrophils increases their circulating respiratory burst activity and ability to induce tissue injury. Systemic PMN priming during hind limb ischaemia-reperfusion injury is associated with the systemic inflammatory response syndrome.

Gut mucosal injury is attenuated by recombinant bactericidal/permeability-increasing protein in hind limb ischemia-reperfusion injury.

Lower limb ischemia-reperfusion injury (IRI) is associated with increased gut permeability to endotoxin, which not only directly damages enterocytes but also stimulates a systemic inflammatory response syndrome (SIRS), compounding gut injury. Recombinant bactericidal/permeability-increasing protein (rBPI21) is a novel anti-endotoxin therapy with proven benefit in sepsis. Its potential role in modulating remote gut injury in hind limb IRI was studied. Male Wistar rats were chosen for a prospective randomized control trial (n = 10 per group). The control group and two groups undergoing 3 hr bilateral hind limb ischemia with 2 hr reperfusion (I/R) were randomized to receive intravenously either control protein thaumatin at 2 mg/kg or rBPI21 at 2 mg/kg, respectively. Quantitative morphometric assessment of the small bowel was used as a measure of gut injury and, using an ex vivo everted gut sac model, translocation of 14C-labeled polyethylene glycol (PEG) was used as a measure of gut permeability. Our results indicate that hind limb IRI is associated with remote gut mucosal injury and increased permeability to macromolecules. rBPI21 anti-endotoxin therapy modulates remote gut injury associated with lower limb IRI in this model.

Extraperitoneal approach reduces neutrophil activation, systemic inflammatory response and organ dysfunctionin aortic aneurysm surgery.

OBJECTIVES: to compare the effects of transperitoneal and extraperitoneal approaches on systemic inflammatory response, neutrophil activation and organ dysfunction in elective abdominal aortic aneurysm (AAA) repair. PATIENTS AND METHODS: twenty patients admitted for elective infrarenal AAA repair were prospectively randomised into transperitoneal (n =10) or extraperitoneal ( n =10) groups. Neutrophil activation was assessed by measuring the plasma levels of neutrophil elastase/alpha(1)-anti-trypsin complexes before surgery, intraoperatively and at 6 h, 12 h, 24 h and then daily after surgery. Venous blood samples for estimation of liver function tests, full blood counts, urea and electrolytes and arterial samples for blood gas analysis were taken daily from preoperatively to day 5 after surgery. Multiple organ dysfunction (MOD) and systemic inflammatory response (SIR) scores were calculated daily. RESULTS: the concentrations of neutrophil elastase/alpha(1)-anti-trypsin complexes were significantly higher in the transperitoneal group at 6 h after surgery compared to the extraperitoneal group (799(455-921) ng/ml (median(i.q.r.)) vs 307(171-395) ng/ml, p<0.005), and at 12 h (397(364-936) ng/ml vs 319(134-352) ng/ml, p <0.05). The MOD scores were significantly higher in the transperitoneal group in comparison to the extraperitoneal group at day 1 (2.5(2-3.3) vs 1(0-1), p<0.001) and day 2 (2.5(2-3.3) vs 1(0-1), p <0.001). The SIR scores were also significantly higher at day 1 (1(0-2) vs 0, p <0.01), day 2 (1.5(0-2.3) vs 0, p <0.01), and day 3 (1(0-1) vs 0, p <0.05). CONCLUSIONS: neutrophil activation, systemic inflammatory response and organ dysfunction are increased in elective AAA repair when a transperitoneal approach is used. This may be related to intestinal manipulation and mesenteric traction which are reduced in the extraperitoneal approach.

Recombinant bactericidal/permeability-increasing protein attenuates the systemic inflammatory response syndrome in lower limb ischemia-reperfusion injury.

OBJECTIVES: Hind limb ischemia-reperfusion (I/R) injury increases gut permeability, and resultant endotoxemia is associated with an amplified systemic inflammatory response syndrome leading to multiple organ dysfunction syndrome. We studied the potential role of recombinant bactericidal/permeability-increasing protein (rBPI(21) ), a novel antiendotoxin therapy, in modulating endotoxin-enhanced systemic inflammatory response syndrome in hind limb I/R injury. METHODS: In this prospective, randomized, controlled, experimental animal study, 48 male Wistar rats, weighing 300 to 350 g, were randomized to a control group (sham) and five groups undergoing 3 hours bilateral hind limb ischemia with 2 hours reperfusion (I/R) (n = 8 per group). The control and untreated I/R groups received thaumatin, a control-protein preparation, at 2 mg/kg. Treatment groups were administered rBPI(21) intravenously at 1, 2, or 4 mg/kg body weight at the beginning of reperfusion; an additional group was administered rBPI(21) intravenously at 2 mg/kg after 1 hour of reperfusion. Plasma interleukin-6 concentration was estimated by bioassay as a measure of systemic inflammation. Plasma endotoxin concentration was determined by use of an amebocyte lysate chromogenic assay. Crossreactive immunoglobulin G and M antibodies to the highly conserved inner core region of endotoxin were measured by use of an enzyme-linked immunosorbent assay. The lung tissue wet-to-dry weight ratio and myeloperoxidase concentration were used as markers of edema and neutrophil sequestration, respectively. RESULTS: I/R provoked highly significant elevation in plasma interleukin-6 concentrations (1351.20 pg/mL [860.16 - 1886.40 pg/mL]) compared with controls (125.32 pg/mL [87.76-157.52 pg/mL; P <.0001]), but treatment with rBPI(21) 2 mg/kg at onset of reperfusion (715.89 pg/mL [573.36-847.76 pg/mL]) significantly decreased interleukin-6 response compared with the nontreatment group ( P <.016). I/R increased plasma endotoxin concentrations significantly (21.52 pg/mL [6.20-48.23 pg/mL]), compared with control animals (0.90 pg/mL [0.00-2.30 pg/mL; P <.0001]), and treatment with rBPI(21) 4 mg/kg at reperfusion significantly decreased endotoxemia (1.30 pg/mL [1.20-2.20 pg/mL]), compared with the untreated group ( P <.001). The lung tissue myeloperoxidase level was significantly increased in the untreated I/R group (208.18% [128.79%-221.81%]), compared with in controls (62.00% [40.45%-80.92%; P <.0001]), and attenuated in those treated with rBPI(21) 2 mg/kg (129.54% [90.49%-145.78%; P <.05]). Data represent median and interquartile range, comparisons made with the nonparametric Mann-Whitney U test. CONCLUSIONS: These findings show that hind limb ischemia-reperfusion injury is associated with endotoxemia, elevations in plasma interleukin-6, and pulmonary leukosequestration. Treatment with rBPI(21) after ischemia reduces endotoxemia, the interleukin-6 response, and attenuates pulmonary leukosequestration in response to hind limb reperfusion injury.

Extraperitoneal approach reduces intestinal and renal dysfunction in elective abdominal aortic aneurysm repair.

BACKGROUND: Intestinal mucosal barrier dysfunction observed in patients undergoing transperitoneal abdominal aortic aneurysm (AAA) repair may contribute to the development of the systemic inflammatory response syndrome and dysfunction of various organs. The aim of this study is to investigate whether an extraperitoneal approach reduces intestinal mucosal barrier and renal dysfunction in elective infrarenal AAA repair. METHODS: Twenty patients admitted for elective infrarenal AAA repair were randomized into either the transperitoneal approach (n=10) or the extraperitoneal approach (n=10). Intestinal permeability was measured preoperatively, and at day 1 and day 3 after surgery using the lactulose/mannitol test by calculating the differential urinary excretion ratio of the two sugars after oral administration. Renal dysfunction was assessed by measuring the urinary albumin/creatinine ratio (ACR) at the same time points. RESULTS: Intestinal permeability was significantly increased in the transperitoneal group at day 1 [0.124+/-0.035 (mean+/-s.e.m.)] compared to the preoperative level (0.020+/-0.003), (p=0.001) and to the extraperitoneal group at day 1 (0.025+/-0.008), (p<0.05) which showed no change in comparison with the preoperative level (0.020+/-0.003). The ACR was also significantly increased in the transperitoneal group at day 1 (16.69+/-5.12) compared to the preoperative level (5.71+/-2.89), (p<0.05) and to the extraperitoneal group at day 1 (4.33+/-1.49), (p<0.05) which showed no significant change at any of the times examined. No correlation was observed between the lactulose/mannitol ratio and the albumin/creatinine ratio, or between age, operating time, aortic clamping time, amount of blood lost or blood transfused. CONCLUSIONS: These results support the suggestion that minimising intestinal manipulation using an extraperitoneal approach in AAA repair preserves intestinal mucosal barrier and renal glomerular functions.

Reperfusion injury is greater with delayed restoration of venous outflow in concurrent arterial and venous limb injury.

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) micromol/l) than in control animals (0.98(0.10) micromol/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.

Intestinal manipulation during elective aortic aneurysm surgery leads to portal endotoxaemia and mucosal barrier dysfunction.

OBJECTIVES: to investigate the effect of intestinal manipulation on intestinal permeability and endotoxaemia during elective abdominal aortic aneurysm (AAA) surgery. DESIGN: prospective randomised controlled study. PATIENTS AND METHODS: fourteen patients undergoing elective infrarenal AAA repair were randomised into either the transperitoneal (n=7) or extraperitoneal approach (n=7). Intestinal permeability was measured preoperatively (PO), and at day 1 (D1) and day 3 (D3) after surgery using the lactulose/mannitol absorption test. Portal and systemic blood samples were taken before clamping, at completion of proximal and distal anastomoses and immediately before abdominal wound closure, for endotoxin measurement using the chromogenic limulus amoebocyte lysate assay. RESULTS: intestinal permeability was significantly increased at D1 (0.107+/-0.04 (mean+/-S.E.M.)) in the transperitoneal group compared to the PO level (0.020+/-0.004, p<0.05) and to the extraperitoneal group at D1 (0.020+/-0.004, p<0.05) which showed no change in comparison with the PO level. No correlation was seen between increased intestinal permeability and aortic clamp time, operation time, amount of blood lost or transfused. However, a significantly higher concentration of portal endotoxin was detected intraoperatively in the transperitoneal group of patients in comparison to the extraperitoneal group (p<0.05). There was a significant positive correlation between portal endotoxaemia and intestinal permeability (r(s)=0.955 p=0.001). CONCLUSION: an increase in intestinal permeability and a greater degree of portal endotoxaemia are observed during transperitoneal approach to the aorta. This suggests that intestinal manipulation may impair gut mucosal barrier function and contribute to the systemic inflammatory response seen in AAA surgery.

Lipopolysaccharide binding protein in acute pancreatitis.

OBJECTIVE: To assess the expression of plasma lipopolysaccharide binding protein (LBP) concentrations and its relationship to markers of the systemic inflammatory response syndrome during acute pancreatitis. DESIGN: A prospective study. SETTING: General surgical units of university teaching hospitals in the Belfast area. PATIENTS: The study included 18 patients admitted with established diagnosis of acute pancreatitis on the basis of elevated serum amylase or by contrast radiology. Patients were retrospectively stratified using the Modified Glasgow Criteria into severe (n = 7) and mild (n = 11) disease. INTERVENTIONS AND MEASUREMENTS: Blood samples were obtained at admission (day 1) and for a further 3 days for the measurement of LBP, C-reactive protein (CRP), tumor necrosis factor, and interleukin (IL)-6. Acute Physiology and Chronic Health Evaluation (APACHE) II scores were calculated on day 1 and day 2. MAIN RESULTS: LBP and CRP concentrations were significantly increased from healthy control values in acute pancreatitis patients at presentation. In the mild group LBP, CRP and IL-6 concentrations remained relatively constant throughout the study period. By comparison, severe acute pancreatitis was associated with significantly higher LBP concentrations and a marked systemic inflammatory response as evidenced by increased CRP, IL-6, and APACHE II scores. The rise in LBP occurred after the observed increase of these markers. Significant correlations were found among CRP and LBP, IL-6 and LBP, and IL-6 and APACHE II scores. There were no fatalities in the mild group, whereas four of the seven patients with severe disease died. CONCLUSIONS: LBP was significantly raised in patients with severe acute pancreatitis but would seem to be of limited use in predicting disease severity. This acute phase protein may have a role in the progression of systemic complications associated with acute pancreatitis.

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.

Intramucosal acidosis and the inflammatory response in acute pancreatitis.

OBJECTIVE: The aim of this study was to assess the host response and diminished bowel perfusion during acute pancreatitis. METHODS: A total of 19 patients admitted with established diagnoses of acute pancreatitis on the basis of clinical findings, elevated serum amylase to more than four times the upper limit or by contrast radiology. Patients were stratified into mild and severe pancreatitis using the Atlanta criteria. Blood samples were obtained from in-dwelling lines or direct venipuncture within 12 h of admission and 24 hourly thereafter for measurements of plasma endotoxin, EndoCab immunoglobulin (Ig)G and IgM antibodies, tumor necrosis factor (TNF), p55 TNF receptor, and IL-6. A gastric tonometer was inserted in place of a nasogastric tube for intramucosal pH evaluation. RESULTS: Episodes of endotoxaemia were more common and endotoxin concentration significantly higher at presentation in the severe group compared to the mild group of patients. A greater consumption of IgM antibody was found in those with severe disease. The decrease in IgM antibody concentration was shown to be a specific host response, as a fall in concentration of antibodies to a neutral antigen, tetanus toxoid, was not observed. Significantly greater elevations were found in p55 TNF receptor and IL-6 concentrations in the severe group in comparison to those suffering mild pancreatitis. Significant correlations were found between gastric intramucosal pH and EndoCab IgM antibody, p55 TNF receptor, and IL-6. CONCLUSIONS: These results suggest that endotoxemia, an acute inflammatory response, and a reduction in bowel perfusion may occur in severe acute pancreatitis. The endotoxemia and inflammatory response may be due to the permeation of bacteria and their breakdown products across a disrupted bowel mucosal barrier.

Characterization of the Kupffer cell response to exogenous endotoxin in a rodent model of obstructive jaundice.

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.

Lower limb ischaemia-reperfusion injury causes endotoxaemia and endogenous antiendotoxin antibody consumption but not bacterial translocation.

BACKGROUND: It has been suggested that reperfusion of the acutely ischaemic lower limb alters gut permeability. The effect of lower limb ischaemia-reperfusion on systemic endotoxin and antiendotoxin antibody concentrations and the incidence of bacterial translocation was investigated. METHODS: Systemic endotoxin and antiendotoxin antibody concentrations were measured in five groups of male Wistar rats: control, after 3 h of bilateral hind limb ischaemia alone, and after 3 h of bilateral hind limb ischaemia followed by 1, 2 or 3 h of reperfusion. A second experiment examined translocation of indigenous bacteria following 2 h of reperfusion in a similar model. RESULTS: Ischaemia followed by reperfusion for 1, 2 or 3 h caused a significant increase in plasma endotoxin concentration to mean(s.e.m.) 10.0(3.0), 44.8(19.2) and 20.2(6.2) pg/ml compared with that in control animals (2.58(0.91) pg/ml) or animals in the ischaemia alone group (1.2(0.9) pg/ml) (P < 0.05). This was associated with a significant reduction in endogenous antiendotoxin antibody (immunoglobulin (Ig) G and IgM) concentration. No significant bacterial translocation was detected in any of the groups studied. CONCLUSION: These results demonstrate that a remote and isolated ischaemia-reperfusion injury to the lower limb, in the absence of infection or bacterial translocation, causes endotoxaemia. Further studies are needed to evaluate the role of endogenous antiendotoxin antibodies in this situation.

The use of tonometry to predict mortality in patients undergoing abdominal aortic aneurysm repair.

OBJECTIVE: To assess the reliability of intramucosal pH (pHi) of the sigmoid colon, IL-6 concentration and the APACHE II score in predicting outcome in patients undergoing elective abdominal aortic aneurysm repair. DESIGN: Prospective study. METHODS: In 42 patients, measurements were made of the sigmoid pHi with the silicone tonometer and plasma IL-6 by enzyme linked immuno-sorbent assay (ELISA). The daily postoperative APACHE II scores were also calculated. In 29 patients a preoperative left ventricular ejection fraction was determined by gated radionuclide angiography. RESULTS: Four out of 42 patients who were studied died. The lowest perioperative pHi, the peak postoperative IL-6 concentration and APACHE II scores were significantly different in the survivors in comparison to the non-survivors. In the non-survivors, the fall in pHi preceded the time of patient's demise by at least 4 days. Significant correlations were observed between changes in pHi, IL-6 and APACHE II. Using receiver operating characteristic curves, pHi was shown to be the most predictive of mortality compared to the other variables. The simplicity, speed and practicality of using the tonometer adds to its superiority over the latter measurements. No relationship was found between ventricular ejection fraction, pHi and outcome. CONCLUSION: Although the number of patients is small, these results support pHi as a valuable predictor of outcome and also suggest a role for the gut in initiating the IL-6 and physiological responses.