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Systemic and portal endotoxemia were studied in rats with biliary obstruction and after relief of the obstruction by internal and external drainage. Endotoxemia was increased after bile duct ligation (p less than 0.001) compared with control values. The incidence of systemic and portal endotoxemia was significantly reduced after internal drainage (p less than 0.001). A significantly higher incidence of portal (86 percent) and systemic (57 percent) endotoxemia, however, was found after external drainage. The persistence of endotoxemia after external drainage, when serum bilirubin levels returned to normal units, indicates that bile flow is important in controlling endotoxemia during preoperative biliary drainage. These results suggest that the systemic endotoxemia observed after relief of obstruction by external drainage may contribute to the increased mortality, as found in previous rat studies. This observation may contribute to an understanding of why patients with preoperative external drainage of biliary obstruction have a higher incidence of septic complications.

Sepsis has been associated with specific plasma amino acid patterns. Sixty-five patients were prospectively investigated as to whether these patterns are indeed sepsis specific, or specific for metabolic stress without concomitant sepsis, or associated with the presence of organ failure. Virtually all aminoacid levels were decreased by 10-30% (p less than 0.05), whereas cystine and phenylalanine were significantly elevated. These changes were more pronounced in severe sepsis. Organ failure was not associated with significantly altered amino acid profiles. No differences were found between sepsis and stress without signs of sepsis. In addition, imminent death was not associated with aberrant amino acid profiles. We conclude that sepsis and metabolic stress are associated with changes in plasma amino acid profiles, but that such changes are aspecific and therefore poor indicators of disease severity.

Feeding a high-cholesterol diet to prairie dogs causes a reduction in contractile responses of gallbladder smooth muscle from these animals. In this study, the influence of cholesterol feeding on the contractile response to calcium and on the concentration of the contractile proteins actin and myosin was determined. Strips of gallbladder smooth muscle, at their optimal length for tension development, were stimulated maximally with carbachol. Then the muscle cell membranes were made permeable and strips were exposed to a maximally effective concentration of calcium. Strips from cholesterol fed animals developed less stress than those from control animals under all conditions. The concentration of actin and myosin was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. There were no differences in the concentrations of either protein between the cholesterol-fed and control animals. Our results indicate that the decreased contractile response seen in muscle from cholesterol-fed animals is not due to alterations in membrane excitation, excitation-contraction coupling, or in total contractile proteins.

Endotoxins play an important role in the pathogenesis of complications of surgery in obstructive jaundice. Preoperative treatment with orally administered deoxycholic acid prevented endotoxin-related complications, such as renal malfunction. Other bile acids, however, were less effective, and the mechanism of action is not known. Endotoxin toxicity is considered to be largely mediated by tumor necrosis factor/cachectin, a cytokine release by mononucler phagocytes. Therefore, we studied the influence of different bile acids on endotoxin-induced tumor necrosis factor production by monocytes in vitro. Bile acids inhibit tumor necrosis factor production through a direct inhibitory effect on the monocytes. Deoxycholic acid was the most effective, chenodeoxycholic acid was less effective and ursodeoxycholic acid was ineffective in the concentrations used. Bile acids did not inactivate endotoxin as measured in a chromogenic Limulus amebocyte lysate assay. The therapeutic effect of bile acids in obstructive jaundice can be explained by an inhibition of endotoxin-induced tumor necrosis factor release by mononuclear phagocytes.

Myoelectric recordings of the opossum gastrointestinal tract were performed during continuous infusion of 16,16-dimethyl prostaglandin E2 at 0.1, 1, 2 and 5 micrograms/kg X h. Continuous administration of prostaglandin caused a dose-dependent reduction of the duration of the migrating myoelectric complex cycle and an increase in the velocity of phase III migration from the duodenum to the terminal ileum. The reduction of the migrating myoelectric complex cycle was due to a shortening of the duration of both phase I and II. Bolus administration of 16,16-dimethyl prostaglandin E2 caused intense spike activity for 2-4 min in all recording sites simultaneously. Administration of indomethacin did not change the myoelectric activity of the gastrointestinal tract. Infusion of prostaglandin E2 caused diarrhoea in eight of forty experiments. These changes in gastrointestinal motility may be important contributory factors in the pathogenesis of prostaglandin-induced diarrhoea.

The myoelectric activity of the sphincter of Oddi was studied both in the fasted and fed states and following administration of gastrointestinal hormones. Electromyographic recordings were obtained from 21 opossums in the fasted state and following administration of 20 Cal/kg of fat, protein, carbohydrate or isocaloric mixture of these three aliments. The proximal segment of the sphincter of Oddi generated spontaneous spike potentials that migrated to the distal segment of the sphincter. The frequency of spike potentials correlated with the migrating myoelectric complex in the duodenum. Following feeding, the migrating myoelectric complex was abolished and substituted by a fed pattern. The duration of the fed pattern and the frequency of spike potentials depended on the kind of aliment. Cholecystokinin and pentagastrin increased and glucagon and secretion decreased the frequency of spike potentials in the sphincter of Oddi. It is concluded from these studies that the sphincter of Oddi may play an important role in controlling the time and rate of biliary drainage into the duodenum.

Mortality following abdominal infection induced by cecal ligation and puncture was studied in rats with obstructive jaundice and after relief of the obstruction by preoperative internal or external biliary drainage. Four groups of adult Sprague-Dawley rats were used: common bile duct ligation (BDL), BDL followed by internal drainage after two weeks, BDL followed by external drainage after two weeks, and sham operation. The serum bilirubin concentration was significantly increased in the BDL group and returned to normal following internal and external drainage. Mortality in the sham group was 16.5% and increased to 83.3% following BDL, but it decreased significantly (25%) to near-normal values after preoperative internal drainage. However, after external drainage no significant reduction in mortality (63%) was found. These findings confirm the poor results of preoperative external drainage in previous studies and establish the efficacy of internal biliary drainage in a well-controlled experimental model that has to be evaluated in the clinical situation.

We have evaluated the effect of various autonomic drugs on the electromyographic activity of the sphincter of Oddi and the small intestine of seven opossums. Hexamethonium bromide and atropine sulfate abolished and bethanechol increased the frequency of spike bursts in the sphincter of Oddi and duodenum. Phenylephrine and epinephrine increased the number of spike bursts in the sphincter of Oddi after a short period of stimulation. No spike potentials were seen in the duodenum after infusion of norepinephrine. Clonidine and dobutamine decreased spike burst activity in the sphincter of Oddi and duodenum. Terbutaline also decreased the frequency of spike bursts in the sphincter of Oddi but did not change the number in the duodenum. Prior infusion of antagonists blocked partially or totally the effect of all respective agonists except for yohimbine, which did not inhibit the effect of clonidine. These findings suggest that the sphincter of Oddi may have cholinergic, alpha 1, alpha 1, beta 1 and beta 2-adrenergic receptors. Cholinergic agonists stimulate and alpha 2, beta 1 and beta 2-adrenergic agonists inhibit the motility of the sphincter of Oddi and the small intestine. Alpha-adrenergic agonists stimulate the motility of the sphincter of Oddi and inhibit the motility of the small intestine.

Patients with proximal stomas or high fistulas and defunctionalized intestine who are receiving total parenteral nutrition (TPN) often develop hepatic enzyme abnormalities and hyperbilirubinemia. A technique was developed to collect intestinal secretions from proximal stoma and to reinfuse these secretions into the distal part of the intestine. This technique was applied in eight patients with a disrupted intestinal tract. A significant decrease (p less than 0.05) in elevated serum bilirubin, alkaline phosphatase and gamma-glutamyl transpeptidase levels was observed. Alanine aminotransferase and aspartate aminotransferase levels did not change significantly. The plasma sodium levels, slightly subnormal before reinfusion (131.0 +/- 4.6 millimolar per liter), despite enormous supplementation, normalized during reinfusion (137.0 +/- 4.0 millimolar per liter). TPN was continued during this infusion. This suggests that TPN by itself does not cause intrahepatic cholestasis. Neither could it be explained by an effect of secondary bile acids because these were most likely not produced as bile did not reach the distal defunctionalized intestine. Three possible mechanisms are suggested. Restoration of passage in the distal intestine may diminish bacterial overgrowth, endotoxin production and absorption. Enlargement of the bile acid pool may diminish the susceptibility of the liver to the deleterious effects of endotoxins. We advocate this reinfusion technique to overcome the metabolic disturbances occurring in those patients with high-output stomas or fistulas arising from the proximal parts of the small intestine.

The purpose of our study was to evaluate changes in gallbladder contractility and mucus secretion in vitro during the early stages of gallstone formation in prairie dogs. Thirty-two animals were divided into five groups. Control animals were fed a trace cholesterol diet. Experimental animals were fed a high-cholesterol diet for 3, 6, 8, and 14 days, respectively. Muscle stress was measured in response to cholecystokinin octapeptide in each of the groups. The maximal stresses in the 8-day diet (68 +/- 7 gm/cm2) (mean +/- SEM) and 14-day diet animals (83 +/- 7 gm/cm2) were found to be significantly lower than those of the control animals (137 +/- 12 gm/cm2). The stress in 3-day diet animals was significantly greater (224 +/- 23 gm/cm2). A significant increase in mucus secretion was observed only in 14-day diet animals (11.0 +/- 0.5 X 10(6) dpm/gm dry wt) compared with the control animals (6.4 +/- 1.0 X 10(6) dpm/gm). The decrease in contractility may be the initial event in cholesterol stone formation, and the prolonged exposure of the gallbladder epithelium to crystals may stimulate the release of mucus into the bile.