Effects of three months of low molecular weight heparin (dalteparin) treatment after bypass surgery for lower limb ischemia--a randomised placebo-controlled double blind multicentre trial.

OBJECTIVES: To test the hypothesis that long-term postoperative dalteparin (Fragmin), Pharmacia Corp) treatment improves primary patency of peripheral arterial bypass grafts (PABG) in lower limb ischemia patients on acetylsalicylic acid (ASA) treatment. DESIGN: Prospective randomised double blind multicenter study. MATERIALS AND METHODS: Using a computer algorithm 284 patients with lower limb ischemia, most with pre-operative ischemic ulceration or partial gangrene, from 12 hospitals were randomised, after PABG, to 5000 IU dalteparin or placebo injections once daily for 3 months. All patients received 75 mg of ASA daily for 12 months. Graft patency was assessed at 1, 3 and 12 months. RESULTS: At 1 year, 42 patients had died or were lost to follow-up. Compliance with the injection schedule was 80%. Primary patency rate, in the dalteparin versus the control group, respectively, was 83 versus 80% (n.s.) at 3 months and 59% for both groups at 12 months. Major complication rates and cardiovascular morbidity were not different between the two groups. CONCLUSIONS: In patients on ASA treatment, long-term postoperative dalteparin treatment did not improve patency after peripheral artery bypass grafting. Therefore, low molecular weight heparin treatment cannot be recommended for routine use after bypass surgery for critical lower limb ischemia.

Effect of short-term indomethacin treatment on the clinical course of acute obstructive cholecystitis.

In acute obstructive cholecystitis the increased intraluminal pressure in the gallbladder is reduced by nonsteroid anti-inflammatory drugs which effectively relieve biliary pain. To investigate if such drugs influence the clinical course, a double-blind study was performed in which indomethacin (suppositories 75 mg b.d.) was tested against placebo in 34 patients with acute obstructive cholecystitis. During the 3-day treatment period both the indomethacin and the placebo group improved significantly as regards pyrexia, pain, abdominal tenderness and leukocytosis. The indomethacin group showed significantly greater improvement than the placebo group in temperature, pain and white blood cell count on day 1, and significantly greater reduction of abdominal tenderness on day 2. The serum bilirubin fell significantly during the 3-day period in the indomethacin, but not the placebo group. The hospital stay in cases without early surgery was significantly shorter in the indomethacin group (5.4 vs. 8.5 days). Because of its favourable effect on the clinical course of acute cholecystitis, rectally administered indomethacin is useful for patients awaiting operation or scheduled for later elective surgery.

Effects of intraluminal prostaglandin E2 in vivo on secretory behavior and ultrastructural changes in mouse gallbladder epithelium.

It has been suggested that glycoproteins play an important role as a nucleating agent in the pathogenesis of gallstone formation. Arachidonic acid, by an indomethacin-sensitive mechanism, is known to enhance gallbladder mucus release, suggesting that prostaglandins may regulate gallbladder epithelial release of mucus. In this study, the glycoprotein granules of the principal cells of the mouse gallbladder epithelium were morphometrically analyzed using electron microscopy. It was shown that 5 micrograms of prostaglandin E2, injected into the gallbladder lumen of the anesthetized mouse, reduced the relative volume of glycoprotein granules from 3.0% to 0.7% of the cytoplasmic volume within 20 min, whereas injection of the same amount of the solvent for prostaglandin E2 had no such effect.

Fluid secretion by gallbladder mucosa in experimental cholecystitis is influenced by intramural nerves.

The normal fluid absorption across the gallbladder mucosa is, in experimental cholecystitis, changed to an active net fluid secretion. This fluid secretion, studied in anesthetized cats, is not abolished by extrinsic gallbladder denervation and is unaffected by atropine but is strongly reduced by intraarterial tetrodotoxin or intraluminal administration of lidocaine hydrochloride. Intravenous somatostatin or hexamethonium administration also reduce this secretion. Indomethacin, known to abolish this fluid secretion, did not further reduce it when administered after nerve blocking agents in the present study. These data demonstrate that the prostaglandin-induced gallbladder fluid secretion in experimental cholecystitis is influenced by intramural nerves. It is suggested that gallbladder inflammation is associated with prostaglandin-induced activation of intrinsic nerves which may stimulate the epithelial cells to fluid secretion. In the obstructed gallbladder, this secretion causes gallbladder distension by increasing the intraluminal pressure. This mechanism may have a key role in the pathophysiology of acute cholecystitis.

Pathophysiology of acute obstructive cholecystitis: implications for non-operative management.

Recent research suggests that disturbances in gallbladder mucosal functions are important in the initiation of acute cholecystitis and its progression. Prostaglandins have pathophysiological significance and prostaglandin synthesis inhibitors such as indomethacin inhibit fluid secretion by gallbladder mucosa, reduce distension and relieve pain. Nerves in the gallbladder wall are involved in disturbed mucosal function, and the benefits of opiates may derive from reduction of active fluid secretion in the inflamed and obstructed gallbladder as well as from central analgesic effects.

Reflex regulation of flow resistance in the feline sphincter of Oddi by hydrostatic pressure in the biliary tract.

Despite wide variations in bile secretion and biliary tract capacitance, the pressure in the bile ducts is fairly constant. Recent studies have demonstrated that both inhibitory and excitatory nerves regulate the activity of the sphincter of Oddi. In the present study, it was consistently found that the resistance by the choledochoduodenal junction to a constant flow, within the physiologic range of hepatic bile output, is reduced when the hydrostatic pressure in the gallbladder and bile ducts is increased from 0 to 10, 0 to 15, and 0 to 20 cmH2O. This response was eliminated by tetrodotoxin or infiltration of the junction between the common bile duct and the cystic duct by mepivacaine, a local anesthetic. The results suggest a homeostatic mechanism during the interprandial periods, when the activity of the sphincter of Oddi is regulated by the distending pressure in the biliary tract. This reflex regulation is mediated by modulation of the activity of inhibitory nerves running along the common bile duct.

Prostaglandin E2 formation by the gall bladder in experimental cholecystitis.

Both experimental cholecystitis and luminal distension inhibit fluid absorption and stimulate motor activity in the gall bladder. These functional alterations are mimicked by exogenous prostaglandins (PGs) and inhibited by potent cyclooxygenase inhibitors, but direct evidence of a primary role of endogenous PGs is not available. Therefore, experiments in the cat were carried out in which the effects of lyso-phosphatidylcholine (lysoPC; 0.5-2.0 mmol/l), implantation of cholesterol stones, and raised intraluminal pressure in the gall bladder lumen were assessed. The gall bladder was perfused in vivo at a constant rate by a buffer solution. PGE2 was determined in the effluent by a radioimmunological method validated by gas chromatography-mass spectrometry. PGE2 output was markedly (p less than 0.01) raised (13.9 +/- 2.6 vs 1.1 +/- 0.5 ng/h; n = 10) during lysoPC perfusions and this response was inhibited by 66% (p less than 0.02) after indomethacin administration (2 mg/kg iv). A significant (p less than 0.05) increase in PGE2 output occurred six weeks after implantation of gall stones (3.7 +/- 1.5 ng/h; n = 6) and in response to distension of the normal gall bladder wall (3.6 +/- 1.2 ng/h; n = 6). These findings support the theory that PGs play an important pathophysiologic role in biliary tract disease.

Cholecystokinin secretion after oral Emtobil, a gallbladder-contracting formula.

Oral Emtobil, a liquid preparation of sorbitol and peanut oil, has been used in roentgenological practice for several years. Emptying of an opacified gallbladder is seen within 15 min after intake of 100 ml of this solution. The main physiological factor responsible for contraction of the gallbladder is cholecystokinin (CCK). In the present study plasma concentrations of CCK in fasting, healthy subjects were studied in response to oral Emtobil. The radioimmunoassay used measures sulphated CCK-8 and CCK-33 with equimolar potency. Neither non-sulphated CCK nor any gastrins are measured. The average concentration, after an overnight fast in nine healthy subjects without gallstones, was 1.2 pmol/l. A peak concentration was seen within 30 min after 'the test meal' and averaged 8 pmol/l. It is suggested that oral Emtobil contracts the gallbladder by release of CCK. Since Emtobil induces a fast and marked rise in the plasma concentration of CCK, it may be used in test procedures to estimate the secretion of CCK.

The effects of morphine and enkephaline on gallbladder function in experimental cholecystitis. Inhibition of inflammatory gallbladder secretion.

Administration of morphine or its derivatives is the traditional way to treat biliary pain. Despite the common use of morphine and its analogues in patients with cholecystitis and biliary pain, their effects on the function of the inflamed gallbladder are not known. In the present study it is demonstrated that morphine usually contracts the normal gallbladder but does not influence the fluid transport across the mucosa. In experimental cholecystitis morphine and enkephaline do not further contract the gallbladder but, by specific opioid receptors, reduce the inflammatory fluid secretion by the mucosa. In case of obstruction of the gallbladder, fluid secretion by the mucosa will distend its wall and induce biliary pain. It is suggested that the pain-relieving effect of morphine in cholecystitis and attacks of biliary pain is mediated not only by a central analgesic effect but also by an influence on the function of the inflamed gallbladder.

Indomethacin reduces raised intraluminal gallbladder pressure in acute cholecystitis.

Indomethacin was recently shown to have a potent analgesic effect on biliary pain. The underlying mechanism is not fully clear, although reduction of increased gallbladder pressure by inhibition of prostaglandin synthesis had been suggested. For further clarification of this mechanism, the effect of intravenous indomethacin on the intraluminal gallbladder pressure was investigated in patients undergoing operation for acute cholecystitis. After laparotomy, gallbladder pressure was measured continuously during 25 min in 20 patients, 10 of whom received 100 mg indomethacin intravenously, while 10 were untreated controls. High intraluminal gallbladder pressure was found in all patients. Indomethacin reduced the average pressure by 11% in 20 min, whereas the corresponding pressure in the controls was constant. The results indicate that acute cholecystitis is associated with substantially raised intraluminal pressure, and that the analgesic action of indomethacin on biliary pain may be attributable to a local effect on gallbladder function, resulting in reduction of intraluminal pressure.

The effect of lysophosphatidylcholine on gallbladder function in the cat.

The effects of lysoPC on gallbladder net fluid transport and motility were investigated by a perfusion technique in the anesthetized cat. It was found that addition of 1 mumol/ml lysoPC to the buffer perfusate resulted in an immediate contraction of the gallbladder and also a change in net fluid transport from a basal absorption of 0.71 ml/hr to a secretion of 0.34 ml/hr. An increased output of hexosamine and protein from the gallbladder accompanied the lysoPC treatment. Indomethacin--a prostaglandin synthetase inhibitor--at a dose of 2 mg/kg caused a relaxation of the gallbladder and abolished the secretion but did not return the gallbladder to its original rate of basal absorption. LysoPC, when added to bile, had a similar effect on net fluid transport but did not induce a contraction of the gallbladder. The results indicate that the effect of lysoPC on gallbladder function could be of importance in acute cholecystitis and that endogenous prostaglandin synthesis may play a part in this lysoPC-induced inflammatory response.