Biomedical subjects

M Siebeck

Publications and source records attributed to M Siebeck.

At least 37 records · Page 2Linked to original sources

PubMed1997

Delayed treatment with desulfato-hirudin prevents fibrin formation in lipopolysaccharide-induced shock.

Previous work has shown that pre-treatment with the thrombin inhibitor recombinant desulfato-hirudin prevented fibrin formation and respiratory dysfunction in porcine lipopolysaccharide shock. We examined the effects of delayed administration of recombinant desulfato-hirudin in bacterial lipopolysaccharide shock. Miniature pigs were studied under anaesthesia and ventilation, and received a bacterial lipopolysaccharide infusion (2 microg/kg/h) for 7 h; recombinant desulfato-hirudin was started 1 h after bacterial lipopolysaccharide in 10 animals (bolus 12.9 nmol/kg; continuous infusion 6.5 nmol/ kg/h); 10 randomised control animals received saline instead of recombinant desulfato-hirudin. Fibrin and thrombin-antithrombin complex levels in plasma were significantly lower in bacterial lipopolysaccharide+recombinant desulfato-hirudin animals than in controls. Both groups displayed a similar rise in pulmonary vascular resistance and other parameters of lung dysfunction; only lung tissue wet/dry ratio was lower in recombinant desulfato-hirudin-treated than in control animals. Both groups had similar circulatory alterations. Recombinant desulfato-hirudin interrupted coagulation activation during ongoing bacterial lipopolysaccharide-induced shock in pigs even when administered with a delay of one hour after start of the bacterial lipopolysaccharide infusion. A protective effect of delayed recombinant desulfato-hirudin administration on bacterial lipopolysaccharide-induced acute lung injury and alterations in the systemic circulation could not be demonstrated in this experiment.

Animals↗

PubMed1997

Tachyphylaxis of the B1 kinin receptor in porcine endotoxin shock.

Previous experiments in anesthetized pigs have demonstrated that blockade of the bradykinin B2 receptor in experimental endotoxin shock attenuates LPS-induced organ failure, lung dysfunction and mortality. Additional B1 receptor blockade in this situation seems to counteract the beneficial effects of B2 blockade. This suggests that the upregulation of B1 receptors during porcine LPS shock may be a useful mechanism of host defense. Furthermore, infusion of a B1 agonist during septic shock may be of therapeutic benefit. In order to prepare an experiment with B1 stimulation in LPS shock, we conducted a study in anesthetized pigs, in which the B1 receptor has been upregulated by infusion of bacterial lipopolysaccharide (LPS), by evaluating the effect of constant intravenous infusions of the B1 agonist des-Arg10-kallidin on the hypotensive response to bolus doses of this agonist. Following infusions of lipopolysaccharide from S. abortus equi, anesthetised pigs received repeated intra-arterial bolus injections of des-Arg10-kallidin before and during continuous infusions of this agonist in doses of 3, 10, 30 and 100 ng/kg/min. We found that all doses greater than 3 ng/kg/min produced attenuation of the hypotensive response produced by bolus administration of the B1 agonist des-Arg10-kallidin. We conclude that tachyphylaxis is an important feature to be considered in experiments with continuous administration of a B1 agonist in LPS shock.

Animals↗

PubMed1997

[Perioperative standards for prevention of anastomotic insufficiency].

Anastomotic leakage is a major cause of morbidity and mortality in gastrointestinal surgery. Its incidence varies in the different segments of the GI tract being highest in the distal rectum. The rate of anastomotic leakages was reduced considerably within the last 20 years. Perioperative measures have contributed to this reduction in addition to improvements and standardization in operative technique. Perioperative nutrition, perioperative antibiotic prophylaxis and mechanical bowel preparation are widely used in colorectal surgery. Therefore they can be considered as standards. High-caloric parenteral feeding is used commonly perioperative. Its efficiency to reduce postoperative septic complications has been proven until now only for malnourished patients. The aim of perioperative antibiotic prophylaxis is to reduce the bacterial count after intraoperative contamination. Therefore tissue levels must be in the therapeutic range to cover for the expected bacteria. The efficiency to reduce postoperative wound infection has been proven, however the influence on the rate of anastomotic leakages is still controversial. Mechanical bowel preparation can reduce the bowel load but not bacterial concentration inside the bowel. Orthograde lavage with polyethylenglycol solution is feasible unless bowel obstruction is present, but its influence on anastomotic healing is still under discussion. Although all of these procedures are widely used, their influence on anastomotic healing has still to be proven by prospective, controlled trials.

Anastomosis, Surgical↗

PubMed1997

[Patient-oriented, risk-adapted tumor aftercare in patients with colorectal carcinoma].

Follow-up programs in patients with colorectal cancer have been criticized concerning their efficacy. Uniform programs for all patients as practised during the last decade did neither influence survival nor did they improve the number of secondary tumor resection for cure. Therefore we developed a follow-up program that considers patient's healthiness, status of resection in primary operative therapy and the risk of tumor recurrence depending on postoperative tumor staging. Because of these considerations we divided patients into three groups: Patients with low risk, high risk and patients treated with palliative aspects. Thus costs of follow-up programs could be reduced to more than 50%.

Aftercare↗

PubMed1996

Autoradiographic visualization of B1 bradykinin receptors in porcine vascular tissues in the presence or absence of inflammation.

B1 bradykinin receptors were visualized by using the B1 bradykinin receptor agonist [3H]des-Arg10-kallidin in receptor autoradiography experiments. Cryosections were prepared from arterial vessels from a healthy control pig, a pig with pre-existing inflammation and an animal with experimental sepsis induced by an infusion of bacterial lipopolysaccharide (LPS). Only diffusely scattered silver grains with no preference for a distinct tissue structure were detected on emulsion-coated coverslips above the cryosections from the healthy control animal. This indicates that under normal circumstances no or only minute amounts of B1 bradykinin receptors are present in these tissues. In contrast, a 3-fold increase in specific B1 bradykinin receptor binding was observed on both the corresponding preparations of the sick piglet and of that with experimentally induced sepsis. A similar enhancement of specific [3H]des-Arg10-kallidin binding occurred in preparations devoid of endothelium. By comparison with the stained cryosection on the slide the silver grains showed a preferential distribution above smooth muscle cells. Taken together our data are consistent with the hypothesis that B1 bradykinin receptors are induced in the muscle layer of large vessels not only after experimentally-induced sepsis but also in pre-existing inflammatory disease.

Animals↗

PubMed1996

Effect of combined B1 and B2 kinin receptor blockade in porcine endotoxin shock.

In order to investigate the contribution of kinin receptor antagonism in the treatment of LPS-induced shock we conducted a randomized study with anaesthetized piglets. Before randomization the animals were stratified according to predetermined health criteria under baseline conditions. One group of control animals received LPS from S. abortus equi (2 micrograms/kg/h i.v. for 8 h) and saline (Group 1). Another group received LPS and the B2 antagonist CP-0127 (3 micrograms/kg/min), beginning 1 h after LPS (Group 2). Group 3 received LPS and the B2 antagonist in the aforementioned doses, and the B1 antagonist Leu9-des-Arg10-kallidin (3 micrograms/kg/min), also beginning 1 h after LPS. Overall survival figures after 8 h of LPS infusion were: Group 1, 10/22 (45%); Group 2, 10/17 (59%); Group 3, 10/28 (36%). Fifty percent (29/58) of animals that were healthy at baseline survived, but only 11% (1/9) of sick animals survived (Log Rank p = 0.0001). In the subset of healthy animals, survival rates for Groups 2 and 3 were 77% and 38%, respectively (p = 0.0519). It appears, therefore, that B2 blockade attenuates LPS-induced mortality whereas additional B1 blockade seems to reverse these beneficial effects. This suggests that in this animal model the B1 receptor does not serve the same purpose as the B2 receptor, and that up-regulation of B1 receptors during LPS shock may be an important mechanism of host defence.

Animals↗

PubMed1996

[Endosonography of tumors of the upper gastrointestinal tract: is routine use justified?].

Major indications of endoscopic ultrasound (EUS) are staging of carcinomas of the oesophagus, stomach, and pancreas, lymphomas of the stomach and the diagnosis of submucosal tumors. Based on a meta-analysis, the accuracy of EUS is 84% in the T-stage of oesophagus carcinoma (1154 patients) and 77% (1035) in the N-stage, and of stomach carcinoma 80% (2699) and 70% (1207), respectively. Drawbacks of EUS: tumor stenosis which cannot be passed by the endoscope; the inability to distinguish between benign and malignant stomach ulcera and the diagnosis of lymph nodes.

Endosonography↗

PubMed1995

Prevention of experimental endotoxin shock by a monocyte activator.

In patients with polytrauma or major surgery, severe bacterial infections leading to septic shock and multiorgan failure are still a major cause of death. Prevention of septic shock in patients at risk would be an alternative to treatment of patients with overt septic shock. We therefore conducted a trial with the monocyte activator muramyl tripeptide phosphatidylethanolamine (MTP-PE) in an experimental pig model. Liposome encapsulated MTP-PE (50 micrograms/kg of body weight) or liposomes alone were given intravenously at 72 or 24 h before endotoxemia was induced by lipopolysaccharide (LPS), simultaneously with the induction of endotoxin shock, or 1 h thereafter. Pretreatment with MTP-PE at 72 and 24 h before endotoxemia was induced resulted in a reduction of endotoxin shock-induced mortality from 81.8% (9 of 11 animals) in the control group to 8.3% (1 of 12 animals) of the MTP-PE-pretreated animals (P < 0.001). The administration of MTP-PE 24 h before the induction of endotoxin shock was more effective (P < 0.01) than administration of MTP-PE 72 h before endotoxemia was induced (P = 0.05). The pretreated animals did not develop fever or cardiovascular complications, and pulmonary function was significantly improved. Furthermore, the alpha-form of the soluble CD14 LPS receptor in pig serum showed a marked decrease in LPS-treated animals, and this decrease was reduced by MTP-PE pretreatment at 24 h before endotoxemia was induced. When MTP-PE was given simultaneously with the induction of septic shock or 1 h thereafter, it did not influence either mortality or morbidity. In conclusion, pretreatment of pigs with MTP-PE improves several parameters of endotoxin shock and it reduces mortality. Patients with high risk of developing septic complications might benefit from a pretreatment with this monocyte-activating substance.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1995

The effect of thoracic surgery on pulmonary function.

BACKGROUND: Pulmonary function is a main factor influencing postoperative morbidity and mortality in thoracic surgery. OBJECTIVE: To determine the significance of surgical trauma on postoperative pulmonary function by comparing the preoperative forced expiratory volume in 1 second with that obtained 14 days after surgery. METHODS: A retrospective study was conducted on 385 consecutive patients undergoing elective thoracic surgery over 3 years. RESULTS: Operative trauma alone effected a reduction of approximately 0.6 L per second in the value of forced expiratory volume in 1 second irrespective of the extent of pulmonary resection. Significant differences in the overall reduction among enucleation, segmental resection, lobectomy, and pneumonectomy were not observed. CONCLUSIONS: The data indicated that the remaining lung tissue was severely compromised throughout the postoperative period and that surgical trauma was the main factor influencing postoperative pulmonary function for at least 2 weeks.

Aged↗

PubMed1994

Delayed treatment with platelet activating factor receptor antagonist web 2086 attenuates pulmonary dysfunction in porcine endotoxin shock.

The triazolodiazepine WEB 2086, a specific platelet activating factor (PAF) receptor antagonist, has previously been shown to prevent pulmonary hypertension, hypoxia, and bronchoconstriction when given before bacterial lipopolysaccharide (LPS). The aim of the present study was to examine whether WEB 2086 reduced these changes even when given after the onset of LPS-induced shock. In a randomized trial LPS was given intravenously (i.v.) in a dose of 1 microgram/kg/h for 8 hours to anesthetized, ventilated pigs. Ten animals received LPS and WEB 2086, 10 mg/kg/h i.v. for 6.5 hours, beginning 1.5 hours after LPS. Ten control animals received LPS and saline. During treatment with WEB 2086, pulmonary hypertension was significantly attenuated compared with the findings in the control group. Gas exchange, airway pressure, extravascular lung water levels, intrapulmonary shunt, and cathepsin B levels in plasma showed a trend toward improvement but the group differences were not statistically significant. These data indicate that the PAF antagonist WEB 2086 can partially block pulmonary dysfunction and enzyme release from inflammatory cells when given during ongoing LPS shock in pigs, and that PAF may be an important mediator of the cardiopulmonary changes seen in septic shock.

Animals↗

PubMed1994

Dextran sulfate activates contact system and mediates arterial hypotension via B2 kinin receptors.

To define some of the mechanisms underlying dextran sulfate (DXS)-induced hypotension, we investigated the effects of either the plasma kallikrein inhibitor des-Pro2-[Arg15] aprotinin (BAY x 4620) or the specific bradykinin B2-receptor antagonist Hoe-140 on the hypotensive response to DXS. In the first study, anesthetized miniature pigs were given DXS alone, DXS plus BAY x 4620 in various doses, or saline. As expected, DXS alone produced a profound but transient systemic arterial hypotension with a concomitant reduction in kininogen. Circulating kinin levels, complement fragment des-Arg-C3a, and fibrin monomer were all increased. Treatment with BAY x 4620 produced a dose-dependent attenuation of these effects with complete blockade of the hypotension as well as the observed biochemical changes at the highest dose (360 mg). In a second study, two groups of pigs were given either DXS alone or DXS plus Hoe-140. DXS-induced hypotension was completely blocked by Hoe-140 pretreatment; however, kininogen was again depleted. We conclude, therefore, that DXS-induced hypotension is produced by activation of plasma kallikrein that results in the production of bradykinin and that liberation of bradykinin and its action on B2 receptors in the vasculature are both necessary and sufficient to produce the observed effects on circulatory pressure.

Animals↗

PubMed1993

Biologic effects of recombinant hirudin (CGP 39393) in human volunteers. European Hirudin in Thrombosis Group.

OBJECTIVES: The purpose of this study was to investigate the biologic efficacy and pharmacokinetics of different doses of recombinant hirudin administered in single or repeated subcutaneous injections in healthy volunteers. BACKGROUND: Hirudin is a highly specific inhibitor of thrombin, the pivotal enzyme in thrombosis. Differences between hirudin and heparin in experimental animals indicate that hirudin may be a superior antithrombotic drug in humans. METHODS: The biologic effect of recombinant desulfato-hirudin (CGP 39393) administered as single or repeated (every 8 h for 3 days or every 12 h for 6 days) subcutaneous injections was studied in 231 healthy human volunteers. RESULTS: Single subcutaneous doses of 0.1, 0.2, 0.3, 0.4, 0.5 and 0.75 mg/kg body weight in 195, 8, 12, 8, 4 and 4 volunteers, respectively, prolonged the activated partial thromboplastin time in a dose-proportional fashion within the 1st 30 min, with a near-maximal effect for 3 to 4 h after the dose. The mean activated partial thromboplastin time increased to 1.48 and 1.93 times baseline values 30 min after single subcutaneous injections of 0.2 and 0.4 mg/kg of CGP 39393, respectively. There was a linear relation over a wide range between the activated partial thromboplastin time prolongation and plasma concentrations of CGP 39393. Plasma clearance was between 1.5 and 1.7 ml/min per kg. The subcutaneous administration of 0.3 and 0.5 mg recombinant hirudin three times a day for 3 days or two times a day for 6 days prolonged the activated partial thromboplastin time by 1.71 to 1.69 and 1.78 to 1.92 times baseline levels, respectively, with the preinjection values maintained in the hypocoagulable range. No prolongation of bleeding time was measured at peak plasma hirudin levels. Because thrombin and prothrombin times are not able to reflect high or low CGP 39393 concentrations, respectively, neither test is suitable for monitoring administration of this drug. CONCLUSIONS: CGP 39393 appears to be well tolerated in volunteers, even after repeated doses. The activated partial thromboplastin time test seems to be well suited to monitor the anticoagulant effect of recombinant hirudin because the dose effect is linear up to 0.5 mg/kg of subcutaneous CGP 39393. The prolongation of activated partial thromboplastin time after subcutaneous injection of CGP 39393 shows a plateau lasting for 3 h. Further studies are now required to determine the dose that will provide the best antithrombotic effect and the lowest bleeding tendency in arterial or venous thrombosis indications.

Biological Availability↗

PubMed1993

Inhibition of plasma kallikrein with aprotinin in porcine endotoxin shock.

Activation of the contact phase of coagulation has been implicated in the pathogenesis of septic shock. We wanted to determine if inhibition of plasma kallikrein can prevent arterial hypotension and liberation of kinins from kininogen, induced by an infusion of bacterial lipopolysaccharide (LPS) in anesthetized, ventilated 20-kg pigs. The LPS was given IV in a dose of 5 micrograms/kg/h for 8 hours. The plasma kallikrein inhibitor aprotinin, 537 mumol, was given IV during 8 hours, resulting in plasma levels above 10 mumol/L. Ten animals (SA) received LPS and aprotinin and ten randomized controls (SC) received LPS and saline. Kinin-containing kininogen was determined on the basis of the amount of kinin releasable in plasma samples by incubation with trypsin. Kininogen decreased to 58% +/- 4% of the baseline value without any difference between groups. This may indicate participation of other processes than degradation by plasma kallikrein in the decrease of kininogen. Arterial blood pressure was higher at 7 hours in the SA animals than in the SC group (101% +/- 11% vs. 68% +/- 8%; mean +/- SEM; p = 0.026). Fibrin monomer and C3adesArg plasma levels were attenuated by aprotinin treatment. These findings underscore the important role of the contact system in LPS shock.

Animals↗

PubMed1993

[Does laparoscopic appendectomy have advantages? Laparoscopic appendectomy in comparison with conventional appendectomy--an observational study during introduction of laparoscopy].

From October 1990 to October 1992 the first 23 laparoscopically operated patients were recorded. 11 patients retrospectively including a supplementary questioning to missing data, 12 patients prospectively with a follow-up 6-8 weeks later. They were compared with 35 from April 1991 to April 1992 conventionally operated and prospectively observed patients. Laparoscopy was performed on patients with subacute clinical signs. The median age was comparable. Acute appendicitis was histologically confirmed in 18% of the laparoscopically and in 80% of the conventionally operated patients. Operating time was in mean 110 minutes for laparoscopic and 65 minutes for open appendectomy. The postoperative complications for laparoscopy included 4 Douglas abscesses (2 x open and 2 x pararectal revisions), one peritonitis due to a defect Roeder-loop and an haematoma of the abdominal wall. One case of wound infection (3%), one pericoecal abscess which needed an ileoascendostomy and a postoperative fatigue syndrome were recorded for open appendectomy. The postoperative return to normal diet was faster for laparoscopy. Return to normal bowel habits, the need of analgesia and the nominal analogue scales concerning pain, quality of sleep, well-being and appetite showed no obvious differences between the two operation methods. The postoperative stay was on average 6.7 days for laparoscopy and 5.6 days for the open operation. The results show the severe complications which may happen when introducing this new operation method. The laparoscopic appendectomy should only be performed electively in subacute appendicitis or when diagnostic exploration shows an inflamed appendix. Careful rinsing of the operation site and perioperative antibiotic treatment are mandatory. We made good experiences when using a stapler for the removal of the appendix.

Adolescent↗

PubMed1993

Sensitive detection of the activation state of blood coagulation in porcine DIC models by a new fibrin immunoassay.

Elevated levels of soluble fibrin in plasma indicate that thrombin converts fibrinogen to fibrin without sufficient inhibitory control. Therefore, measurement of soluble fibrin (SF) in plasma may be considered as a laboratory test for intravascular coagulation. We have demonstrated that a new immunoassay for detection of SF in human plasma (Lill et al., Blood Coag Fibrinol 1993; 4: 97-102), based on a fibrin specific monoclonal antibody, also detects porcine SF with high sensitivity. Thrombin-dependent generation of SF in porcine plasma in vitro resulted in increased reactivity of the assay system, which was time and dose dependent. Dextran sulphate (DXS) and bacterial lipopolysaccharide (LPS) were used as stimuli in in vivo experiments in pigs. Plasma levels of SF increased steadily after intravenous administration of DXS (5 mg/kg for 1 h) to 38 +/- 7.8 micrograms/ml (mean +/- SEM) at 2 h, whereas LPS (2 micrograms/kg/h for 6 h) markedly increased plasma SF levels to over 120 micrograms/ml (at 6 h) after a lag phase of 2 h. In conclusion, this new immunoassay for human fibrin allows specific and sensitive detection of soluble fibrin in porcine plasma.

Animals↗

PubMed1992

Establishment of a pneumococcal septicemia model in the miniature swine.

Human pneumococcal septicemia, the prominent postsplenectomy complication, was as yet difficult to study in the porcine model, since this species appeared to be fairly resistant against pneumococcal infections. We have used two strains of pneumococci (serotype 1 and 6B) both of which had been isolated from patients with systemic infection and both of which were maintained in a virulent state by regular mouse passage. After challenge with 10(9) type 1 pneumococci, however, only one of the 5 pigs developed fever, none showed profound hematological alterations and each animal exhibited a rapid clearance of bacteria from peripheral blood. By contrast, challenge of 7 animals with type 6B pneumococci resulted in a slower and incomplete bacterial clearance with persistent bacteremia for up to 24 hours. All animals developed fever and a profound leukopenia with less than 5,000 leukocytes/ml and 3 of the 7 animals died after injection of type 6B pneumococci. The results show that potentially the type 6B pneumococci can be successfully employed for studies of gram positive septicemia in the miniature swine.

Animals↗

PubMed1992

Effects of protease inhibitors in experimental septic shock.

Endotoxin shock and contact system activation were used to study effects of hirudin, antithrombin III, eglin C, aprotinin, and [Arg15]-aprotinin in anesthetized pigs. Alterations in the systemic and pulmonary circulation were in part prevented by administration of the inhibitors.

Animals↗

PubMed1992

Effect of the elastase inhibitor eglin C in porcine endotoxin shock.

We wanted to demonstrate that the neutrophil elastase inhibitor eglin C reduces the loss of intravascular protein in endotoxin (LPS) shock and that effective concentrations are present in lymph. We used 45 anesthetized miniature pigs in a randomized, controlled trial. LPS 10 micrograms/kg/hr was given for 6 hr. Recombinant eglin C was given before LPS (250 nmol/kg) and continuously at 250 nmol/kg/hr (n = 18); septic controls received saline (n = 18); nine nonseptic controls were used. Eglin C significantly reduced the loss of intravascular protein (plasma volume times plasma protein concentration) from -0.79 g/kg in septic controls to 0.42 g/kg in eglin C-treated animals and reduced plasma concentration of neutrophil elastase, bound to the leukocyte neutral protease inhibitor (LNPI), but systemic hypotension was unchanged. Six additional pigs were anesthetized, prepared with a thoracic lymph fistula, and received eglin C at 475 nmol/kg/hr; three received saline; three received LPS. Eglin C concentrations in lymph were comparable to those in plasma. We conclude that eglin C reduced the loss of intravascular protein during LPS shock and attained effective concentrations in lymph.

Animals↗