Biomedical subjects
Publications and source records attributed to K Werdan.
PNAB and IAB have totally different action on BCM. PNAB inhibit the contractile function of BCM by producing a reversible standstill and by disturbing the synchronization of the BCM-monolayer. IAB are cytotoxic and depend on the presence of complement.
For 'the total population of patients with sepsis, sepsis syndrome or SIRS', the question of whether intravenous immune globulin (IVIG) reduces mortality is neither proved nor disproved. For the sepsis subgroups 'postoperative sepsis with a sepsis score more than 19' and 'endotoxaemic, early septic shock', a significant reduction in mortality by IVIG has been documented in a single, placebo-controlled, small trial of each subgroup; subsequent studies are needed for confirmation. The incidence of some severe infections in defined 'patients at risk' and 'operations at risk' is lowered by IVIG prophylaxis. Postoperative APACHE II-score identification of high-risk cardiac surgery patients prone to sepsis and severe SIRS may represent one approach to optimize individual, early therapy. Applying this concept to immune globulin treatment in a pilot study, the administration of IgG-IVIG and IgGMA-IVIG yielded similar results.
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Six months after sustaining a posterior wall myocardial infarction a 40-year-old man had a further infarction in the anterior wall region. After thrombolysis treatment with recombinant tissue plasminogen activator the patient was at first symptom-free and haemodynamically stable, but 48 hours later another anterior wall re-infarction occurred with cardiogenic shock. Despite infusions of catecholamines at highest dosage and successful coronary angioplasty the circulation became critically unstable and percutaneously introduced intraaortic balloon counterpulsation (IABCP) was commenced. As the haemodynamics improved catecholamine dosage was markedly reduced and then discontinued over the subsequent 24-48 hours and inspiratory oxygen concentration of the ventilated patient was decreased from 100% to 40%. After a total of 5 days the IABCP catheter was removed without complication. The cardiac pump action showed further improvement in the following days. 6 months later the patient's condition was stable in grade II-III (New York Heart Association classification) heart failure. This case illustrates the place of IABPC as a highly effective treatment option in myocardial infarction with cardiogenic shock, especially when combined with interventional revascularisation procedures.
A 65-year-old woman with dermatomyositis for which she had been treated for ten years with prednisone (latterly 15 mg daily) suddenly experienced severe pain in the left thoracolumbar region. Cardiovascular, pulmonary and vertebral causes of the pain were excluded. But serological tests indicated inflammatory disease and the haemoglobin concentration was low (10.4 g/dl). Left pleural effusions were repeatedly aspirated and some haemorrhagic fluid obtained (haematocrit 0.31 in blood, 0.28 in the pleural effusion). Five days after admission her cardiovascular status became unstable and she developed respiratory failure (haemoglobin 7.6 g/dl). Chest radiograph showed increased pleural effusion. Subsequent thoracotomy revealed a left coagulothorax which was removed and flushed. During this procedure severe bleeding occurred from a covered perforation of the descending aorta, 1.5 x 1.5 cm in size. Although the aortic wall was thin, there was no aneurysm but arteriosclerotic changes and an external erosion near an abscessing mediastinitis, originating from a chronic purulent pleuritis and bronchopneumonia. The severe blood loss caused circulatory failure from which the patient could not be resuscitated.
Directional coronary atherectomy (DCA) has received increased attention, especially as a bail-out procedure after failed balloon angioplasty. However, this technique may also be burdened by severe pitfalls. We report a patient with a balloon-resistant left coronary artery lesion subsequently treated with DCA. Despite its over-the-wire guidance, as the rotating cutter was advanced, it deviated from its intra-housing course and intruded into the vascular wall. Dislocation of the rotating blade was due to pressure from hard plaque tissue. After having carefully pulled back the complete catheter system, a severe spasm of the left main stem occurred, which was reversed by intracoronary nitroglycerine. The final angiography showed a left coronary artery without significant, residual stenosis. The case report underscores that DCA passes must be performed under continuous fluoroscopic control, especially for balloon-resistant lesions because of the unpredictability of DCA-imminent complication.
Exposure of neonatal rat cardiomyocytes for 3 days to the muscarinic cholinoceptor agonist carbachol led to a concentration-dependent increase in adenylyl cyclase stimulation by the beta-adrenoceptor agonist isoproterenol by up to 115% (at 1 mmol/l carbachol). In addition, direct adenylyl cyclase stimulation by forskolin was increased in carbachol (1 mmol/l)-treated cells by 32%. Pretreatment of the rat cardiomyocytes with pertussis toxin, which enhances adenylyl cyclase activity by a functional inactivation of the inhibitory G-protein (Gi), was performed to investigate the possible role of Gi-proteins in carbachol-induced sensitization of adenylyl cyclase stimulation. After pretreatment of the cells with pertussis toxin, the carbachol-mediated increase in forskolin-stimulated adenylyl cyclase activity was lost and the carbachol-mediated increase in beta-adrenoceptor-stimulated adenylyl cyclase activity was attenuated. Labelling of the 40 kDa pertussis toxin substrates in cardiomyocyte membranes was decreased by carbachol in a concentration-dependent manner by up to 34% (at 1 mmol/l carbachol). The number and affinity of beta 1-adrenoceptors was unaltered following the chronic carbachol treatment. The specific protein synthesis inhibitor Pseudomonas exotoxin A was used to study whether the carbachol-induced decrease in the level of pertussis toxin-sensitive G-proteins and increase in adenylyl cyclase activity depend on de-novo protein synthesis. Pseudomonas exotoxin A inhibits peptide chain elongation by ADP-ribosylating elongation factor 2. Treatment of the cells with 1 ng/ml Pseudomonas exotoxin A for 3 days led to a reduction in the subsequent ADP-ribosylation of elongation factor 2 in the cytosol of the heart muscle cells by 57%.(ABSTRACT TRUNCATED AT 250 WORDS)
This study focuses on the role of platelet membrane glycoproteins and platelet-leucocyte adhesion in patients with sepsis and multiple organ failure (MOF). Specifically, the study raises the following issues: (1) the influence of sepsis and MOF on platelet activation as assessed by surface expression of platelet membrane glycoproteins GPIIb-IIIa and thrombospondin; and (2) the effect of sepsis and MOF on platelet adhesion to circulating leucocytes. In addition, platelet activation and platelet-leucocyte adhesion are evaluated according to clinical outcome. Forty-five patients with suspected sepsis or MOF were evaluated by intensive care scoring systems (APACHE II and Elebute) to assess severity of disease. Flow cytometric techniques were used to examine platelet membrane expression of various adhesion molecules on circulating platelets and the appearance of platelet specific antigen (CD41) on leucocytes as an index of platelet-leucocyte adhesion. The results were compared with severity of disease and according to outcome in patients. Twenty-eight patients of the total study population were septic and 17 were non-septic. Twenty-two of the 28 septic patients suffered from severe MOF (APACHE II > or = 20) whereas in six septic patients MOF was absent. Eleven of the non-septic group suffered from moderate MOF whereas in six, severe MOF was present. In septic patients fibrinogen receptor activity on platelets was significantly above normal values (P < 0.001). When MOF was present, thrombospondin surface expression on circulating platelets also increased significantly (P < 0.05). Concomitantly, platelet-leucocyte adhesion was increased in sepsis (P < 0.05) and decreased in patients with MOF (P < 0.05). Significant lower levels of circulating platelet-leucocyte aggregates occurred in non-survivors (P < 0.05). We conclude that sepsis is associated with increased surface expression of platelet adhesion molecules and an increased occurrence of circulating platelet-leucocyte aggregates. The decrease in circulating platelet-leucocyte peripheral sequestration. An increased platelet-leucocyte adhesion and sequestration might account for development of MOF in the course of sepsis.
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The effects of opioid peptides on immunoreactive endothelin (ir ET) release from cultured porcine aortic endothelial cells over a 1-hr period (4-5 or 23-24 hr) were determined by radioimmunoassay and high-performance liquid chromatography after treatment for either 4 or 23 hr. Endogenous opioids, the synthetic delta opioid [D-Pen2,5]enkephalin and, for comparison, atrial and brain natriuretic peptides were added to the culture medium in concentrations ranging from 10(-12) to 10(-7) M. Thrombin (0.1-10 U/ml) served as a stimulatory reference. 1) Brain natriuretic peptide displayed only insignificant effects on ir ET release at 5 hr, but strongly inhibited ir ET release at 24 hr. 2) Opioids modulated release rates at 5 hr but did not display significant effects at 24 hr: metorphamide with predominant mu/kappa and weak delta opioid receptor activity stimulated release in a dose-dependent manner, whereas [Met5]enkephalin-Arg6-Phe7 with mu/delta activity and the delta agonists [Leu5]enkephalin, sulfated [Leu5]enkephalin and [D-Pen2,5]enkephalin decreased release rates; [Leu5]enkephalin was the most potent of the latter drugs. 3) Coincubation with either the nonselective opioid receptor antagonist naloxone (10(-5) M) or the delta receptor-selective antagonist ICI-174,864 (N,N-bisallyl-Tyr-D-Ala-Aib-Aib-Phe-Leu-OH) (10(-5) M) abolished all opioid-induced inhibitory effects, but rather potentiated or unmasked stimulatory effects of opioid peptides on ir ET release rates at 5 hr and also at 24 hr in the case of the delta agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
The hyperacute rejection reaction of xenogeneic organs is supposed to be triggered by xenoreactive natural antibodies of the recipient organism. In an experimental set-up allowing for rapid medium exchange, primary cultures of spontaneously beating neonatal rat cardiomyocytes were challenged with dialyzed human serum containing xenoreactive natural antibodies. After adding the serum specimens, a reproducible pattern of disturbed contractility was observed: following an initial increase in beating frequency, spontaneous contractions stopped completely. This standstill was reversible in all experiments. No signs of permanent cytotoxicity were observed. The temporary cessation of contractions was prevented by raising extracellular calcium concentration, but not by extracellular electrical stimulation. After absorption of xenoreactive natural antibodies, cellular contractions ensued without interruption. Inactivated serum specimens produced similar effects on contractility, although the duration of the standstill period was significantly shorter. The same qualitative phenomenon occurred when sera of other xenogeneic species were used. These results point to a temporary functional disturbance of parenchymal cells by xenoreactive natural antibodies, whereas no chronic cytotoxicity was conspicuous in these experiments.
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Treatment of neonatal rat cardiomyocytes for 72 h in the presence of tumor necrosis factor alpha (TNF alpha) (10 U/ml) lead to a decrease in basal and alpha 1-adrenoceptor-induced formation of the calcium-mobilizing second messenger inositol trisphosphate (IP3) and its metabolites, IP2 and IP1, by 35 and 26%, respectively. The synthesis of phosphatidylinositol bisphosphate (PIP2), the substrate of PI-specific phospholipase C, was decreased by 45% following the TNF alpha (10 U/ml) exposure. Time courses of TNF alpha (10 U/ml)-induced alterations in rat cardiomyocytes showed a parallel decline of basal inositol phosphate formation and PIP2 synthesis suggesting that the decrease in inositol phosphate formation was due to the reduction in PIP2 synthesis. As the TNF alpha-induced decrease of PIP2 synthesis was associated with a decreased synthesis of the phospholipid phosphatidylinositol (PI), the precursor of PIP2, by 33%, the decreased availability of PIP2 is apparently, at least in part, the result of the decreased synthesis of PI. As an apparent functional consequence of the decrease in IP3 formation following the TNF alpha exposure, the alpha 1-adrenoceptor-mediated induction of arrhythmias by 100 mumol/l noradrenaline + 10 mumol/l timolol was abolished in TNF alpha-pretreated rat cardiomyocytes. To investigate one of the possible mechanisms of the TNF alpha-induced decrease of PIP2 formation, the effect of TNF alpha pretreatment on glycerol-3-phosphate dehydrogenase (GDH), a key enzyme of lipogenesis, was studied: Exposure of the rat cardiomyocytes for 72 h to TNF alpha induced a concentration-dependent decrease in GDH activity by maximally 55%.(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVES: The efficacy of selective synchronized suction and retroinfusion of coronary veins was compared with synchronized coronary venous retroperfusion in preventing ischemic reduction of regional myocardial function and myocardial oxygen tension. BACKGROUND: Because incomplete protection by synchronized coronary venous retroperfusion during ischemia might result from nonselective retroinfusion and only passive drainage of the veins, a suction device was added to a retroinfusion system. METHODS: Regional myocardial function (ultrasonic crystals) and myocardial oxygen tension (polarographic electrodes) were studied in 30 pigs during 10-min occlusion of the left anterior descending coronary artery (ischemia), followed by reperfusion. During ischemia, group A (n = 10) was supported by selective synchronized suction and retroinfusion; group B (n = 10) was supported by synchronized coronary venous retroperfusion, and group C (n = 10) was not supported by retroinfusion. RESULTS: In group A, subendocardial segment shortening decreased from 21 +/- 4% (mean +/- SD) before ischemia to 11 +/- 5% during ischemia. In contrast, systolic dyskinesia was observed in group B (-2 +/- 4%, p < 0.001) and group C (-2 +/- 5%, p < 0.001). During ischemia, the decrease in intramyocardial oxygen tension was less pronounced in group A (41 +/- 15 vs. 27 +/- 12 mm Hg) than in group B (40 +/- 10 vs. 19 +/- 10 mm Hg, p = 0.1) or group C (33 +/- 11 vs. 12 +/- 8 mm Hg, p = 0.002). During ischemia, myocardial surface oxygen tension was preserved > 0 mm Hg only in group A. CONCLUSIONS: Preservation of regional myocardial function and myocardial oxygen tension was substantially higher by selective synchronized suction and retroinfusion of coronary veins than by synchronized coronary venous retroperfusion in pigs.
OBJECTIVE: In order to obtain direct evidence for tissue hypoxia in patients with sepsis oxygen, partial pressure was measured within skeletal muscle. Furthermore, serial intermittent and continuous measurements of skeletal muscle PO2 in patients with sepsis were used to find out whether skeletal muscle oxygenation may change in the course of sepsis and depends on the severity of sepsis. DESIGN: Prospective study. SETTING: Intensive care unit of a university hospital. PATIENTS: Intensive care patients (n = 98) with sepsis (group 1, n = 39; group 4, n = 28), limited infection (group 2, n = 16), and cardiogenic shock (group 3, n = 15). INTERVENTIONS: Pulmonary artery catheterization; standard antibiotic therapy and volume replacement. MEASUREMENTS AND MAIN RESULTS: Skeletal muscle PO2 was determined by polarographic needle electrodes or catheter probes. In patients with sepsis (n = 67), no evidence for skeletal muscle hypoxia was obtained from the PO2 distribution within biceps muscle. Mean skeletal muscle PO2 was increased in patients with sepsis (group 1, 48 torr [6.4 kPa]) compared with patients with limited infection (group 2, 28 torr [3.7 kPa]), p < .001) and with patients with cardiogenic shock (group 3, 22 torr [2.9 kPa], p < .001). Serial measurements of the PO2 distribution during seven consecutive days in another 28 patients (group 4) with sepsis showed that a more severe degree of sepsis was associated with an increase of mean skeletal muscle (p < .001). These results were confirmed by continuous measurements of mean skeletal muscle PO2, using PO2 catheters. CONCLUSIONS: In patients with sepsis, oxygen transport to skeletal muscle was not critically reduced. Serial intermittent and continuous measurements of skeletal muscle PO2 showed that skeletal muscle PO2 increased in relation to the severity of the stage of sepsis. Our findings suggest that oxygen utilization within skeletal muscle decreased with deterioration of sepsis, thereby increasing skeletal muscle PO2.
In patients at risk for sepsis after cardiac surgery, the efficacy of intravenous immunoglobulin (Ig) treatment was compared with a historical control population, equivalent in patient characteristics and disease severity. Using APACHE II scores, especially in the high-risk group (IgG), we could discriminate between low-risk patients (score < 19; mortality 1 percent) and the small groups at risk (score 19 to 23) and high risk (score > or = 24) with a significantly higher mortality (14 percent and 76 percent, respectively) [corrected]. Subsequently, among 1,341 consecutive patients we prospectively identified and treated (IgG n = 41 IgGMA: n = 25) these at-risk groups. In contrast to controls (risk: n = 21; high-risk; n = 21), we found a marked fall in APACHE II scores, especially in the high-risk group (IgG, n = 26: p < 0.05; IgGMA, n = 13: p = 0.08) [corrected]. In this group, Ig therapy produced higher (p < 0.05) response rates (score decrease 7 within 4 days: IgG: 54 percent, IgGMA: 62 percent; controls: 19 percent) and reduced mortality (IgG: 46 percent, IgGMA: 46 percent; controls: 76 percent), statistically significant (p < 0.05) for Ig treatment overall. Thus, early Ig treatment improves disease severity and may improve prognosis in prospectively score-identified high-risk postcardiac surgical patients.