[Perioperative coagulation disorders].
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Anticoagulants↗
Biomedical subjects
R U Scherer
Publications and source records attributed to R U Scherer.
[Haemostaseological aspects of perioperative blood management].
Recent studies in humans have shown that tissue factor on the surface of endothelial cells, monocytes, or subendothelial structures sparks plasmatic coagulation. In vivo, there is no functional separation of an "endogenous" and "exogenous" pathway of the coagulation cascade. However, global laboratory tests run along such pathways due to preincubation with specific activators and, hence, allow localization of inherited coagulation defects. Coagulation inhibitors such as antithrombin or activated protein C are accelerated in their activity by cell surface glycoproteins and almost completely inactivate procoagulant activity in the microcirculation. Antithrombin binds to endothelial glycosaminoglycans and then significantly increases anticoagulant activity. Protein C is activated by the thrombin-thrombomodulin-complex and inactivates factors V a and VIII a, respectively. Additionally, activated protein C has a profibrinolytic effect. Both systems physiologically counteract the procoagulant transformation of endothelial and monocyte cell surfaces which occurs in critically ill patients due to induction of tissue factor, suppression of thrombomodulin, and removal of glycosaminoglycans from the cell surface. The distinction of static and dynamic coagulation disorders is useful since static disorders seldom require therapeutic interventions although global laboratory tests may continuously deteriorate. Dynamical disorders are symptoms of an underlying disease, and consumption coagulopathy with disseminated fibrin deposition and oozing occurs when coagulation turnover cannot be stopped. Antithrombin substitution is a well documented therapeutic option along with fresh frozen plasma and erythrocyte concentrate transfusion for blood substitution. Recent case reports in patients with irreversible bleeding complications favour the application of a recombinant factor VII concentrate. A rising perspective to decrease the use of heterologous blood and blood products may be intraoperative plasma retransfusion. The quality of such plasma undergoing consecutive filtration steps has to be clinically studied. The application of a synthetic platelet substitute, the "plateletsome", containing platelet glycoproteins led to significantly improved haemostasis without generating systemic procoagulant activity. In a far future, procoagulant cell surface transformation may be influenced by topic application of inhaled thrombomodulin loaded liposomes or by sense or antisense oligonucleotides inducing thrombomodulin expression or suppressing tissue factor expression, respectively.
Blood Coagulation↗
[Actions of Antithrombin (AT): experimental and clinical results].
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Antithrombins↗
Influence of heparin and hirudin on endothelial binding of antithrombin in experimental thrombinemia.
OBJECTIVE: During the last decade, experimental and clinical evidence has accumulated that antithrombin (AT) exerts anti-inflammatory effects when given in high doses. Meanwhile, AT substitution has been shown to significantly increase prostacyclin release. However, the link between endothelial AT binding and anti-inflammatory AT effects remains to be established in vivo, although heparin has been shown to counteract anti-inflammatory AT effects. We hypothesized that the administration of heparin in endotoxin-challenged rats would decrease endothelial AT binding and systemic prostacyclin concentrations. DESIGN: Prospective, randomized, controlled experimental in vivo study. SETTING: Research laboratory of a university hospital. ANIMALS: Fifty-six Wistar rats. INTERVENTIONS: Baseline values of coagulation variables were measured in six animals. Forty of 50 Wistar rats in the study groups were given endotoxin (50 mg x kg(-1) iv) and were treated with saline (group LPS), AT (15 units x kg(-1) x hr(-1)) (LPS+AT), AT and heparin (80 IU x kg(-1) x hr(-1)), or AT and hirudin (0.12 mg x kg(-1) x hr(-1)); the other 10 received saline instead of endotoxin and were treated with AT alone. Before endotoxin application, a tracheostomy was performed, and venous and arterial catheters were inserted for blood sampling and infusion. MEASUREMENTS: Intravital endothelial AT binding was studied by using fluorescence isothiocyanate-marked antibodies during intravital microscopy of intestinal submucosal venules. Systemic prostacyclin, thrombin-AT complex, and fibrinogen concentrations were measured after 4 hrs. Intergroup differences were tested by Kruskal-Wallis analysis of variance on ranks. MAIN RESULTS: AT and AT + heparin were equally effective in inhibiting systemic procoagulant turnover as reflected by fibrinogen concentrations. Only the administration of AT + hirudin significantly prevented fibrinogen consumption (p < .05). In contrast with all other treatments, the administration of heparin significantly reduced intravital endothelial AT binding (p < .05). However, prostacyclin concentrations were similarly increased in all endotoxin-challenged study groups irrespective of the anticoagulatory treatment. CONCLUSIONS: There is evidence that heparin in contrast with hirudin prevents AT from being bound to the endothelial cell surface in this experimental model. Under low-dose AT substitution, systemic prostacyclin concentrations do not depend on whether heparin or hirudin is used for thrombin inhibition. These results support the view that heparin may counteract anti-inflammatory AT effects by keeping AT away from its endothelial binding sites; however, the results question the view that decreased endothelial prostacyclin release is solely responsible.
Animals↗
Consequences of haemostasis disorders on anaesthestic management.
New molecular markers of coagulation and fibrinolysis activation have been developed and used to identify patient subgroups that frequently develop increased procoagulant turnover and, hence, disseminated intravascular coagulation and organ dysfunction. The idea of inhibiting the coagulation hyperactivation by the administration of antithrombin has led to experimental findings that pinpoint an anti-inflammatory action of antithrombin. Preliminary clinical trials of high-dose antithrombin administration in sepsis are promising. Point-of-care coagulation testing remains controversial since a variety of perioperative therapeutic regimens such as aprotinin administration obviously do not require 'on-line' coagulation monitoring.
Journal Article↗
Procoagulant activity in patients with isolated severe head trauma.
OBJECTIVE: To determine the degree of regional and systemic coagulation activation soon after isolated severe head injury. DESIGN: Prospective, controlled clinical study. SETTING: The emergency room and intensive care unit (ICU) of a trauma center in a university hospital serving a population of 5 million people. PATIENTS: Twenty-four trauma victims: 20 patients with isolated severe head injury (head trauma group, Glasgow Coma Score of < or =8) and four patients with isolated bone fracture (control group). INTERVENTIONS: Insertion of central venous, i.e. superior caval vein, jugular bulb, and arterial catheters for blood sampling. MEASUREMENTS AND MAIN RESULTS: Central venous (i.e., superior caval vein) global coagulation variables (i.e., prothrombin time, activated partial thromboplastin time, fibrinogen concentration, antithrombin III activity, and platelet count) and central venous and jugular bulb activation coagulation and fibrinolysis variables (i.e., prothrombin fragment F1+2, thrombin-antithrombin III complex, soluble fibrin, and D-dimer concentration) were measured soon after trauma (<6 hrs) and 3 hrs later. When compared with the control group patients, upon ICU admission, fibrinogen concentration (p < .005) and platelet count (p < .025) were significantly decreased in the head trauma group. Thrombin-antithrombin III complex (p < .025), prothrombin fragment F1+2 (p < .025), and D-dimer (p < .005) concentrations measured at the time of ICU admission were significantly higher in the head trauma group than in the control group. Only in the head trauma group were soluble fibrin concentrations increased above the normal range; thrombin-antithrombin III complex and the prothrombin fragment F1+2 were found to be significantly higher in cerebrovenous blood than in central venous blood (p < .025). There was no cerebrocentral venous difference in the concentrations of soluble fibrin or D-dimer in either group. CONCLUSIONS: Within 6 hrs after severe isolated head trauma, systemic procoagulant overflow from the traumatized cerebral microvasculature proceeds to the thrombin level and is then inhibited by antithrombin III. Regional and systemic hypercoagulability and increased D-dimer concentrations appear to be common among head trauma patients. Increased procoagulant and consecutive fibrinolytic turnover may, therefore, spark disseminated intravascular coagulation in this patient group.
Adolescent↗
Retroperitoneal and intraperitoneal CO2 insufflation have markedly different cardiovascular effects.
Both retroperitoneoscopic and laparoscopic surgical approaches to kidney and adrenal gland have been reported but their cardiopulmonary pathophysiology has been incompletely characterized. To test the hypothesis that these approaches have markedly different impact on the circulatory and respiratory systems, we assessed at similar insufflation pressures alterations in cardiovascular and respiratory variables during retroperitoneal and intraperitoneal CO2 insufflation. Eighteen healthy, anesthetized (propofol, alfentanil, vecuronium), mechanically ventilated pigs were randomly instrumented for either retroperitoneoscopic (n = 9) or laparoscopic (n = 9) surgery. After CO2 insufflation cardiovascular and respiratory variables were measured at four cavity pressures (baseline, 10, 15, and 20 mmHg), while end-expiratory CO2 tension was maintained by adjusting tidal volume. Data were analyzed for both insufflation-pressure-dependent and group effects by one-way and two-way ANOVA for repeated measurements, respectively, followed by Newman-Keuls post hoc test (P < 0.05). Cardiac output, mean arterial, pulmonary artery, central venous, and femoral venous pressures increased significantly in both groups in an insufflation-pressure-dependent fashion. However, changes in cardiac output (P < 0.001), pulmonary artery (P < 0.007), central venous (P < 0.001), and iliac venous pressures (P < 0.001) for the same insufflation pressure were markedly and significantly greater with intraperitoneal than retroperitoneal CO2 insufflation. Most important, intraperitoneal unlike retroperitoneal insufflation induced a marked inferior vena caval pressure gradient (8.9 +/- 1.1 mmHg vs 1.0 +/- 0.5 mmHg, P < 0.00001). While both retroperitoneal and intraperitoneal CO2 insufflation required increased tidal volumes to adjust endtidal CO2 tension to baseline, intraperitoneal CO2 insufflation resulted in a significantly greater increase of mixed venous and arterial carbon dioxide tensions (P < 0.007) even at similar insufflation pressures. Furthermore, significantly greater peak airway pressures (P = 0.018) were required with intraperitoneal than with retroperitoneal insufflation to administer the same tidal volume, indicating a greater decrease in quasi-static compliance with intraperitoneal insufflation (P = 0.0436). Thus, (i) cardiovascular and respiratory changes are much less during retroperitoneal than intraperitoneal CO2 insufflation, even at the same insufflation pressures, and (ii) retroperitoneal CO2 insufflation unlike intraabdominal CO2 insufflation does not induce an inferior vena caval pressure gradient and hence does not appear to impair systemic lower body venous return up to insufflation pressures of 20 mmHg.
Animals↗
Incidence of neurologic complications related to thoracic epidural catheterization.
BACKGROUND: Due to potential neurologic sequelae, the risk:benefit ratio of thoracic epidural analgesia is controversial. Surprisingly, however, few available data address neurologic complications. The incidence of neurologic complications occurring after thoracic epidural catheterization was studied in patients scheduled for abdominal or abdominothoracic surgery. METHODS: A total of 4,185 patients were studied, including 2,059 during the prospective phase of the study and 2,126 during the retrospective phase. After thoracic epidural catheterization, all patients received general anesthesia. Patients' neurologic status was assessed by an anesthesiologist using clinical criteria after operation and after epidural catheter removal. If neurologic complications were suspected, a neurologist was consulted. The incidence of specific complications was compared for different thoracic puncture sites: upper (T3/4-6/7), mid (T7/8-8/9), and lower (T9/10-11/12) catheter insertion levels. RESULTS: The overall incidence of complications after thoracic epidural catheterization was 3.1% (n = 128). This included dural perforation (0.7%; n = 30); unsuccessful catheter placement (1.1%; n = 45); postoperative radicular type pain (0.2%; n = 9), responsive to catheter withdrawal in all cases; and peripheral nerve lesions (0.6%; n = 24), 0.3% (n = 14) of which were peroneal nerve palsies probably related to surgical positioning or other transient peripheral nerve lesions (0.2%; n = 10). No signs suggesting epidural hematoma were recognized, and there were no permanent sensory or motor defects attributable to epidural catheterization. Unintentional dural perforation was observed significantly more often in the lower (3.4%) than in the mid (0.9%), or upper (0.4%) thoracic region. A single patient experienced severe respiratory depression after receiving epidural buprenorphine but recovered without sequelae. CONCLUSIONS: Thoracic epidural catheterization for abdominal and thoracoabdominal surgery is not associated with a high incidence of serious neurologic complications. In fact, the incidence of puncture- and catheter-related complications is less in the mid and upper than in lower thoracic region, and the predicted maximum risk for permanent neurologic complications (upper bound of the 95% confidence interval) is 0.07%.
Analgesia, Epidural↗
The influence of C1-esterase inhibitor substitution on coagulation and cardiorespiratory parameters in an endotoxin-induced rabbit model of hypercoagulability.
In a short-time model of endotoxin-induced (lipopolysaccharide from Escherichia coli, 120 micrograms kg-1 i.v.) hypercoagulability in rabbits, the therapeutic effects of C1-esterase inhibitor (C1I) substitution (bolus 400 U kg-1 i.v. followed by continuous infusion of 400 U kg-1 4 h-1 i.v.) were studied. When compared to endotoxin-challenged untreated animals, C1I substitution significantly stabilized mean arterial pressure (p < 0.01), increased central venous oxygen saturation (p < 0.05), prevented the decrease of antithrombin III (p < 0.05), and reduced fibrin deposition in the microcirculation of the liver and the lungs to approximately 30% of that observed in the untreated animals (p < 0.01). Although C1I substitution did not reduce systemic procoagulant turnover, the improvement of blood pressure and blood flow and local inhibitory actions in the coagulation and complement cascade prevented fibrin deposition in the microcirculation of vital organs. This study supports the beneficial role of C1I substitution during early disseminated intravascular coagulation.
Animals↗
Hemodynamic changes after retroperitoneal CO2 insufflation for posterior retroperitoneoscopic adrenalectomy.
Intraoperative complications and hemodynamic alterations during posterior capnoretroperitoneoscopic adrenalectomy in the prone position were investigated in 16 consecutive patients using invasive hemodynamic monitoring. Under general anesthesia with propofol and fentanyl, hemodynamic changes were made before (M1) and during retroperitoneal CO2 insufflation (15 mm Hg) [M2]; 20 mm Hg [M3]. Retroperitoneal insufflation resulted in a significant increase of cardiac output (+72%), stroke volume (+42%), mean arterial pressure (+39 %), and mean pulmonary arterial pressure (+36%). Although retroperitoneal inflation was accompanied by a significant increase of central venous pressure (+37%), an increase of preload may have lead to higher filling pressures. Heart rate, systemic vascular resistance, and pulmonary vascular resistance did not show significant changes. One pneumothorax and two cutaneous emphysemas occurred. We have demonstrated, in a small number of patients, that retroperitoneal CO2 insufflation for posterior capnoretroperitoneoscopic adrenalectomy in the prone position results in hemodynamic changes without apparent adverse effects.
Adolescent↗
Short-time rabbit model of endotoxin-induced hypercoagulability.
We describe a short-time endotoxin-induced rabbit model of hypercoagulability for the study of the coagulation cascade and the therapeutic effects of coagulation inhibitors. Cardiorespiratory function was maintained in rabbits under general anesthesia and standardized mechanical ventilation (tidal volume, 6 ml/kg; 60 breaths/min) via tracheostomy and low-dose inotropic support. Coagulation parameters such as prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen concentration, platelet count, fibrin monomers, D-dimers, antithrombin III and factor XIII activities, thrombelastography, and platelet aggregometry were measured during a 4-h period after sequential double endotoxin administration (80 and 40 micrograms/kg of body weight, intravenously). Mean arterial pressure and arterial and central venous blood gas tensions were monitored. Global clotting, activation parameters of coagulation, and leukocyte count deteriorated significantly in the endotoxin-treated animals but was mainly unaltered in controls (P < 0.05). Tissue specimens of the lungs, liver, brain, and kidneys were examined. Endotoxin-induced, disseminated fibrin deposition was found in the lungs and liver (P < 0.01). We conclude that this short-time model of hypercoagulability in rabbits reliably induced disseminated intravascular coagulation. Tracheostomy and mechanical ventilation provided a reproducible model in which the differences between the controls and the endotoxin-treated animals were exclusively due to administration of endotoxin and not to unforeseen complications of the respiratory system. This model allows the study of therapeutic effects of coagulation inhibitors on endotoxin-induced changes.
Animals↗
Recovery of antithrombin III in patients undergoing orthotopic liver transplantation after administration of an antithrombin III concentrate.
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Adult↗
Shunt flow and caval pressure gradient during veno-venous bypass in human orthotopic liver transplantation.
The routine use of veno-venous bypass during the anhepatic phase of orthotopic liver transplantation is controversial. Decreased shunt flows (1.5-3.0 litre min-1), as reported in the literature, may explain the lack of beneficial effects on outcome. We have studied the influence of bypass flows on caval pressure gradient (CPG) and renal perfusion pressure (RPP) in 45 patients undergoing orthotopic liver transplantation using a portofemoro-subclavian veno-venous bypass system. Mean shunt flow was 3.63 litre min-1. Second-order polynomial regressions best described the relationship between shunt flow and CPG (r = 0.674), RPP (r = 0.727), and cardiac output (r = 0.602). Shunt flows less than 3.0 litre min-1 failed to normalize CPG and RPP, whereas flows greater than 5.0 litre min-1 did not substantially improve haemodynamic state.
Adult↗