| 1. |
- Basu, Samar, et al.
(author)
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Effects of melagatran, a novel direct thrombin inhibitor, during experimental septic shock
- 2000
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In: Expert Opinion on Investigational Drugs. - : Informa Healthcare. - 1354-3784 .- 1744-7658. ; 9:5, s. 1129-1137
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Journal article (peer-reviewed)abstract
- Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of melagatran to inhibit thrombin, thereby counteracting thrombin's cellular effects. Thus, it can be seen, using this experimental model of septic shock, that melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.
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| 2. |
- Basu, Samar, et al.
(author)
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Propofol (Diprivan-EDTA) counteracts oxidative injury and deterioration of the arterial oxygen tension during experimental septic shock
- 2001
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In: Resuscitation. - 0300-9572 .- 1873-1570. ; 50:3, s. 341-348
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Journal article (peer-reviewed)abstract
- PURPOSE: Human septic shock can be replicated in the endotoxaemic pig. Endotoxaemia causes a multitude of events, including reduced PaO(2) and increased lipid peroxidation. This study was designed to evaluate the possible effects of a commonly used anaesthetic drug with known antioxidant properties (propofol) during porcine endotoxaemia.METHODS: Ten pigs were anaesthetised and given a 6 h E. coli endotoxin infusion. The animals received, randomly, a supplementary continuous infusion of propofol emulsion (containing 0.005% EDTA) or the corresponding volume of vehicle (controls). Pathophysiologic responses were determined. Non-enzymatic (by measuring plasma 8-iso-PGF(2 alpha) and enzymatic (by measuring plasma 15-keto-dihydro-PGF(2 alpha)) lipid peroxidations were evaluated. Plasma levels of the endogenous antioxidants alpha- and gamma-tocopherols, were also analysed.RESULTS: Endotoxaemia increased plasma levels of 8-iso-PGF(2 alpha) (1st-4th h) and 15-keto-dihydro-PGF(2 alpha) (1st-4th h) significantly more in controls than in the propofol+endotoxin group. PaO(2) was significantly less affected by endotoxin in the propofol treated animals (2nd-4th h). Mean arterial pressure (4th-6th h) and systemic vascular resistance (6th h) were reduced significantly more by endotoxin among the propofol-treated animals. Vitamin E (alpha-tocopherol) increased in all animals, significantly more in the propofol+endotoxin group (1/2-6th h) than in the control group.CONCLUSIONS: Propofol reduced endotoxin-induced free radical mediated and cyclooxygenase catalysed lipid peroxidation significantly. The implication is that propofol counteracts endotoxin-induced deterioration of PaO(2).
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| 3. |
- Eriksson, Mats, et al.
(author)
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Increased platelet microvesicle formation is associated with mortality ina porcine model of endotoxemia
- 1998
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In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 42:5, s. 551-557
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Journal article (peer-reviewed)abstract
- Background:Gram-negative sepsis in humans and endotoxemia in pigs induce the formation of platelet microvesicles. These microvesicles are active in homeostasis and may thus contribute to the outcome in patients with activated coagulation and fibrinolysis. We decided to prospectively evaluate the effects of endotoxemia on microvesicle formation and some common physiologic variables against survival in a porcine model.Methods:Nineteen included pigs were anesthetized, monitored and subjected to an infusion of E. coli endotoxin. Microvesicle formation was determined by flow cytometry.Results:The formation of microvesicles was significantly increased in the 6 pigs that died during endotoxin exposure. This increased formation became significant from the 3rd hour of endotoxemia. Microvesicle formation did not increase in surviving endotoxemic pigs. Cardiac index, mean arterial blood pressure, base excess and systemic vascular resistance index were distinctly reduced in the animals that died as compared to those surviving the endotoxemic period.Conclusion:The increased formation of platelet microvesicles seems to be associated with poor prognosis in porcine endotoxemia. Since microvesicles are active in coagulation, they may contribute to the derangement of the coagulation system caused by endotoxemia. Different degrees of microvesicle formation may reflect inter-individual responses to a given challenge.
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| 4. |
- Högberg, Peter, et al.
(author)
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Factors determining the 13C abundance of soil-respired CO2 in Boreal forests
- 2005
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In: Stable isotopes and biosphere-atmosphere interactions. - : Elsevier. - 9780120884476 ; , s. 47-68
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Book chapter (peer-reviewed)abstract
- Analysis of the isotopic composition of the CO2 respired from soils may reveal information about the important component of the ecosystem C balance. This is crucial, since a large terrestrial sink for atmospheric CO2 has been located in the northern hemisphere, and the vast boreal forests may be largely responsible. At the same time, boreal and arctic ecosystems have large amounts of C stored in the soil, and could potentially become a source of CO2 in a warmer climate promoting more rapid decomposition of soil organic matter. Furthermore, the northern hemisphere has complex dynamics in terms of annual fluctuations in both the concentration of CO2 in the atmosphere and its δl3C. It is of utmost importance to understand the causes of this variability, since it interferes with the partitioning between the ocean and the terrestrial contributions in global models. This chapter aims to provide an update on the reviews by Flanagan and Ehleringer and Ehleringer et al. on the causation of the δ13C of the soil CO2 efflux and, in doing this, focuses on the boreal forests.
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| 5. |
- Kiiski, Ritva, et al.
(author)
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An inhibitor of angiotensin converting enzyme (enalapril) augments endotoxin-induced hypotension in the pig
- 1999
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In: Upsala Journal of Medical Sciences. - 0300-9734. ; 104:2, s. 163-176
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Journal article (peer-reviewed)abstract
- Septic shock causes an extensive inflammatory reaction including increased capillary leakage and a decrease in systemic blood pressure. Human septic shock can be replicated in the endotoxaemic pig. Angiotensin converting enzyme (ACE) is involved in the degradation of bradykinin, an inflammatory mediator, and in the regulation of blood pressure. Inhibition of ACE is a common approach to reduce hypertension as well as left ventricular insufficiency. Fifteen anaesthetised pigs received a continuous 3 h endotoxin infusion. The animals were randomly given an inhibitor of ACE (enalpril) [at a dose (0.5 mg x kg-1) that did not per se reduce mean arterial blood pressure (MAP); (n = 7)], or the corresponding volume of saline (n = 8). Another seven pigs were randomised for treatment with enalapril (0.5 mg x kg-1) + saline (n = 3). Four pigs were randomised to serve as untreated controls (saline + saline). Basic physiologic variables were registered. Endotoxaemia progressively reduced MAP. This decrease was significantly augmented by enalapril. Hypovolemia caused by increased permeability or salt/water excretion did not seem to explain this effect as neither blood haemoglobin nor plasma sodium differed between the two groups of endotoxaemic pigs. Inhibitors of ACE are known to potentiate the cardio-depressant effect of bradykinin. This may explain the reduction in MAP by enalapril during porcine endotoxaemia.
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| 6. |
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| 7. |
- Markström, Agneta, et al.
(author)
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Impact of different inspiratory flow patterns on arterial C02-tension
- 2000
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In: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 105:1, s. 17-29
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Journal article (peer-reviewed)abstract
- Ventilation with decelerating inspiratory flow is known to reduce the dead space fraction and to decrease PaCO2. Constant inspiratory flow with an end-inspiratory pause (EIP) is also known to increase the removal of CO2. The aim of the study was to elucidate the effect of the pause/no-flow period while both the pattern and rate of inspiratory flow was unchanged, and when the lung was ventilated with sufficient PEEP to prevent end-expiratory collapse. Surfactant depleted piglets were assigned to decelerating or constant inspiratory flow with 24 breaths per minute (bpm) or 12 bpm, or to constant flow, without and with an end-inspiratory pause of 25%. By adding an EIP the total time without active inspiratory flow of the respiratory cycle was kept unchanged. Gas exchange, airway pressures, functional residual capacity (using sulfurhexafluoride) and haemodynamics (thermo-dye indicator dilution technique) were measured. Irrespective of ventilatory frequency, PaCO2 was lower and serial dead space reduced with decelerating flow, compared with constant inspiratory flow. With an end-inspiratory pause added to constant inspiratory flow, serial dead space was reduced but did not decrease PaCO2. The results of this study corroborate the assumption that total time without active inspiratory flow is important for arterial CO2-tension.
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| 8. |
- Mutschler, Diana K., et al.
(author)
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Effects of mechanical ventilation on platelet microparticles in bronchoalveolar lavage fluid
- 2002
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In: Thrombosis Research. - 0049-3848 .- 1879-2472. ; 108:4, s. 215-220
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Mechanical ventilation (MV) is considered to contribute to lung injury. Platelet membrane-derived microparticles (PMPs) are procoagulant and participate in the inflammatory process. The bronchoalveolar space could, besides plasma, be a site of origin of these microparticles. We evaluated the presence of these PMPs and two prostaglandin-derived metabolites in bronchoalveolar lavage fluid (BALF) regarding their possible relation to MV.MATERIALS AND METHODS: Before and after 1 h of MV, PMPs and prostaglandin metabolites were analyzed, in BALF from 14 anesthetized pigs, by flow cytometry and RIA, respectively. Tracheal mucus from five humans was analyzed for PMPs at extubation after surgery.RESULTS: Activated PMPs and prostaglandin metabolites were present in all BALF samples. The time needed to count 5000 cellular events was prolonged six-fold after 1 h of mechanical ventilation (p<0.001). The relative content of PMPs was constant in all samples. The PMPs were thrombogenic, i.e. they were fibrinogen, p-selectin and von Willebrand factor positive. Lavage did not per se affect the period necessary to count 5000 cellular events. PMPs in human tracheal mucus were in the same range as in the pig after 1 h of MV aiming at a PaCO(2) between 5.0 and 5.5 kPa.CONCLUSIONS: Activated PMPs are present in the pulmonary air-liquid interface. The prolongation of the time needed to count 5000 cellular events in BALF after MV indicates activation and adherence. Adherent microparticles bind neutrophils, which may aggravate pathological processes leading to pulmonary dysfunction. Evaluation of PMPs in BALF may be useful in evaluating strategies for lung-protective ventilator treatment.
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| 9. |
- Mutschler, Diana K., et al.
(author)
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Microdialysis-evaluated myocardial cyclooxygenase-mediated inflammation and early circulatory depression in porcine endotoxemia
- 2003
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In: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 31:6, s. 1780-1785
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate the early myocardial biochemical inflammatory response with the microdialysis technique during porcine endotoxemia and to simultaneously monitor systemic hemodynamics. DESIGN: Prospective, randomized, placebo-controlled trial with parallel groups. SETTING: Animal research laboratory at the University Hospital of Uppsala, Sweden. SUBJECTS: Thirteen piglets aged 12-14 wks receiving general anesthesia. INTERVENTIONS: After thoracotomy and the insertion of microdialysis probes in standardized locations in the left ventricle of the heart and in the quadriceps muscle, seven pigs received a continuous infusion of endotoxin, initiating a severe endotoxemic shock. Six pigs received saline instead of endotoxin. MEASUREMENTS AND MAIN RESULTS: Endotoxemia caused a rapid and pronounced elevation of a metabolite obtained from prostaglandin degradation, 15-keto-dihydro-PGF(2alpha), in myocardial microdialysate fluid being specific of cyclooxygenase (COX)-mediated inflammation (p <.001 vs. saline-infused controls). Simultaneously, we observed a decrease in left ventricular stroke work index in the endotoxemic pigs (p <.01 vs. saline-infused controls). Endotoxemia did not alter 15-keto-dihydro-PGF(2alpha) levels in quadriceps muscle. Endotoxemia caused increases in taurine, hypoxanthine, and magnesium in myocardial microdialysate (p <.05 vs. saline-infused controls), whereas the contents of pyruvate, lactate, inosine, adenosine, and calcium were not significantly changed. CONCLUSION: Endotoxemia induced a myocardial COX-mediated inflammation without signs of ischemia. In parallel, a depletion of myocardial energy substrates and a deterioration in myocardial performance were seen.
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