Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Time-related changes in eicosanoid release and hemodynamic parameters were characterized in baboons during the early development of sepsis induced by intravenous (i.v.) infusion of live Escherichia coli (4 x 10(10) organisms/kg) in baboons. Plasma levels of thromboxane B2 (TxB2), a stable metabolite of thromboxane A2 (TxA2), rose rapidly in arterial, venous, and pulmonary arterial blood after infusion of live E. coli, attaining maximal increases at 30 min and returning to control values by 60 min. In contrast, plasma concentrations of 6-keto-PGF1 alpha rose slowly after infusion, reaching peak concentrations at 120 min, then slowly returned to control values between 4 and 5 hr after infusion of live E. coli. Hemodynamic values remained stable during the first 2 hr after infusion, although early changes in cellular energy metabolism and incipient hemodynamic failure were inferred from pyrexia, tachycardia, and metabolic acidosis. At 3 hr, signs of further hemodynamic compromise developed, including increased venous PCO2, reduced pulmonary capillary wedge pressure, and reduced stroke volume, followed by gradual increases in systemic and pulmonary vascular resistance. These factors coincided with progressive reductions in cardiac output and deteriorating circulatory efficiency. The time course of events following infusion of live E. coli indicates that alterations in cellular energy provision occurred early (within 1 hr), whereas central hemodynamic parameters decayed much more slowly. Additionally, TxA2 and PGI2 appear related to the early events in the development of sepsis as their release preceded cardiocirculatory failure.
 ...
PMID:Eicosanoids and the hemodynamic course of live Escherichia coli-induced sepsis in baboons. 268 55

There is considerable evidence from animal and human studies of sepsis and acute lung injury that prostacyclin and PGE1 may have a beneficial effect on tissue perfusion with a reduction in the severity of tissue damage associated with these disorders. As yet, there are no good data from controlled clinical trials that these agents improve survival and it is not clear whether in the future such data will be forthcoming. Nevertheless, using various physiological end-points, both prostaglandins seem to be beneficial in sepsis and when used in combination with the whole process of Intensive Therapy, may contribute to the survival of some cases. Although the assessment of combinations of agents designed to inhibit mediator release might be more useful, it remains to be seen whether the relatively insensitive controlled clinical trial, with survival as its endpoint, is the appropriate tool for assessing efficacy in the ITU. Perhaps, the 'consensus' approach has something to offer in this situation!
 ...
PMID:The therapeutic value of vasodilator prostaglandins in multiple organ failure associated with sepsis. 306 68

Group B beta hemolytic streptococcal sepsis has many of the characteristics of gram negative sepsis (Hellerqvist, et al., 1981). This is further shown in the model developed for this study. The newborn piglet septic model developed for this study appears to be an adequate model for group B, beta-streptococcal sepsis characterized by the development of significant hypotension by six hours. As with human sepsis, this model develops hypoglycemia, hemoconcentration as noted by the increased hematocrit, thrombocytopenia and a significant drop in WBC with an increase in immature forms (Wilson, 1986). The only finding not correlated to the septic newborn is the development of DIC as characterized by an increased PT/PTT and increased FSP. As with other animal models for both gram positive and negative sepsis, the cyclooxygenase inhibitor, indomethacin significantly increased survival out to 72 hours. Previous studies with thromboxane synthetase inhibitors have not shown increased survival, but shunting into the prostacyclin pathway has occurred and the effect of this on survival could not be ruled out (Short, et al., 1983). The use of a thromboxane receptor site antagonist should not cause this shunt, and thus may help to evaluate the effect of thromboxane blockade. In this model no effect of the receptor site antagonist was noted, but due to the short half-life of this compound, a different dosing schedule may be needed before its efficacy can be determined. In summary, the cyclooxygenase inhibitors do appear to have a protective effect in gram positive sepsis, but the mechanisms of action are still to be determined.
 ...
PMID:Group B streptococcal (GBSS) newborn septic shock model: the role of prostaglandins. 313 20

The pathophysiology of renal dysfunction in generalized sepsis remains unknown. In this study, 24 hours after surgical induction of peritonitis in 20 volume-loaded sheep, three patterns of renal function were seen. In group 1 (n = 8), glomerular filtration rate (GFR) decreased by 70%, urine volume by 85%, absolute sodium excretion by 95%, and fractional sodium excretion by 83%. Group 2 (n = 4) exhibited similar sodium retention but GFR did not fall. Group 3 (n = 8) showed no change in GFR or urine volume and only minimally reduced sodium excretion. Mean arterial pressure fell 17% in group 1 only; central venous pressure, pulmonary capillary wedge pressure, and plasma volume were maintained at or above presepsis values in all groups. Cardiac index was either increased or unchanged, and renal plasma flow was maintained in all groups; there was thus no hemodynamic evidence to suggest volume contraction. Histologic examination showed only minor changes with no consistent pattern. Renal functional changes correlated with other manifestations of severe sepsis--GFR and sodium retention correlated significantly with increased cardiac index, decreased systemic vascular resistance, pulmonary arterial hypertension, leukopenia, hypoproteinemia, and hypoglycemia. All of these changes were most marked in group 1. In groups 1 and 2, plasma renin activity (PRA) increased and urinary kallikrein excretion decreased. PRA correlated inversely with GFR, urine volume, and sodium excretion; urinary kallikrein excretion correlated positively with urine volume and sodium excretion. Urinary excretion of 6-keto-PGF1 alpha was increased in groups 1 and 2 and correlated inversely with mean arterial pressure in group 1 animals. During sepsis, urinary thromboxane B2 excretion continued at presepsis values in all groups. The results suggest that unusual reciprocal changes in activity of the renin-angiotensin and renal kallikrein-kinin systems may play a role in the renal response to sepsis. PGI2 synthesis is increased and may affect systemic hemodynamics and renal function; the role of thromboxane A2 in this context is unknown.
 ...
PMID:Vasoactive hormones in the renal response to systemic sepsis. 327 70

Neonatal group B streptococcal (GBS) sepsis produces pulmonary arterial hypertension and hypoxemia that are preventable by pretreatment with the selective thromboxane A2 synthase inhibitor, dazmegrel. In the present experiment we administered dazmegrel (8 mg/kg) 2 h after the initiation of a 2 1/2 h infusion of 5 X 10(8) GBS/kg/h in ten 2- to 3-wk-old piglets. The multiple inert gas elimination technique was used to measure intrapulmonary shunt and alveolar ventilation to pulmonary perfusion mismatching. Thromboxane B2, the stable metabolite of thromboxane A2, and 6-keto-prostaglandin F1 alpha, the stable metabolite of prostacyclin, were assayed in arterial blood. Pulmonary arterial pressure increased immediately after initiation of the GBS infusion, rising from 12 +/- 2 to 34 +/- 4 torr (p less than 0.02); pulmonary vascular resistance increased by 400% (p less than 0.01). Arterial hypoxemia developed (p less than 0.02) in association with an increase in the low ventilation-perfusion ratio index but without a significant increase in intrapulmonary shunt. Thromboxane B2 levels increased 10-fold. Infusion of the carrier substance for dazmegrel after 2 h of GBS infusion produced no change in any variables. In contrast, infusion of the drug resulted in the return to pre-GBS infusion baseline values for both pulmonary arterial pressure and pulmonary vascular resistance. However, no improvement in arterial pO2 or in the low ventilation-perfusion ratio index occurred. Both pulmonary vascular resistance and pulmonary arterial pressure remained normal for 0.5 h after dazmegrel administration despite continued GBS infusion. Thromboxane B2 levels were decreased 30 min after dazmegrel (p less than 0.02), but remained greater than pre-GBS levels.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Neonatal group B streptococcal sepsis: effects of late treatment with dazmegrel. 328 20

Thromboxane A2 may play a major role in circulatory shock. In some species, thromboxane synthetase inhibitors have a beneficial effect on shock induced by endotoxin, trauma, sepsis and administration of arachidonate. In some shock models, however, results with thromboxane synthetase inhibitors have been conflicting. The effect of UK-38,485, a selective thromboxane inhibitor, was evaluated in ponies injected with endotoxin intraperitoneally. Four groups of ponies were used to compare the effects of endotoxin alone, UK-38,485 alone, treatment with UK-38,485 before endotoxin challenge and treatment with UK-38,485 after endotoxin challenge. Haematological, metabolic, eicosanoid and clinical responses in each group were evaluated. The results indicated that UK-38,485 is an effective inhibitor of thromboxane A2 generation following endotoxin challenge. Prostacyclin values were elevated compared with baseline in ponies administered UK-38,485 and endotoxin. However, prostacyclin values were not significantly different from those of ponies receiving endotoxin alone. Furthermore, UK-38,485 failed to attenuate the haematological, metabolic and clinical manifestations commonly seen in the pony after endotoxin challenge.
 ...
PMID:Effects of a specific thromboxane synthetase inhibitor in equine endotoxaemia. 331 81

The blood coagulation system is activated regularly in severe forms of shock, polytrauma, and sepsis. Arising thrombin cleaves the fibrinopeptides A and B from fibrinogen, and it generates monomers of fibrin, which are initially kept in solution by the remaining excess fibrinogen. The effects of soluble fibrin (fibrin monomer/oligomer-fibrinogen complexes) and fibrinopeptides A and B were investigated in blood-free perfused, isolated rabbit lungs. Urea Tris buffer-dissolved fibrin monomers were injected into the pulmonary artery in the presence of circulating excess fibrinogen. In doses above 5 mg, the monomers consistently provoked a sharp rise in pulmonary artery pressure, which was followed by an elevated pressure plateau. Changing to fresh perfusate devoid of soluble fibrin did not restore the pressure to baseline, and a second administration of the soluble fibrin caused a pressor response larger than the first. Only a modest increase in lung weight (less than 2 g) was observed, and lung inflation pressure was not altered. The pressor responses were accompanied by a rapid release of thromboxane A2 and a more delayed release of prostaglandin I2 into the perfusion fluid. A significant correlation between the height of the fibrin-induced pressure rise and the amount of thromboxane release was noted. Inhibition of cyclooxygenase (indomethacin) suppressed the generation of both prostanoids, whereas inhibition of thromboxane synthetase (OKY-046 and imidazole) selectively blocked the liberation of thromboxane. All three inhibitors caused an immediate decline in pulmonary artery pressure, which had been previously elevated due to administration of soluble fibrin, and markedly reduced the pressor response evoked by a subsequent fibrin application in the same lung.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Pulmonary vasoconstrictor response to soluble fibrin in isolated lungs: possible role of thromboxane generation. 334 71

The effects of Pseudomonas aeruginosa cytotoxin on the pulmonary microvasculature were studied in blood-free, perfused, isolated rabbit lungs. Cytotoxin was administered to the recirculating Krebs Henseleit albumin (1%) buffer during two consecutive 30-min-perfusion phases (phases 1 and 2) at a concentration of 13 micrograms/ml, followed by a third perfusion phase (phase 3) without toxin. After perfusion phases 2 and 3, the capillary filtration coefficient (Kf,c) and vascular compliance were determined gravimetrically from two-step microvascular pressure increments under zero-flow conditions. Cytotoxin caused a continuous release of K+ and lactate dehydrogenase, which started within the first 5 min and amounted to about 50% of the total lung cellular K+ and 5 to 7% of the total lactate dehydrogenase by the end of the experiment. The toxin caused the continuous generation of prostaglandin I2, which was detectable in the perfusates of all perfusion phases at maximum values five times above the control values and which was measured in the bronchoalveolar lavage fluid at the end of the experiment. Thromboxane generation in toxin-treated lungs did not significantly exceed that of control lungs or of lungs with mechanically induced edema. Cytotoxin caused a gradual increase in pulmonary vascular resistance, to maximum values 2.5 times above the control, starting within 1 min; the increase was partially reversible after washout of the toxin. After a lag period of 20 to 30 min, the lungs gained weight, amounting to a mean gain of 9.1 g at the end of the experiments. After perfusion phases 2 and 3, an almost fourfold increase in Kf,c, which was not reversible after washout of the toxin, was measured, whereas the values of vascular compliance were not altered. We conclude that pseudomonal cytotoxin may be an important factor in the pathogenesis of prolonged microvascular injury, encountered in states of P. aeruginosa sepsis or acute lung failure with secondarily acquired P. aeruginosa pneumonia.
 ...
PMID:Pulmonary microvascular injury induced by Pseudomonas aeruginosa cytotoxin in isolated rabbit lungs. 351 62

Activated complement, thromboxane A2, prostacyclin, and activated granulocytes have been implicated in hemodynamic dysfunction after trauma, in sepsis, and in hypovolemic and septic shock. This study evaluated the interaction of plasma concentrations of complement components C3a and C5a, thromboxane B2 (TxB), prostaglandin 6-keto-F1 alpha (PGI), and granulocyte aggregation in clinical sepsis and hypotension. Forty-eight critically ill patients were followed clinically for as long as 10 days. Plasma C3a, C5a, TxB, and PGI were measured daily by the radioimmunoassay method. Granulocyte aggregation, the percentage of maximum aggregation of zymosan-activated plasma standard curves, was performed with patient plasma and normal human leukocytes. Patients were studied in four groups: group I, nonseptic, normotensive; group II, hypovolemic shock, group III, normotensive severe sepsis; and group IV, septic shock. Plasma from 12 normal adults was the control value. PGI, TxB, C3a, C5a, and granulocyte aggregation in patients were greater than that in the control subjects. Granulocyte aggregation was increased in groups III and IV versus groups I and II. C3a was increased in group IV versus groups II and III. C5a and TxB did not vary between groups. PGI was greatly increased in group IV compared with groups I through III. C3a and C5a decreased in nonsurvivors. PaO2/FiO2 ratios correlated directly with PGI and inversely with C3a and TxB/PGI. Plasma PGI and C3a are increased in septic shock. C3a and TxB/PGI imbalances are involved in hypovolemic and septic shock.
 ...
PMID:Interaction of prostaglandins, activated complement, and granulocytes in clinical sepsis and hypotension. 352 Sep 16

Prostacyclin and thromboxane A2 have been implicated as mediators of septic shock. Correlations between the human prostanoid response to sepsis and experimental paradigms are poorly understood. The purpose of this study was to compare changes in plasma levels of prostaglandin 6-keto-F1 alpha (PGI) and thromboxane B2 (TxB) during septic shock in Sprague-Dawley rats, domestic pigs, mongrel dogs, and man. Severe sepsis followed by septic shock (systolic BP less than 90 mmHg) was induced in rats by inoculation of 1.0 X 10(9) Aeromonas hydrophila, in pigs by graded IV infusion of 1.0 X 10(9)/ml A. hydrophila; and in dogs by an IV bolus injection of 5.0 X 10(9)/ml Escherichia coli. Plasma PGI and TxB (pg/ml) were measured by radioimmunoassay in control, septic, and septic shock experimental blood samples, and in normal controls, severly septic, and septic shock (systolic BP less than 90 mmHg) S.I.C.U. patients. Control, septic, and septic shock TxB levels in the dog and the pig were significantly greater than in the rat and man. PGI levels in the dog were significantly greater than in other species. TxB increased significantly in murine sepsis and PGI increased significantly in sepsis and septic shock. TxB increased during porcine sepsis and septic shock. In man, both PGI and TxB were significantly increased in severe sepsis, compared to normal controls, but only PGI was significantly higher in septic shock versus normotensive sepsis. Patterns of change in TxB/PGI ratios were similar for all species studied. Changes in PGI in the porcine septic experiments most closely paralleled those observed clinically.
 ...
PMID:Prostacyclin and thromboxane A2 in septic shock: species differences. 353 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>