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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In pathological states associated with hypermetabolism, such as acute sepsis, there is marked negative N balance. It has been suggested that the pathway for this response is via leukocyte pyrogen (interleukin I) acting on cyclooxygenase to stimulate prostaglandin release, which then stimulates proteolysis via the lysosomal pathway. In vitro, cyclooxygenase inhibitors decrease proteolysis in muscle tissue from septic rats. We tested this hypothesis in vivo in severely septic patients by using aspirin as the test cyclooxygenase inhibitor. Septic patients (n = 4) were given a primed, constant infusion (183 mg prime, then 37 mg/hr) of 15N-labeled urea for 6 hr to obtain a blood [15N]urea plateau. Blood samples were taken every 30 min. At 180 min 1500 mg of aspirin was given po. If aspirin inhibited protein breakdown, the plateau level should rise, since less cold urea derived from protein breakdown will enter the urea pool. Aspirin did not cause any change in either the BUN concentration, its 15N enrichment, or any of the plasma amino acids. In conclusion, cyclooxygenase inhibition by aspirin in vivo does not decrease protein breakdown in hypercatabolic septic patients.
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PMID:The effect of aspirin on protein breakdown in septic man. 309 51

Previous studies have indicated that various arachidonic acid metabolites are involved in the cardiovascular dysfunction seen during endotoxemia and sepsis. However, the possible role of these metabolites in mediating the metabolic alterations under similar conditions remains to be elucidated. Thus, the purpose of the present study was to determine if cyclooxygenase and lipoxygenase blockade could prevent the elevated rates of glucose appearance (Ra), glucose recycling, and hyperlactacidemia seen during hypermetabolic sepsis. Sepsis was induced in chronically catheterized conscious rats by multiple injections of live Escherichia coli via a subcutaneous catheter. Septic animals received intravenous (i.v.) injections of BW755C every 6-8 h to block both the cyclooxygenase and lipoxygenase pathways. Glucose kinetics were assessed in 24-h fasted rats by using a constant i.v. infusion of [6-3H] and [U-14C]-glucose. Treatment with BW755C prevented the 1-2 degrees C increase in body temperature induced by sepsis in the vehicle-treated animals. Septic rats receiving saline instead of BW755C exhibited an elevated plasma lactate concentration and increased rates of glucose appearance, recycling, and metabolic clearance. The sepsis-induced alterations in these variables were not attenuated by BW755C. These results suggest that neither arachidonic acid metabolites nor elevated body temperature are responsible for increasing glucose production and utilization in hypermetabolic septic rats.
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PMID:Inhibition of eicosanoid production by BW755C does not attenuate sepsis-induced alterations in glucose kinetics. 310 59

Previous studies have suggested that alterations in the classical neuroendocrine system may not be responsible for the increased glucose metabolism observed during hypermetabolic sepsis. The purpose of the present study was to determine whether inhibition of the cyclooxygenase pathway with indomethacin, which prevents the production of arachidonic acid metabolites by this pathway and the sepsis-induced increase in body temperature, would abolish the increases in glucose appearance (Ra), recycling, and hyperlactacidemia. Sepsis was induced in chronically catheterized conscious rats by multiple injections of live Escherichia coli via a subcutaneous catheter. Septic animals received iv injections of indomethacin (5 mg/kg) every 6-8 hr to block the cyclooxygenase pathway. Glucose kinetics were assessed in 24-hr fasted rats using a constant iv infusion of [6-3H]- and [U-14C]glucose. Treatment with indomethacin prevented the 1-2 degrees C increase in body temperature observed in septic animals. Septic rats exhibited an elevated plasma lactate concentration and increased rates of glucose appearance and recycling. The sepsis-induced alterations in these variables were not attenuated by indomethacin. These results suggest that neither elevated body temperature nor the generation of arachidonic acid metabolites of the cyclooxygenase pathway is responsible for increasing glucose production in hypermetabolic septic rats.
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PMID:Fever is not responsible for the elevated glucose kinetics in sepsis. 311 80

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.
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PMID:Group B streptococcal (GBSS) newborn septic shock model: the role of prostaglandins. 313 20

Although there are no specific therapies for septic shock or acute lung injury that have proven efficacy in humans, a growing understanding of mechanisms of tissue injury has suggested interventions that may prevent or treat this injury. These therapies range from immunization against the glycopolysaccharide core of endotoxin to cyclooxygenase inhibitors to specific oxygen radical scavengers. Each of these treatments is effective in ameliorating at least one of the pathophysiologic manifestations of acute lung injury, although the effect of these agents in the prevention of the sequelae of fibrosis is unknown. Interaction between several factors and mediators is likely necessary for the development of acute lung injury. It is hoped that with additional knowledge regarding mechanisms of injury gained through basic science and clinical research, we can apply definitive therapy that may salvage patients who now die with sepsis and acute lung injury.
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PMID:Therapeutic implications of acute lung injury. 333 66

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)
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PMID:Pulmonary vasoconstrictor response to soluble fibrin in isolated lungs: possible role of thromboxane generation. 334 71

It has been recently suggested that increased muscle protein degradation during injury or infection is at least partially mediated by the increased production of prostaglandin E2 in muscle, and some have suggested that cyclooxygenase inhibitors might decrease protein loss in injured or septic patients. In these experiments, fractional synthesis rates of mixed muscle and liver protein and whole-body tyrosine flux were measured by constant intravenous infusion of tyrosine labeled with carbon 14 in 17 rats with sham operations and 15 severely septic rats with or without indomethacin treatment (20 mg/kg/d). Fractional synthesis rates in muscle and liver were decreased in late sepsis and were lowest in the septic group receiving indomethacin. Unlike the fractional synthesis rate, which was affected by indomethacin in septic rats only, tyrosine flux was significantly lower in indomethacin-treated rats with sham operations and those with sepsis. Although indomethacin reduced total-body protein breakdown during sepsis, it was also associated with lower plasma albumin levels and with decreased protein synthesis in muscle and liver at a time when the survival of the septic host may be dependent on its ability to produce new protein for a variety of vital functions. These results do not support the use of indomethacin in sepsis.
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PMID:The effect of indomethacin on muscle and liver protein synthesis and on whole-body protein degradation during abdominal sepsis in the rat. 346 35

Infusions of group B streptococci cause pulmonary hypertension in several neonatal animal models. A continuous infusion of prostaglandin D2 reduced the magnitude of this pulmonary hypertensive response; indomethacin completely blocked the response. Prostaglandin D2 or cyclooxygenase inhibitors may be important therapeutic agents for infants with group B streptococcal sepsis who manifest pulmonary hypertension.
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PMID:Influence of prostaglandin D2 on hemodynamic effects of group B streptococcus in neonatal lambs. 353 Jun 74

The role of steroids in the treatment of sepsis and septic shock remains controversial, and it is not known if a possible beneficial effect is due to inhibition of the cyclooxygenase or lipoxygenase pathway of arachidonic acid metabolism. In this investigation we studied the effect of methylprednisolone (MP), the cyclooxygenase inhibitor indomethacin (IM), and the lipoxygenase inhibitor diethylcarbamazine (DE) on survival rate in an experimental trauma-sepsis model in rats consisting of laparotomy and intravenous infusion of live E. coli. Groups of rats received saline (control) or MP (30 mg/kg) intravenously 30 min before or after induction of trauma-sepsis. In other groups of animals IM (4 mg/kg) or DE (0.2 mmol/kg) was administered intravenously 30 min before trauma-sepsis. Survival rate was significantly improved by MP or DE given 30 min before trauma-sepsis while the other treatments did not affect the outcome. The results indicate that the beneficial effect of MP on survival rate in the present trauma-sepsis model did not reflect inhibited prostaglandin synthesis but might have been due to inhibited production of leukotrienes.
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PMID:Effect of methylprednisolone, indomethacin, and diethylcarbamazine on survival rate following trauma and sepsis in rats. 354 76

Endotoxemia and gram negative sepsis remain a clinically important problem since mortality rate is still high in these diseases. Recently, the participation of some new potential mediators in this pathology is beginning to be demonstrated but the results obtained on animal models with specific inhibitors are contradictory. In order to clarify the pathological importance of icosanoids and PAF-acether in the septicemic process, we investigated the effects of indomethacin (IND) a cyclooxygenase inhibitor, NDGA and EP 10045 two lipoxygenase inhibitors, dexamethasone (DXM) a phospholipase A2 inhibitor and BN 52021 a PAF-acether receptor antagonist, on the Salmonella enteritidis-induced endotoxic shock (E.S.) in the rat. Injected subcutaneously 15 min before the test, NDGA, EP 10045 and IND were moderately effective when DXM completely prevented the endotoxin lethality. BN 52021 decreased the death rate in a dose-related manner and exerted at a non-active dose a synergistic effect on IND treatment. Furthermore, given orally 1 hour before endotoxin, it provided a potent protective effect. Our results seem to confirm that PAF-acether exerted alone, or in conjunction with products of the cyclooxygenase pathway, a key role in E.S. when LTs seem to play a role of minor importance.
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PMID:The relative role of PAF-acether and icosanoids in septic shock. 377 51


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