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

The clinical presentation of patients with multiorgan failure caused by septic conditions is very similar to that seen in patients with multiorgan failure after cardiopulmonary bypass. It has been hypothesized that the same mechanisms are at work in both instances. This commonality of presentation and mechanisms is denoted by the new term systemic inflammatory response syndrome. The systemic inflammation resulting from cardiopulmonary bypass is manifested by the development of adult respiratory distress syndrome. Overall mortality for this condition is high, and the absence of a specific therapy reflects the lack of understanding of the mechanisms involved. The risk factors associated with multiorgan failure include the age of the patient, the number of failed organs, and whether these organ failures persist or resolve. The release of a variety of inflammatory mediators has been implicated in the pathogenesis of sepsis. These include the cytokines (tumor necrosis factor, interleukin-1, interleukin-6), lipid and arachidonate metabolites, platelet-activating factor, and activation of the coagulation cascade. There seems to be marked synergy between these different mediators, suggesting that a combination of small amounts of them all may be more toxic than a large release of one by itself. During cardiopulmonary bypass, increased levels of circulating endotoxin have been associated with the activation of the complement system and increased levels of tumor necrosis factor. Interleukin-6 level has been shown to be elevated during bypass. The action of the inflammatory mediators to induce injury may be related to the activation of leukocytes and endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure. 823 45

Experiments using a murine model of heat-killed Staphylococcus aureus-induced gram-positive bacterial sepsis indicate that the lethal bacterial effects can be prevented if mice are pretreated with CL 184,005, a platelet-activating factor (PAF) antagonist. CL 184,005 was ineffective when administered after bacterial challenge. Plasma of mice pretreated with CL 184,005 contained significantly less tumor necrosis factor (TNF), suggesting that CL 184,005 interferes with TNF synthesis induced by S. aureus. Spleen-associated TNF protein was also decreased by pretreatment with CL 184,005. Although TNF levels were significantly decreased in mice treated with CL 184,005, interleukin-6 levels in serum were significantly increased. Athymic mice were also susceptible to the lethal effects of S. aureus, suggesting that T cells were not involved. When rats rendered hypotensive with S. aureus were treated with CL 184,005, their blood pressure was normalized. Mice treated with enterotoxin B were not protected if they were pretreated with CL 184,005; however, TNF levels in these mice were significantly lower, suggesting that mediators other than PAF and TNF may contribute to the lethal effects of enterotoxin.
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PMID:Effect of CL 184,005, a platelet-activating factor antagonist in a murine model of Staphylococcus aureus-induced gram-positive sepsis. 827 76

We hypothesized that plasma levels of cytokines such as interleukin-6 and tumor necrosis factor (TNF) are elevated in critically ill infants with sepsis and necrotizing enterocolitis (NEC) and that the magnitude of their elevation is correlated with mortality rate. We measured plasma levels of interleukin-6 and TNF in 62 newborn infants with suspected sepsis or NEC. Eighteen infants had bacterial sepsis, 9 had bacterial sepsis plus NEC, and 15 had NEC but negative culture results. Twenty comparably ill infants with negative results on culture of systemic specimens served as study control subjects. Interleukin-6 levels were five- to tenfold higher in infants with bacterial sepsis plus NEC at the onset of disease than in infants with bacterial sepsis alone, in infants with NEC but negative culture results, and in control infants (p < 0.01). These differences persisted throughout the 48-hour study period. Interleukin-6 levels were also significantly higher in nonsurvivors than in survivors (p < 0.001). In contrast, plasma TNF values were not consistently increased in any of the groups. We conclude that plasma interleukin-6 is a more reliable indicator of bacterial sepsis and NEC than plasma TNF and may identify infants who might benefit from immunotherapeutic strategies.
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PMID:Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. 807 69

Tumor necrosis factor (TNF) is considered to be a pivotal mediator of endotoxin-induced lethality. To assess the intermediate role of TNF in specific systemic inflammatory responses known to contribute to tissue injury in endotoxemia, eight healthy adult chimpanzees were intravenously injected with Escherichia coli endotoxin (4 ng/kg). In four of these animals the administration of endotoxin was followed immediately by a bolus intravenous injection of an anti-TNF monoclonal antibody (15 mg/kg). Treatment with anti-TNF completely prevented the endotoxin-induced increase in serum TNF activity, and profoundly reduced the appearance of interleukin-6 and -8 (both P < .05). Neutrophilia and lymphopenia were not affected by anti-TNF, whereas neutrophil degranulation, as measured by the plasma concentrations of elastase-alpha 1-antitrypsin complexes, was only slightly reduced (peak levels after endotoxin alone 31.0 +/- 3.4 ng/mL, versus 25.5 +/- 3.4 ng/mL after endotoxin with anti-TNF; P < .05). Anti-TNF did not influence endotoxin-induced activation of the coagulation system, as reflected by unchanged increases in the plasma concentrations of the prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes. In contrast, anti-TNF strongly attenuated the activation of the fibrinolytic system, ie, peak plasma levels of plasmin-alpha 2-antiplasmin were 33.8 +/- 11.1 nmol/L after endotoxin alone and 17.0 +/- 2.9 nmol/L after endotoxin with anti-TNF (P < .05). These results suggest that TNF is not the common mediator of systemic inflammatory changes in low-grade endotoxemia. Moreover, the finding that in this mild model anti-TNF specifically inhibited fibrinolysis suggests that treatment with anti-TNF potentially may enhance the tendency towards microvascular thrombosis in sepsis.
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PMID:Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. 828 42

Although plasma levels of tumor necrosis factor (TNF) are elevated and hepatocellular dysfunction occurs even in the early hyperdynamic stage of sepsis, the precise mechanism responsible for this dysfunction remains unknown. Although TNF at high doses produces circulatory failure, it is not known whether the dose of TNF that does not adversely affect hemodynamics alters hepatocellular function. To study this, recombinant murine TNF-alpha was infused intravenously (0.05 or 0.25 mg/kg) over 30 min in normal rats. At 1 and 4 h after infusion of TNF-alpha or an equivalent volume of saline, hepatocellular function [i.e., maximum velocity (Vmax) and Michaelis constant (Km)] was assessed using in vivo indocyanine green clearance without blood sampling. Additional parameters measured were as follows: cardiac output by dye dilution, hepatic microcirculation by laser Doppler flowmetry and colloidal carbon infusion, plasma TNF and interleukin-6 (IL-6) by cytokine-dependent cellular assays, and plasma glucose enzymatically. The results indicate that although infusion of 0.05 mg/kg TNF-alpha did not affect Vmax and Km, its infusion at 0.25 mg/kg produced a significant depression of hepatocellular function and markedly increased the synthesis and/or release of IL-6. TNF-alpha-induced hepatocellular dysfunction was not associated with any significant changes in hepatic microcirculation, plasma glucose, cardiac output, and other measured hemodynamic parameters. Thus hepatocellular dysfunction observed after TNF infusion may be due to the direct effect of this cytokine alone or in combination with IL-6.
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PMID:Tumor necrosis factor-alpha produces hepatocellular dysfunction despite normal cardiac output and hepatic microcirculation. 820 42

Cytokines are suspected of playing an important role in the pathophysiology of septic shock. This study was undertaken to determine whether tumor necrosis factor alpha (TNF-alpha) induces the production of other cytokines and mediates mortality in a neonatal rat model of sepsis caused by group B streptococci (GBS). We have measured TNF-alpha, interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), and gamma interferon (IFN-gamma) levels in neonatal rats infected with different strains (H738, 259, and 90) and doses (1 50% lethal dose [LD50] and 5 90% lethal doses [LD90]) of type III GBS. TNF-alpha and IL-6 were detected by the L929 cytotoxicity and the B9 proliferation assays, respectively, in serial plasma samples. IL-1 alpha and IFN-gamma were measured in spleen homogenates by enzyme-linked immunosorbent assay kits by using antibodies raised against the corresponding mouse cytokines. Plasma TNF-alpha levels significantly rose above baseline values within 12 h after intraperitoneal challenge with 5 LD90 of GBS strain H738, corresponding to 3 x 10(3) CFU. A mean peak TNF-alpha concentration of 232 +/- 124 U/ml was reached at 20 h. Peak IL-1 alpha and IL-6 levels of 766 +/- 404 U/g and 1,033 +/- 520 U/ml, respectively, were reached at 24 h after bacterial challenge. Maximal spleen concentrations of IFN-gamma (449 +/- 283 U/g) were measured at 36 h. Concentrations of TNF-alpha, but not other cytokines, remained significantly elevated at 72 h, a time when mortality approached 100%. Significant correlations were found between concentrations of each of the cytokines tested and the logs of CFU concentrations in the blood. In order to ascertain whether TNF-alpha influenced the production of other cytokines, rat pups received two injections of anti-murine TNF-alpha or normal rabbit serum at 2 h before and at 26 h after challenge with live GBS. Plasma TNF-alpha bioactivity was undetectable in anti-TNF-alpha-treated animals, while IL-6 and IFN-gamma, but not IL-1 alpha, levels were significantly reduced, compared with normal serum controls. Rat pups pretreated with anti-TNF-alpha serum and infected with 1 and 5 LD90 of strains H738 and 259 showed enhanced early (48 to 72 h) survival. However, by 96 h this protection was no longer apparent.
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PMID:Cytokine appearance and effects of anti-tumor necrosis factor alpha antibodies in a neonatal rat model of group B streptococcal infection. 841 44

In previous studies, we have shown that administration of monoclonal antibody (MoAb) C6B7 against human factor XII to baboons challenged with a lethal dose of Escherichia coli abrogates activation of the contact system and modulates secondary hypotension. To evaluate the contribution of activated contact proteases to the appearance of other inflammatory mediators in this experimental model of sepsis, we studied the effect of administration of MoAb C6B7 on activation of complement and fibrinolytic cascades, stimulation of neutrophil degranulation, and release of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Activation of the complement system, as reflected by circulating C3b/c and C4b/c levels, was significantly reduced in five animals that had received MoAb C6B7 before a lethal dose of E coli as compared with five control animals that had been given a lethal challenge only. Inhibition of contact activation also modulated the fibrinolytic response, since the release of tissue-type plasminogen activator (t-PA) and the appearance of plasmin-alpha2-antiplasmin (PAP) complexes into the circulation was significantly attenuated upon pretreatment with anti-factor XII MoAb. In contrast, plasma levels of plasminogen activator inhibitor (PAI) were modestly enhanced in the treatment group. Degranulation of neutrophils, as assessed by circulating elastase-alpha1-protease inhibitor complexes, and release of IL-6 but not of TNF-alpha was decreased in anti-factor XII-treated animals. Observed differences in the inflammatory response between treatment and control groups were not likely due to different challenges, since the number of E coli that had been infused, as well as circulating levels of endotoxin after the challenge, were similar for both groups. These data suggest that activation of the contact system modulates directly or indirectly various mediator systems involved in the inflammatory response during severe sepsis in nonhuman primates.
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PMID:Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase. 863 Mar 96

The serum levels of immunoreactive interleukin-6 (IL-6) and tumor necrosis factor (TNF) were analyzed in 14 leukopenic patients with documented sepsis, at 60 min (T0), 24 h (T1), and one week (T3) after the onset of sepsis syndrome. Sera from 10 leukopenic patients without sepsis (controls) were also tested. All septic patients had high IL-6 levels at T0. These levels persisted only in the seven patients who died of septic shock, presenting a 30-fold increase (p<0.001) as compared to the survivors and the controls. At T3, 7 survivors had recovered from sepsis and showed low IL-6 serum levels. The TNF serum concentration always <30 pg/ml in both the subjects and in the controls. The C-reactive protein (CRP) and clinical parameters appeared to be less specifically associated with shock and mortality than IL-6.
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PMID:High IL-6 serum levels are associated with septic shock and mortality in septic patients with severe leukopenia due to hematological malignancies. 865 74

Pentoxifylline can decrease the production of tumour necrosis factor alpha (TNF alpha) by endotoxin-stimulated macrophages and may improve survival in animals with overwhelming bacterial sepsis. In this study various doses of pentoxifylline were administered to mice with systemic Candida albicans infection to determine its effect on serum TNF alpha levels, organ fungal burden, and host survival. Intraperitoneal injections of pentoxifylline at 20 mg/kg every 8 h did not affect these endpoints. However, fungal counts were significantly higher in kidneys of animals that received 30 and 60 mg/kg of pentoxifylline every 8 h when compared to controls. Injection of 60 mg/kg of pentoxifylline at 8 h intervals also significantly shortened mean survival from 5.8 to 3.8 days (P = 0.01). Pentoxifylline did not affect peripheral WBC counts, serum TNF alpha and interleukin-6 levels, or the density of neutrophils in tissues. In vitro, pentoxifylline decreased the production of TNF alpha by C. albicans-stimulated macrophages in a dose-dependent manner, but only at concentrations greater than 100 mg/L. In contrast, pentoxifylline suppressed TNF alpha production by endotoxin-stimulated macrophages at concentrations as low as 10 mg/L. Thus, higher doses of pentoxifylline are detrimental in systemic C. albicans infection. However, the detrimental effect is not mediated by alterations in serum TNF alpha or interleukin-6 levels or the aggregation of neutrophils in tissues.
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PMID:Effect of pentoxifylline on the course of systemic Candida albicans infection in mice. 873 44

Systemic Inflammatory Response Syndrome (SIRS) is a new concept of entry criteria for sepsis. This concept, when applied to area of Multiple Organ Failure (MOF), is considered to be a preparatory state for MOF. To study the significance of SIRS state at cardiac surgery, we measured the body temperature, white blood cell count, respiratory rate and heart rate of 18 patients who underwent elective cardiac surgery, from the 1st post-operative day to the 7th post-operative day. We also measured Interleukin-6 and 8 (IL-6 and IL-8) to understand the relationship between the SIRS state and inflammatory cytokines just after cardiopulmonary bypass (CPB), at the 1st, 3rd and 6th postoperative day. The result was as follows: Patients with CPB more than 120 minutes have more frequency and longer duration of SIRS than patients with CPB less than 120 minutes. Serum levels of IL-8 at SIRS state were revealed statistically higher than at non-SIRS case. Duration of SIRS state was related to CPB time and serum levels of IL-6 and IL-8 just after CPB. We concluded that SIRS state is an indication for anti-cytokine therapy to prevent MOF, and it is important to shorten CPB time in order to decrease the duration of SIRS.
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PMID:[Significance of systemic inflammatory response syndrome at cardiopulmonary bypass]. 875 88


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