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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study explored the relationship between cytokines (TNF, IL-1, IL-6), coagulation and fibrinolytic factors in the early stage of sepsis syndrome and the relation between these factors with the severity of inflammatory illness as measured by the Simplified Acute Physiology Score (SAPS). Twenty-one normal controls were compared to 34 patients divided into three categories ranging from uncomplicated postoperative patients, to patients with severe infectious conditions including septic shock. A major hemostatic imbalance was demonstrated with particularly marked reduction in fibrinolytic activity [drop of antithrombin III (ATIII) and protein C with an increase of plasminogen activator inhibitor (PAI-1) levels] which were directly correlated with the severity of the inflammatory state. Both ATIII and PAI-1 levels were correlated with the levels of TNF and IL-6 and the severity of illness as measured by SAPS. We established an index, ATIII/PAI-1 antigen that is significantly different among the four groups (p < 0.001) and strongly correlated with the SAPS (p < 0.001). As PAI-1 could be secreted not only by TNF activating endothelial cells but also by hepatocytes activated by insulinemia, treatment of sepsis with cytokine-specific agents might be of limited effect.
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PMID:Coagulation/fibrinolysis balance in septic shock related to cytokines and clinical state. 795 54

Sepsis is the most important cause of mortality in the Intensive Care Units. At present, sepsis is understood to be the inflammatory response of the host to infection, rather than a direct effect of microbial aggression. From the clinical standpoint, this inflammatory response is known as systemic inflammatory response syndrome (SIRS). Pathophysiologically, SIRS is characterized by the activation of several groups of cell (monocytes/macrophages, PMNs, and endothelial cells) and by the release of inflammatory mediators (cytokines and others). Tumor necrosis factor (TNF) is the first cytokine released by endotoxin action over monocyte/macrophage. TNF secretion, modulated by interferon gamma (IFN gamma) and interleukin 10 (IL-10), is followed by release of other cytokines such as interleukins (IL) (IL-1, IL-6 and IL-8). These mediators are able to act over hemostasis activating the extrinsic pathway through tissue factor expression. The action of the mediators over endothelial cells induces an increase in plasminogen activator inhibitor type 1 (PAI-1) levels with inhibition of fibrinolysis. Both coagulation activation and fibrinolysis blockade result in fibrin deposit in the microvascular system. The complexity of the mechanisms implicated in systemic inflammatory response make a general rule so difficult to establish, because patient response is highly individualized and it is not possible to know which moment of this dynamic process is being analyzed.
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PMID:Inflammatory mediators and their influence on haemostasis. 795 61

Mild infection or sublethal dose of endotoxin elicits a brief elevation of GH and PRL in the serum. These hormones have proinflammatory and immunostimulatory effect. In severe trauma, sepsis and shock, GH and PRL are suppressed, whereas glucocorticoids and catecholamines are elevated. Under these conditions an acute phase response is initiated by tissue derived (cytokine) hormones, namely IL-1, IL-6, TNF alpha, and several others, which elicit a neuroendocrine response and initiate major metabolic alterations. There is fever and catabolism prevails, whereas the synthesis of acute phase proteins in the liver, cell proliferation in the bone marrow, and protein synthesis by leukocytes is elevated. This is an emergency reaction to save the organism after the local immune/inflammatory response has failed to contain and eliminate the infectious agent. During sepsis and endotoxin shock the systemic activation of the complement system and of leukocytes releasing enzymes and highly toxic cytokines seriously threaten survival. Glucocorticoids suppress proinflammatory cytokine production and potentiate the secretion of acute phase proteins. Some of these proteins, such as C reactive protein, or LPS binding protein, are designed to combine with microorganisms and trigger their destruction by the activation of complement system and of phagocytes. The increased production of some complement components also helps host resistance. The rise in serum fibrinogen promotes blood clotting which can serve to isolate the invading agent by triggering thrombosis in infected tissues. A number of enzyme inhibitors are produced as acute phase proteins, which are likely to serve to curb the nonspecific damage inflicted by enzymes released from activated phagocytes and from damaged cells into the circulation during sepsis and shock. Catecholamines are also elevated, which serve to inhibit inflammatory responses and to promote, even initiate, the acute phase response. If the acute phase reaction fails to protect the host, shock will develop. Patients with subclinical adrenal insufficiency succumb to septic shock almost invariably if glucocorticoid therapy is not given. However, glucocorticoid treatment of septic patients with normal adrenal function has not been helpful. The use of antibiotics to control infection did not lead to spectacular success either because of the emergence of resistant bacterial strains or the enhanced release of endotoxin by this therapy. The new approaches to prevent and treat septic shock involve the use of antibodies capable of neutralizing LPS and of cytokines and the inhibition of cytokine action by antagonist agents.
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PMID:Neuroendocrine defence in endotoxin shock (a review). 797 6

Biomaterials in the peritoneal cavity disrupt the physiology of the host and may cause bacterial translocation. The current study was performed to determine whether biomaterials exacerbate intra-abdominal infections. Adult male rats were divided into four groups: group 1, celiotomy+intraperitoneal (i.p.) saline; group 2, celiotomy+i.p. Escherichia coli (3 x 10(8) cfu); group 3, i.p. rubber+i.p. saline; and group 4, i.p. rubber+i.p. E. coli (3 x 10(8) cfu). Twelve h after the challenge, enteric bacterial translocation, bacterial population levels in the cecum and serum levels of IL-6 and TNF were measured. Bacterial translocation to mesenteric lymph nodes and the liver was observed in animals from groups 2 and 3, but significantly increased in group 4 with a concomitant elevation of serum levels of TNF and IL-6, as compared with group 1. Histological examination revealed a more pronounced inflammatory reaction in the peritoneum and distal ileum in group 4 than in groups 2 and 3. These results suggest that the presence of rubbers in the peritoneal cavity aggravates intra-abdominal sepsis.
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PMID:Abdominal rubber drain piece aggravates intra-abdominal sepsis in the rat. 798 41

In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism.
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PMID:Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism. 798 76

Cytokines are considered to be important mediators in the pathophysiology of sepsis and septic shock. We investigated if continuous arteriovenous haemofiltration (CAVH) could be used to remove excessive amounts of the cytokines tumour necrosis factor-alpha (TNF alpha), interleukin (IL)-1 alpha and IL-6 from peripheral blood in critically ill patients. Nine septic patients with renal failure were treated with CAVH. Ultrafiltrate and plasma were tested for cytokines by ELISA. All patients had detectable TNF alpha and IL-6 plasma levels, ranging from 10-750 pg/ml and 50-4,575 pg/ml, respectively. TNF alpha was removed by the ultrafiltrate with concentrations ranging from 10-1,000 pg/ml. The TNF alpha levels were significantly higher in the ultrafiltrate samples than in the corresponding plasma samples (P < 0.003). IL-6 was undetectable in the ultrafiltrate from five of the patients despite concomitant high plasma levels. IL-1 alpha was detectable in both plasma and ultrafiltrate in four patients. All patients developed multi-organ failure and septic shock and seven died. It is concluded that TNF alpha and IL-1 alpha but not IL-6 can be removed by CAVH in patients with sepsis.
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PMID:Cytokines in plasma and ultrafiltrate during continuous arteriovenous haemofiltration. 812 31

The addition of recombinant human interleukin-6 (rIL-6) to either soleus or extensor digitorum longus (EDL) muscle preparations did not affect the rate of protein breakdown as measured by the rate of tyrosine released to the medium. In addition, the presence of the cytokine did not influence either the rate of protein synthesis or that of alpha-(methyl)-aminoisobutyric acid (MeAIB) uptake by the muscle preparations. It is concluded that IL-6 is not the mediator in activating muscle protein turnover during sepsis in the rat.
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PMID:Interleukin-6 does not activate protein breakdown in rat skeletal muscle. 812 60

Platelet-activating factor (PAF) has been postulated to play a role in the pathogenesis of sepsis. Additionally, in vitro studies have revealed tight interactions between PAF and the cytokine network, and PAF is considered to be an important stimulator of neutrophil functions. To assess the intermediate role of PAF in the induction of cytokines and neutrophil degranulation in endotoxemia in vivo, 12 healthy adult chimpanzees were i.v. injected with a bolus dose of Escherichia coli endotoxin (4 ng/kg); four animals received endotoxin alone, whereas the other chimpanzees were infused with the specific and potent PAF antagonist TCV-309 (bolus of 100 micrograms/kg, followed by either 100 micrograms/kg/h (n = 4) or 500 micrograms/kg/h (n = 4) for 5 h). At both doses TCV-309 significantly inhibited the endotoxin-induced rise in cytokine levels. Peak TNF concentrations after injection of endotoxin alone were 366 +/- 96 pg/ml, vs 105 +/- 47 and 115 +/- 56 pg/ml after administration of endotoxin together with the lower or higher dose of TCV-309, respectively (p < 0.05). TCV-309 also reduced the appearance of soluble TNFRs. Maximal levels of the type I soluble TNFR were diminished from 2.53 +/- 0.27 ng/ml (endotoxin alone) to 1.69 +/- 0.36 ng/ml (high dose TCV-309; p < 0.05); peak values of the type II soluble TNFR were diminished from 8.62 +/- 1.19 ng/ml to 5.76 +/- 0.92 ng/ml (p < 0.05). Furthermore, TCV-309 attenuated the endotoxin-induced release of IL-6 (160 +/- 82 pg/ml after endotoxin alone, vs 63 +/- 30 pg/ml in the low dose TCV-309 group (p < 0.05) and 65 +/- 29 pg/ml in the high dose group (p = 0.07) as well as that of IL-8 (279 +/- 168, vs 71 +/- 15 and 46 +/- 17 pg/ml, respectively; both p < 0.05). TCV-309 tended to reduce the endotoxin-provoked rise in serum IL-1R antagonist levels. In contrast, TCV-309 did not affect the neutrophilic leukocytosis elicited by endotoxin, nor did it inhibit endotoxin-induced neutrophil degranulation, as monitored by the plasma levels of elastase-alpha 1-antitrypsin complexes. We conclude that PAF plays a role, either directly or indirectly, in the stimulation of the cytokine network and in the shedding of soluble TNFR in endotoxemia. PAF does not seem to be an important intermediate factor in endotoxin-induced neutrophilia or neutrophil degranulation.
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PMID:Platelet-activating factor antagonist TCV-309 attenuates the induction of the cytokine network in experimental endotoxemia in chimpanzees. 813 55

The efficacy, safety and usefulness of murine anti-endotoxin monoclonal IgM antibody "E5, an intravenous dose of 2 mg/kg" were evaluated in 88 patients with suspected Gram-negative sepsis from 37 institutes in Japan. Out of these, 74 patients were evaluable for the efficacy, 85 for safety and 75 for clinical usefulness. In assessing the efficacy, the patients were divided into 3 groups based on the plasma endotoxin levels (Endospecy with new PCA treatment of plasma): H group with a level of above 9.8 pg/ml and M group with a level of 3.0-9.8 pg/ml and L group with a level of below 3.0 pg/ml. 1. The efficacy rates as assessed following administration of E5 were 73.1% in the H group, 70.4% in the M group and 38.1% in the L group being higher in the groups with significantly high plasma endotoxin levels. 2. In both the H and M groups in whom plasma endotoxin levels were significantly high, the majority of the patients showed rapid reduction of the levels after administration of E5. 3. In all groups, improvement in body temperature, pulse rate, blood TNF-alpha and blood IL-6 was observed after treatment with E5. In the H and M groups with an endotoxin level of > or = 3.0 pg/ml, improvement in platelet count as well as in CRP was noted. The H group showed also improvement in WBC. 4. Improvement in the shock score was noted in all the groups but was more outstanding in the H and M groups in the early stage of treatment. 5. Side effects were seen in 5 (5.9%) of 85 patients and all thought to be allergic in symptoms such as rash, itching, fever and flare. 6. The reaction to the prick test performed before administration of E5 was negative in all these 5 patients. For 3 of the 5 patients, anti-E5 IgE antibody was measured. In all of them, the IgE levels were higher than those of healthy controls. Also, in 47.6% of patients, an elevation of anti-E5 IgG antibody was noted two weeks after the administration. 7. Clinical laboratory abnormalities were observed in 3 (3.5%) of 85 patients. They were an elevation of S-GOT.S-GPT and lowering of BUN, increased Al-p and decreased CH50, increased neutrophilia (%) and were all slight in the degree of the changes. 8. The clinical usefulness of E5 was evaluated for 75 patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Phase II study of edobacomab (E5) in the treatment of gram-negative sepsis]. 813 82

Patients with advanced cancer and cachexia typically demonstrate modestly increased rates of energy expenditure in the presence of diminished food intake due to anorexia and to gastrointestinal disturbances. Rates of glucose production by the liver, gluconeogenesis and glycolysis to lactate (Cori cycle) are increased, fat mobilisation and oxidation are accelerated. There is a redistribution of body proteins away from muscle towards visceral proteins, resulting in marked muscle protein loss. Cancer cachexia differs from simple starvation and demonstrates metabolic similarities to sepsis or polytrauma. The metabolic response in the patient with cancer is largely due to mediators released by the tumour or by the host; recently the role of cytokines such as tumour necrosis factor alpha (TNF alpha), interleukin-1 (IL-1) and -6 (IL-6) and interferon gamma (INF gamma) has been emphasized. Catabolic hormones such as glucocorticoids and adrenaline have also been implicated. Cytokines have the potential to reproduce experimentally the clinical syndrome of cancer cachexia. There is evidence of increased production of several of them in certain types of cancer. There are overlapping activities of the cytokines TNF alpha, IL-1, IFN gamma and IL-6. The contribution of each of them to cancer cachexia remains unclear. Inhibition of cytokine activity using specific antibodies in cancer-bearing experimental animals demonstrated partial prevention of cachexia. A positive feedback between macrophage-derived IL-1 and tumour-derived IL-6 has been demonstrated recently in experimental cancer cachexia. Cytokines may support tumour growth by acting as growth factors.
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PMID:Pathophysiology of cancer cachexia. 815 43


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