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

The complex pathophysiology of adult respiratory distress syndrome (ARDS) makes preventive and therapeutic concepts difficult. Ample experimental evidence indicates that ARDS can be prevented by blocking systemic inflammatory agents. Clinically, only heparin, for inhibition of coagulation phenomena, is presently used among this array of approaches. Corticosteroids have not proven to be beneficial in ARDS. Alternative antiinflammatory agents are being proposed and are under current clinical investigation (e.g. indomethacin, acetylcysteine, alpha 1-proteinase inhibitor, antitumor necrosis factor, interleukin 1 receptor antagonist, platelet-activating factor antagonists). Symptomatic therapeutic strategies in early ARDS include selective pulmonary vasodilation (preferably by inhaled vasorelaxant agents) and optimal fluid balance. Transbronchial surfactant application, presently tested in pilot studies, may be available for ARDS patients in the near future and may have acute beneficial effects on gas exchange, pulmonary mechanics, and lung hemodynamics; its impact on survival cannot be predicted at the present time. Strong efforts should be taken to reduce secondary nosocomial pneumonia in ARDS patients and thus avoid the vicious circle of pneumonia, sepsis from lung infection, and perpetuation of multiple organ dysfunction syndrome. Optimal respirator therapy should be directed to ameliorate gas-exchange conditions acutely but at the same time should aim at minimizing potentially aggravating side effects of artificial ventilation (barotrauma, O2 toxicity). Several new techniques of mechanical ventilation and the concept of permissive hypercapnia address these aspects. Approaches with extracorporeal CO2 removal and oxygenation are being used in specialized centers.
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PMID:Prevention and therapy of the adult respiratory distress syndrome. 761 57

Previous studies have demonstrated that the administration of the cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF)(20 micrograms/kg) to rats in a fasting state can produce many and perhaps most of the metabolic alterations found in patients with sepsis and injury. The purposes of the present study were 1) to define the metabolic effects of IL-1 and TNF during a fed state provided by continuous intravenous feeding for 20 h and 2) to characterize the unique effects of IL-1 among the overall response to cytokines by using IL-1 receptor antagonist (IL-1RA; 5 mg/kg). The effects were also explored during the endotoxemic condition induced by infusion of 200 micrograms/kg of endotoxin into rats. The results showed that during feeding IL-1 is responsible for the increase in glucose flux and plasma insulin, the development of insulin resistance, and plasma zinc depression during condition mimicking sepsis and injury, similar to effects observed in the fasting state. The changes in energy expenditure have a more complex mechanism. The results also suggested that certain host responses to cytokines or endotoxin, particularly related to protein metabolism, differed between the fed and fasting states. These data may have a special clinical relevance for the insulin-resistant state that develops during severe infection, since using IL-1RA in conjunction with nutritional therapy may offer additional advantages in the treatment of these severe metabolic disorders.
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PMID:Differential effects of interleukin-1 receptor antagonist in cytokine- and endotoxin-treated rats. 786 1

Over a period of 14 days a longitudinal analysis was performed on the effects of filgrastim (recombinant human granulocyte colony stimulating factor, rhG-CSF) administered to 20 postoperative/posttraumatic patients at risk of or with sepsis. The following parameters were determined: leukocyte counts, serum cytokine levels and the surface expression of functional antigens and adhesion molecules. Filgrastim (1 mu g/kg.day) was infused continuously on the first 3 days and tapered to 0.5 mu g/kg.day on the following 4 days or until discharge from the surgical intensive care unit. During infusion of filgrastim, G-CSF levels increased in 16 out of the 20 patients within 48 h. In these 16 patients, leukocyte counts increased in 15 out of 16 patients. Expression of CD64 was upregulated within 24 h. The expression of CD32 was upregulated in 8 out of 9 patients with an initial expression < 55%. LAM-1 expression was downregulated in all patients revealing an initial expression of LAM-1 > 40%. Soluble ICAM increased in 9 out of 11 patients. IL-8 decreased in all 6 patients presenting initial values of IL-8 > 90 pg/ml. IL-1RA increased in 10 patients. Filgrastim had no effect on the expression of CD14, CD16 and CD34 and on the levels of TNF-alpha and sTNF-R type I (p55). In conclusion, infusion of filgrastim in postoperative/post traumatic patients at risk of and with sepsis resulted in improved generation and function of neutrophils and appeared to counterregulate hyperactivation of proinflammatory processes.
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PMID:Filgrastim (RHG-CSF) related modulation of the inflammatory response in patients at risk of sepsis or with sepsis. 883 41

Soluble type II interleukin 1 receptor (IL-1r II) and interleukin 1 receptor antagonist (IL-1ra) regulate inflammation by competitively inhibiting the binding of IL-1 beta to the signalling IL-1 receptor. In addition, glucocorticoids also regulate IL-1 beta by suppressing gene transcription. More recently, glucocorticoids have been shown to increase soluble IL-1r II concentrations, which may contribute to their anti-inflammatory properties. Interestingly, increased serum levels of soluble IL-1r II and IL-1ra have been measured in septic patients, although the mechanism is unclear. In this respect, the authors characterize new pathways in which IL-1r II and IL-1ra may be regulated in sepsis through combined stimulation with lipopolysaccharide (LPS) and dexamethasone of peripheral blood mononuclear cells (PBMC). This paper confirms that while dexamethasone induces release of IL-1r II, LPS augments dexamethasone-induced IL-1r II release 45-fold. Furthermore, LPS plus dexamethasone induces IL-1r II protein and mRNA, whereas LPS alone does not. Additionally, it was shown by flow cytometric analysis that the monocyte is the primary IL-1r II producer in response to LPS and dexamethasone administration. Therefore, LPS and dexamethasone synergism in IL-1r II induction may be important in controlling IL-1 beta effects. In contrast, LPS alone induces IL-1ra, while dexamethasone attenuates this LPS-induced response. Although IL-1r II and IL-1ra may work together to suppress IL-1 beta effects in sepsis, inflammatory cells differentially regulate these cytokines.
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PMID:The combination of endotoxin and dexamethasone induces type II interleukin 1 receptor (IL-1r II) in monocytes: a comparison to interleukin 1 beta (IL-1 beta) and interleukin 1 receptor antagonist (IL-1ra). 904 79

We measured the plasma levels of anti-inflammatory cytokines, including interleukin 1 receptor antagonist (IL-1ra), IL-4 and IL-10; inflammatory cytokines, including IL-2, IL-6, IL-8 and tumor necrosis factor receptor I and II (TNFR I and TNFR II); and endotoxin in 11 patients with septic shock associated with gram-negative bacteria and 12 patients with sepsis not associated with shock. The plasma levels of IL-1ra and IL-10 were elevated in the septic shock group compared with the sepsis group. TNFR I and TNFR II levels tend to be higher in the septic shock group. The plasma level of TRNF-alpha was significantly correlated with levels of IL-1ra, IL-4, IL-10, TNFR I, and TNFR II. The elevated levels of the anti-inflammatory cytokines, TNFR I, and TNFR II, appeared to reflect an attempt to suppress the shock syndrome.
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PMID:Anti-inflammatory cytokine levels in patients with septic shock. 943 13

Almost 60 randomized controlled clinical trials have been undertaken, testing the hypothesis that modulation of the endogenous host inflammatory response can improve survival for patients with a clinical diagnosis of sepsis. The results have been tantalizing, but frustrating, and no new agent has been introduced into clinical practice. Analysis of pooled data from studies of the use of an neutralizing antibody to tumor necrosis factor, or recombinant interleukin 1 receptor antagonist, show that these two approaches yield a statistically significant, but small improvement in 28 day all-cause mortality. However variability in results from one study to the next, the small absolute mortality reduction, the emerging evidence of a substantial potential for harm, and the predicted costs of recombinant biologic agents has engendered a climate of caution and pessimism. The challenge is to find methods of refining investigative approaches to maximize benefit and minimize harm. This paper reviews the recent history of sepsis clinical trials, focussing on emerging insights into the limitations of study entry criteria and measures of biologic activity and clinical benefit that may inform and direct future investigations. The biologic complexity of systemic inflammation, and the multiple interactions between clinical biology and the process of care suggest that future success in clinical research in sepsis will occur through the conduct of highly focussed investigations in a small number of dedicated centres of excellence.
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PMID:Clinical trials of mediator-directed therapy in sepsis: what have we learned? 1078 62

Host immune responses strongly control the outcome of infectious disease, and the resistance to bacterial infections in humans is in part genetically determined. Responses to Gram-negative bacterial endotoxin are affected by the concentration of plasma lipoproteins and lipid transport proteins that are genetically controlled. Alterations of plasma lipid profiles by genetic manipulation in mice indeed strongly modify resistance to bacterial infections. Recently, the TLR-4 receptor has been identified as the endotoxin receptor, and TLR-4 mutations are the cause of endotoxin resistance in mice. It is probable that such defects also exist in humans, although they must be rare. The capacity of monocytes to produce TNFalpha varies more than tenfold, and several polymorphisms within the TNFalpha gene have been associated with increased TNFalpha production and increased mortality of sepsis. However, these associations most likely result from linkage disequilibrium with other immune response genes on chromosome 6. Polymorphisms within the IL-1beta and the IL-1RA genes (located on chromosome 2) are associated with altered protein production rates, and certain haplotypes have been linked to inflammatory disease (no studies in bacterial infectious disease have been published). Mutations in the receptors for IL-12 and IFNgamma, both critical for clearance of intracellular infectious pathogens, occur in consanguineous populations and are associated with severe recurrent infections with Salmonella species and mycobacteria. In conclusion, no human cytokine deficiency syndromes are known, and it remains uncertain whether genetically determined differences in the production rate of pro-inflammatory cytokines alter the outcome of sepsis. In contrast, mutations in the IL-12 and IFNgamma receptor (and possibly the endotoxin receptor) genes are associated with recurrent bacterial infections, whereas TNFR1 mutations cause fever of unknown origin.
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PMID:Cytokine and cytokine receptor polymorphisms in infectious disease. 1078 65

Multiple organ failure (MOF) is a serious condition that involves simultaneous or consecutive functional failure of several important organs. Furthermore, sepsis is known to play an important role in the occurrence of MOF. Hemoadsorption therapy with the endotoxin adsorption column containing polymyxin B immobilized fibers by direct hemoperfusion (PMX-DHP) is reportedly effective in the treatment of septic shock. This study examined the changes induced on cytokines upon PMX-DHP treatment in 25 patients who underwent emergency abdominal surgery and were immediately started on a postoperative regimen of continuous hemodiafiltration (CHDF) and PMX-DHP. Postoperative MOF was observed in these patients with a mean APACHE II SCORE of 25.5. Eighty percent of patients survived for more than 1 month. We were able to reduce the necessary dose of dopamine in 85.7% of patients because hemodynamic stability improved after administration of PMX-DHP. Interleukin 6 blood levels did not change significantly before or after PMX-DHP treatment in either the surviving or nonsurviving patients. Blood interleukin 1 receptor antagonist levels decreased in both groups. Intercellular adhesion molecular-1, NOx, and thrombomodulin did not change significantly during the course of treatment in either group. Decreased blood levels of PAI-1 levels were found in the surviving patients whereas increased levels of PAI-1 were found in the non-surviving patients. In conclusion, PMX-DHP treatment may be limited clinically in its ability to remove inflammatory cytokines and humoral mediators. However, PMX-DHP treatment is useful for hemodynamic stabilization, which prevents development of MOF.
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PMID:Changes of cytokines in direct endotoxin adsorption treatment on postoperative multiple organ failure. 1125 8

Efforts to unravel the events in the evolution of tissue damage in acute pancreatitis have shown a number of inflammatory mediators to be involved. The pathways of damage are similar, whatever the etiology of pancreatitis, with three phases of progression: local acinar injury, systemic response, and generalized sepsis. The proinflammatory response is countered by an anti-inflammatory response, and an imbalance between these two systems leads to localized tissue destruction and distant organ damage. Cytokines lie at the heart of the problem and are involved in all aspects of the cascade leading to systemic inflammatory response syndrome and multiple organ dysfunction syndrome. This review discusses the present knowledge about the role of various mediators in this process, their genetic control, and the effects of their modulation. The major proinflammatory mediators are tumor necrosis factor, interleukins 1, 6, and 8, platelet activation factor, and the chemokines. The major anti-inflammatory factors include interleukin 10, and interleukin 1 receptor antagonist. Emerging knowledge of new mediators as well as future strategy of damage control is discussed.
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PMID:Cytokine storm in acute pancreatitis. 1248 60

Gene- and signal-specific adaptation/tolerance of blood leukocytes to lipopolysaccharide endotoxin (LPS) occurs during human and animal septicemia. These phenotypes can be modeled in vitro. LPS-TLR4-adapted human THP-1 promonocytic cells cross-adapt to lipoteichoic acid (LTA)-TLR2-induced IL-1beta/TNF-alpha production, suggesting disruption of a common intracellular signaling event(s). A plausible explanation for homologous adaptation of TLR4 with heterologous adaptation of TLR2 is a persistent inactivation and degradation of IRAK1 following TLR4 activation. LTA stimulation of TLR2 also produces homologous adaptation of TLR2 with inactivation of IRAK1, but there is no detectable degradation of IRAK1. Strikingly, such LTA-adapted cells still respond to LPS stimulation of TLR4 with rapid activation and degradation of IRAK1, and robust IL-1beta/TNF-alpha production. Moreover, cells adapted to either LTA- or LPS-production of IL-1beta/TNF-alpha normally produce soluble interleukin 1 receptor antagonist (sIL-1Ra) anti-inflammatory protein when stimulated by either agonist. We conclude that: (i) disruption of a unique TLR2 signaling component upstream of IRAK1, but downstream of TLR2 sensing, induces homologous adaptation to LTA; (ii) disruption of IRAK1 may induce homologous adaptation of TLR4 to LPS and cross-adaptation of TLR2 to LTA; and (iii) TLR2/TLR4 signaling events that control sIL-1Ra translation do not adapt to LPS or LTA, indicating that TLR4 and TLR2 can still function. We present a hypothetical model of adaptation based on a signalsome, with IRAK1 evolving after IRAK4 to regulate TLR4 adaptation tightly.
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PMID:Distinct post-receptor alterations generate gene- and signal-selective adaptation and cross-adaptation of TLR4 and TLR2 in human leukocytes. 1269 17


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