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

Severe sepsis is a life-threatening complication of infection. Due to associated organ-failure treatment in an Intensive Care Unit is usually indicated. Since sepsis is defined by the combination and progression of clinical events, correct definitions are essential to enable good comparison between study results and determination of suitable treatment. Severe sepsis is associated with a mortality of 20-60% and decreases the health-related quality of life in survivors. It is estimated that annually in the Netherlands 9000 patients are admitted to an Intensive Care Unit with severe sepsis. Direct medical costs of severe sepsis are estimated at [symbol: see text] 19,500 per patient. Costs correlate strongly with the length of stay. Annually Euro dollar 168,6 million is spent on severe sepsis, which represents 0.5% of all health-care costs and 1.7% of the annual hospital budget in the Netherlands.
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PMID:[Sepsis, a complicated syndrome with major medical and social consequences]. 1518 21

Severe sepsis is a heterogeneous syndrome in a heterogeneous population. The current scheme of classification does not enable distinction between systemic inflammatory response syndrome, sepsis and severe sepsis on the basis of the underlying biochemical, immunological and abnormal coagulation features. Planning, implementation and assessment of results of intervention studies on severe sepsis thus present enormous challenges. Two such studies were published in the year 2001. The study investigating the drug drotrecogin alfa (activated) was positive in the day-28 mortality endpoint; however, post-hoc analyses have raised controversies regarding the manner in which the study was carried out, the consistency of results presented, and the suggested mechanism of action. On the other hand, the KyberSept study that investigated antithrombin III reported negative results for the day-28 mortality endpoint, despite correct performance of the study. This, however, was not interpreted to mean proof of therapeutic inefficacy of administering antithrombin III and post-hoc analyses raise the suspicion of an undesirable drug interaction between antithrombin III and heparin. Apparently, neither of the sepsis studies meets the criteria which lie at the basis of critical assessment of the success or failure of clinical trials that could more significantly affect clinical treatment decisions.
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PMID:Comparison of mechanisms after post-hoc analyses of the drotrecogin alfa (activated) and antithrombin III trials in severe sepsis. 1518 75

Severe sepsis and septic shock are an important cause of mortality. Until recently, in spite of major progresses in our understanding of the pathogenic mechanisms of this syndrome, clinicians had only a limited therapeutic arsenal. Considerable efforts have been made in the past few years to develop novel therapeutic interventions to reduce mortality in sepsis. So far, five specific therapies have proven their efficacy to achieve such goal in large randomised controlled trials: early goal-directed therapy, recombinant activated protein C, moderate doses of steroids, low tidal volume ventilation in acute respiratory distress syndrome and intensive insulin therapy to control hyperglycemia. This review will focus on these recently acquired therapeutic modalities, that are presently available to clinicians for the treatment of severe sepsis and septic shock.
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PMID:[New therapeutic strategies in severe sepsis and septic shock]. 1529 39

Severe sepsis remains both an important clinical challenge and an economic burden in intensive care. An estimated 750,000 cases occur each year in the US alone (300 cases per 100,000 population). Lower numbers are estimated for most European countries (e.g. Germany and Austria: 54-116 cases per year per 100,000). Sepsis patients are generally treated in intensive care units (ICUs) where close supervision and intensive care treatment by a competent team with adequate equipment can be provided. Staffing costs represent from 40% to >60% of the total ICU budget. Because of the high proportion of fixed costs in ICU treatment, the total cost of ICU care is mainly dependent on the length of ICU stay (ICU-LOS). The average total cost per ICU day is estimated at approximately 1200 Euro for countries with a highly developed healthcare system (based on various studies conducted between 1989 and 2001 and converted at 2003 currency rates). Patients with infections and severe sepsis require a prolonged ICU-LOS, resulting in higher costs of treatment compared with other ICU patients. US cost-of-illness studies focusing on direct costs per sepsis patient have yielded estimates of 34,000 Euro, whereas European studies have given lower cost estimates, ranging from 23,000 Euro to 29,000 Euro. Direct costs, however, make up only about 20-30% of the cost of illness of severe sepsis. Indirect costs associated with severe sepsis account for 70-80% of costs and arise mainly from productivity losses due to mortality. Because of increasing healthcare cost pressures worldwide, economic issues have become important for the introduction of new innovations. This is evident when introducing new biotechnology products, such as drotrecogin-alpha (activated protein C), into specific therapy for severe sepsis. Data so far suggest that when drotrecogin-alpha treatment is targeted to those patients most likely to achieve the greatest benefit, the drug is cost effective by the standards of other well accepted life-saving interventions.
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PMID:Economic aspects of severe sepsis: a review of intensive care unit costs, cost of illness and cost effectiveness of therapy. 1529 12

Severe sepsis and trauma complicated with multiple organ dysfunction syndrome (MODS) are among the leading causes of death in intensive therapy units, with mortality rate exceeding 50%. The outcome is not determined only by infection or trauma, but also by the intensity of immuno-inflammatory response, which is essential for host defence, but if uncontrolled leads to MODS. Pro-inflammatory cytokines (tumor necrosis factor-alpha--TNF-alpha, IL-1, IL-8, IL-12, IFN-gamma, etc.) represent a part of this immuno-inflammatory response to an insult. The results of the clinical investigation of correlation between pro-inflammatory cytokines (IL-8, IL-12, TNF-alpha, IFN-gamma), the outcome (survivors, non-survivors), and the severity (systemic inflammatory response syndrome--SIRS--less severe, and MODS--more severe) in polytraumatised patients with sepsis are presented in this paper. Mean values of IL-8 were 1.3-fold higher in non-survivors (p<0.05), and 60-fold higher in MODS group (p<0.01). Mean values of IL-12 were 1.6-fold higher in survivors (p<0.01), while the values between SIRS and MODS group did not differ significantly; mean values of TNF-alpha were 3-fold higher in survivors (p<0.05), and 46-fold higher in MODS group (p<0.01). Mean values of IFN-gamma did not differ significantly between the two groups regarding the outcome and severity. The obtained results indicated that IL-8 was a reliable predictor of lethal outcome and MODS (p<0.01), IL-12 a reliable predictor of survival (p<0.05), and TNF-alpha a reliable predictor of survival (p<0.05) and MODS (p<0.01).
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PMID:[Importance of determination of proinflammatory cytokines in the blood of polytraumatized patients with sepsis]. 1529 18

Severe sepsis and septic shock are important causes of death in intensive care units. Although Gram-negative infections were predominant in the 1960s, Gram-positive infections have increased in the past two decades and now account for about half of the cases of severe sepsis. In this study, we examined the effect of a Limulus anti-LPS factor (LALF)-derived peptide on lung and liver Th1/Th2 cytokine mRNA levels during a Gram-positive sepsis. We also examined the morphopathological changes observed in these organs during the disease. Mice challenged with a high dose of Staphylococcus haemolyticus showed severe damage in lung. In contrast, the liver of challenged mice showed an accumulation of bacterial particles in the sinusoids, associated with a severe inflammatory response due to high levels of tissue mRNA proinflammatory cytokines. Treatment with the peptide LALF(32-51) ameliorated the sepsis-induced effects in the lung and liver and increased the survival of mice in a dose- and time-dependent manner. Pretreatment with the peptide LALF(32-51) differentially regulates TNF-alpha, IFN-gamma, IL-12p40, IL-2 and IL-10 mRNA levels in lung and liver of peptide-treated mice, and limits the systemic inflammatory response. These findings support for the first time the effectiveness of an LALF-derived peptide in the treatment of a Gram-positive sepsis. Modulation of the Th1/Th2 pattern in tissues relevant for sepsis correlates with an improved outcome of the disease as denoted by increased survival.
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PMID:Differential regulation of Th1/Th2 in relevant tissues for sepsis pathogenesis with a Limulus anti-LPS factor-derived peptide increases survival in Gram-positive sepsis. 1531 32

Severe sepsis is a major healthcare problem, characterised by a high incidence, mortality and cost. New breakthroughs in treatment are quite diverse, including: (i) more effective regimens for generic, inexpensive broad anti-inflammatory agents (corticosteroids); (ii) a recombinant protein (drotrecogin-alfa [activated]); and (iii) a protocol-based treatment approach (early goal-directed therapy). Economic analyses of new sepsis agents should adopt the societal perspective, which requires prolonging the time horizon beyond that currently typically studied in sepsis trials, so that patient-centred outcomes can be more fully captured. Sepsis affects a very diverse group of patients, and if findings are to be generalisable, careful attention must be paid to study entry criteria and differences in effects and costs across different patient subgroups. Existing care patterns for sepsis are also quite diverse, with the consequence that the incremental effects on costs and outcomes could vary widely by practice pattern, again affecting generalisability. Furthermore, many sepsis patients receive multiple other therapies, which together with therapies under study may have varied and unintended, potentially costly or dangerous adverse effects, which could have a large influence on cost-effectiveness estimates. Finally, there are a number of large yet potentially hidden costs of sepsis, such as the long-term costs of managing patients who develop sepsis or the costs of introducing different interventions into clinical practice. Such costs must also be addressed in economic analyses. The search for new anti-sepsis strategies remains vigorous and exciting. We recommend wider incorporation of economic analyses into the study of potential new therapies, with appropriate attention to the caveats discussed above. Clinical demand to use new agents must be balanced against the economic consequences of their use.
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PMID:Pharmacoeconomic implications of new therapies in sepsis. 1536 27

While severe sepsis continues to plague hospitals worldwide, new treatment modalities, including activated recombinant protein C (drotrecogin alfa, Xigris, Lilly), have become a standard treatment alternative in many institutional algorithms. Drotrecogin alfa was shown to have a beneficial effect on mortality versus placebo in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial (p = 0.005), but its use is not completely without risk. An increased risk of bleeding, including severe bleeding episodes, exists ranging 3.5 - 5.2% in the drotrecogin alfa treatment group versus 2.0 - 5.0% in the placebo group. Patients at risk include those on concomitant heparin therapy (> 15,000 units/day), those with platelet counts <or= 30,000/mm(3), and those undergoing an invasive procedure during the scheduled infusion period. After almost three years on the US market, the reported incidence of severe bleeding episodes has risen only slightly from the pre-marketing era, at that time notable for restrictive treatment protocols, devoid of at-risk patients. Drotrecogin alfa, while a promising agent for severe sepsis, requires prudent patient evaluation for bleeding risks.
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PMID:Safety of drotrecogin alfa (activated) in the treatment of patients with severe sepsis. 1550 Apr 21

Severe sepsis leads to long-term systemic and local immunosuppression, which is the cause of a number of complications, including pulmonary infection. A therapeutic strategy that reverses this immunosuppression is required, given the ongoing high mortality rate of patients who have survived a severe sepsis. The present study demonstrates that experimental severe sepsis renders the lung susceptible to a normally innocuous Aspergillus fumigatus fungus challenge, due to a dominant lung type 2 cytokine profile. Dendritic cells (DCs) obtained from the lungs of mice subjected to cecal ligation and puncture (CLP) model were skewed toward type 2 cytokine profile, which occurred with exaggerated expression of Toll-like receptor 2 (TLR2). The intrapulmonary transfer of bone marrow-derived DCs (BMDCs) in postseptic mice prevented fatal Aspergillus infection. This therapy reduced the overall inflammatory response and fungal growth in the lung, and promoted the balance of proinflammatory and suppressive cytokines in the lung. Thus, intrapulmonary DC supplementation appears to restore the pulmonary host response in the postseptic lung in our animal model. These data strongly suggest that lung DCs are profoundly affected as a consequence of the systemic impact of severe sepsis, and the identification of mechanisms that restore their function may serve as a key strategy to reverse sepsis-induced immunosuppression.
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PMID:Reversal of long-term sepsis-induced immunosuppression by dendritic cells. 1560 23

Severe sepsis is known to cause multiple organ failure, including renal dysfunction. During sepsis, endotoxin targets the renal proximal tubular cells, the function of which can be evaluated on the basis of urinary N-acetyl-beta-glucosaminidase (NAG). We investigated whether urinary NAG activity is altered in patients with severe sepsis and whether treatment with polymyxin B immobilized fibers (PMX-F) affects this activity. Subjects of this study were 120 patients with severe sepsis and 60 healthy volunteers matched for age and gender. Patients were randomly assigned to one of two treatments: PMX-F treatment (n = 70) or conventional treatment (n = 50). The plasma endotoxin level was significantly reduced, from 34.6 +/- 10.2 to 6.8 +/- 2.4 pg/ml (p < 0.01) in patients treated with PMX-F, and the urinary NAG/creatinine ratio was reduced from 46.5 +/- 26.8 U/gm to 18.6 +/- 13.6 U/gm (p < 0.01). The plasma endotoxin level and urinary NAG/creatinine ratio were unchanged in patients who received conventional treatment. The increased urinary NAG/creatinine ratio in patients with severe sepsis may reflect proximal tubular dysfunction. PMX-F is effective in reducing proximal tubular dysfunction, in part owing to reduced plasma endotoxin levels.
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PMID:Effects of polymyxin B immobilized fiber on urinary N-acetyl-beta-glucosaminidase in patients with severe sepsis. 1567 89


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