Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nosocomial infection surveillance is common in the USA and in some European countries but in Italy few hospitals use it. In order to evaluate its usefulness in clinical practice we performed a one year prospective epidemiological study that included 178 patients, admitted to an intensive care unit (ICU) for more than 48 h. Median ICU stay was 16 days. Trauma and neurological diseases accounted for 65% of admissions. The selected population had high severity scores and required a large number of invasive procedures for diagnosis and therapy. The most common infections were: pneumonia 46/1000 ventilator-days; urinary tract infections 17/1000 catheter-days; central venous catheter infections 14.5/1000 catheter-days with 1.7/1000 CVC-related sepsis; bacteraemic sepsis 12/1000 ICU-days. The most frequent pathogens were Staphylococcus aureus,Pseudomonas aeruginosa, other Gram-negative aerobes and Candida spp. Antimicrobial resistance was substantial, with 68% methicillin-resistance in S. aureus and 76% of P. aeruginosa displaying antibiotic resistance. Severe sepsis or septic shock occurred in 30 patients (8/1000 ICU-days), and three patients died from septic shock of unknown origin (10% case fatality rate). There were no case fatalities for pneumonia and bacteraemic sepsis. Overall, ICU-acquired infections were not associated with an increased risk of death.
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PMID:Surveillance of infections acquired in intensive care: usefulness in clinical practice. 1239 4

The tumor necrosis factor alpha (TNF-alpha) -308 G/A and TNF-beta NcO1 polymorphisms have been described to be associated with an increased risk for sepsis in critically ill patients. Functional consequences associated with these polymorphisms remain unclear. We compared the genotype distribution of these TNF polymorphisms with susceptibility to severe sepsis and leukocyte function in blunt trauma patients (n = 70; mean injury severity score, 24 points [range, 4 to 57). Severe sepsis was defined according to the American College of Chest Physicians-Society of Critical Care Medicine consensus conference criteria. Genotyping for the NcO1 polymorphism (alleles TNFB1 and TNFB2) was performed by PCR and digestion of the products with NcO1, and that for the TNF-alpha -308 G/A polymorphism (alleles TNF1 and TNF2) was performed by real-time PCR. Leukocyte function was assessed by measurement of the production of endotoxin-induced cytokines (TNF-alpha, interleukin-6 [IL-6], and IL-8) in whole blood. TNF-alpha, IL-6, and IL-8 were determined by enzyme-linked immunosorbent assay. For the genotypes of the TNF-alpha -308 G/A polymorphism, differences in the frequency of development of severe sepsis were not detectable. Patients developing severe sepsis after trauma were significantly more likely to possess a homozygous genotype of the TNF-beta NcO1 polymorphism. Compared with heterozygotes, the odds ratio for the TNFB2/B2 genotype for the development of severe posttraumatic sepsis was 11 (P = 0.01), and that for the TNFB1/B1 genotype was 13 (P = 0.014). TNF-alpha -308:TNF-beta NcO1 haplotype analysis showed that the TNFB2:TNF2 haplotype is significantly negatively associated with development of severe sepsis. Patients homozygous for the TNFB1 or TNFB2 allele showed a persistently higher cytokine-producing capacity during at least 4 to 8 days after trauma than the heterozygotes. In patients homozygous for the TNF1 allele, a higher TNF-alpha- and IL-8-producing capacity was found only at day 1 after trauma. Although the TNF-beta NcO1 polymorphism appears to be less likely to be causative for development of severe sepsis after trauma, it is thus far the only genetic marker identified which can be used as a relevant risk estimate for severe sepsis in trauma patients immediately after the injury.
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PMID:Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma patients. 1241 51

Despite extensive research into the etiology and treatment of severe sepsis, little is known about its epidemiology in children. We sought to determine the age- and sex-adjusted incidence, outcome, and associated hospital costs of severe sepsis in United States children using 1995 hospital discharge and population data from seven states (24% of the United States population). Of 1,586,253 hospitalizations in children who were 19 years old or less, 9,675 met International Classification of Diseases, 9th revision, clinical modification-based severe sepsis criteria or 42,364 cases of pediatric severe sepsis per year nationally (0.56 cases per 1,000 population per year). The incidence was the highest in infants (5.16 per 1,000), fell dramatically in older children (0.20 per 1,000 in 10 to 14 year olds), and was 15% higher in boys than in girls (0.60 versus 0.52 per 1,000, p < 0.001). Hospital mortality was 10.3%, or 4,383 deaths nationally (6.2 per 100,000 population). Half of the cases had underlying disease (49.0%), and over one-fifth (22.9%) were low-birth-weight newborns. Respiratory infections (37%) and primary bacteremia (25%) were the most common infections. The mean length of stay and cost were 31 days and $40,600, respectively. Estimated annual total costs were 1.97 billion US dollars nationally. Severe sepsis is a significant health problem in children and is associated with the use of extensive healthcare resources. Infants are at highest risk, especially those with a low birth weight.
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PMID:The epidemiology of severe sepsis in children in the United States. 1243 70

Severe sepsis and septic shock is a common problem encountered in the critical care unit with an estimated incidence in the US of 750,000 cases/year and a mortality rate of 30-50%. Sepsis involves a complex interaction between bacterial factors and the host immune system producing a systemic inflammatory state that may progress to multiple organ failure and death. Endotoxin (a lipopolysaccharide) released from Gram-negative bacteria has been implicated as a potent, prototypical stimulus of the immune response to bacterial infection. Current antiendotoxin strategies utilise various approaches ranging from the prevention of binding to endotoxin receptors with antibodies (monoclonal or polyclonal) against endotoxin or endotoxin receptor/carrier molecules (antiCD14 or antilipopolysaccharide-binding protein antibodies), enhancing clearance or neutralisation (haemoperfusion, lipoproteins, lipopolysaccharide-neutralising proteins) or impairing cellular signalling (lipid A analogues, tyrosine kinase inhibitors). In the future, innovative therapies involving Toll-like receptors and their downstream signalling elements will be developed. This review discusses current knowledge regarding endotoxin signalling, antiendotoxin therapies currently under development, and future areas for research.
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PMID:Novel therapies for sepsis: antiendotoxin therapies. 1245 39

The protein C pathway, which plays an important role in maintaining normal hemostasis and is a critical link between the inflammatory and procoagulant host responses to infection, is involved in modulating the coagulation and inflammation associated with severe sepsis. Recombinant human activated protein C (APC), or drotrecogin alfa (activated), shares the intrinsic pharmacologic activity of endogenous APC. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, drotrecogin alfa (activated) decreased absolute mortality by 6% and relative risk of mortality by 19% compared with placebo. Drotrecogin alfa (activated) is an important advancement in the treatment of adult patients with severe sepsis.
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PMID:Pharmacology, clinical efficacy, and safety of drotrecogin alfa (activated). 1249 25

The key issues clinicians are facing regarding drotrecogin alfa (activated) include questions concerning the pathophysiology and appropriate patient selection for administration of this drug. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the efficacy of drotrecogin alfa (activated) was demonstrated in patients with severe sepsis. Because of this trial's strict inclusion and exclusion criteria, however, the applicability of the study criteria to different types of patients raises important issues. Coupling the data from the PROWESS trial with additional information being gained from expanding clinical experience, as well as additional studies, clinicians will be able to better understand and refine the use of activated protein C within their respective practices.
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PMID:Current issues regarding the use of drotrecogin alfa (activated). 1249 27

Selecting patients for drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN) therapy outside of a clinical trial setting requires knowledge of the rationale that led the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) investigators to select the various entry criteria for the trial. Enrollment criteria for the study included a known or suspected infection, presence of at least 3 systemic inflammatory response syndrome (SIRS) criteria, and dysfunction of > or =1 organ or system. The infection criteria used in PROWESS were designed to be straightforward and were based on common clinical and radiological data. Although previous definitions of sepsis required only 2 SIRS criteria, the PROWESS trial investigators required the presence of > or =3 SIRS criteria to improve the sensitivity and specificity of these criteria for the diagnosis of sepsis. Acute organ dysfunction, the diagnostic criterion for severe sepsis, was used to define the study population because it identifies patients at significant risk of death. Characteristics of drotrecogin alfa (activated)-treated patients, including infection, modified SIRS criteria, and organ dysfunction, were similar to those of the placebo group and the general sepsis population. Proper clinical judgment and use of the these inclusion criteria as a guide will help clinicians select and treat sepsis patients with drotrecogin alfa (activated).
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PMID:Selecting patients with severe sepsis for drotrecogin alfa (activated) therapy. 1252 13

Historically, clinical trials evaluating treatment of patients with severe sepsis have failed to show a reduction of mortality. However, retrospective analyses of some of these trials showed benefits in certain patient subgroups. Conversely, the recent Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, which evaluated the safety and efficacy of drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN), a recombinant form of human activated protein C, in adult patients with severe sepsis, is notable in that it is the first trial to show a reduction in 28-day all-cause mortality in the intent-to-treat population compared with the placebo group. When assessing a new intervention, patient exclusion criteria are important considerations in evaluating the evidence from a controlled clinical trial. Appropriate patient selection will be a key factor in the use of this newly approved therapeutic agent to treat severe sepsis. A review of the exclusion criteria used in the PROWESS trial should provide clinicians with a way of differentiating those patients in the critical care setting who will benefit most from treatment with drotrecogin alfa (activated) from those who should not be treated.
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PMID:Identifying patients with severe sepsis who should not be treated with drotrecogin alfa (activated). 1252 14

Severe sepsis, defined as sepsis with acute organ dysfunction, is associated with high morbidity and mortality rates. The development of novel therapies for sepsis is critically dependent on an understanding of the basic mechanisms of the disease. The pathophysiology of severe sepsis involves a highly complex, integrated response that includes the activation of a number of cell types, inflammatory mediators, and the hemostatic system. Central to this process is an alteration of endothelial cell function. The goals of this article are to (1) provide an overview of sepsis and its complications, (2) discuss the role of the endothelium in orchestrating the host response in sepsis, and (3) emphasize the potential value of the endothelium as a target for sepsis therapy.
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PMID:The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. 1254 69

Severe sepsis is a common disease process affecting some 2-11% of hospital admissions in the US. Severe sepsis and septic shock are associated with considerable morbidity and mortality, and account for a large part of intensive care unit costs. Until recently, the management of septic shock relied on the treatment of underlying infection with antimicrobial agents and surgical removal of any infectious source, and individual support of failing organs. However, in the last few years we have seen huge strides being made in our understanding of the pathophysiology of the sepsis response, and in our ability to manipulate that response. In the last couple of years these advances have come to fruition with the development of a drug, drotrecogin alfa, which specifically reduces mortality from this all too often fatal disease. While intensive early resuscitation remains the cornerstone of management, new approaches are beginning to form part of sepsis management protocols and will lead to improved outcomes for patients with this disease process.
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PMID:Management of septic shock. 1255 1


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