Search PubMed⌕ Search

Biomedical subjects

Steven M Opal

Publications and source records attributed to Steven M Opal.

14 recordsLinked to original sources
PubMed2003

2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.

OBJECTIVE: In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were to "provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well. The general definitions introduced as a result of that conference have been widely used in practice, and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes. DESIGN: Several North American and European intensive care societies agreed to revisit the definitions for sepsis and related conditions. This conference was sponsored by the Society of Critical Care Medicine (SCCM), The European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). METHODS: 29 participants attended the conference from Europe and North America. In advance of the conference, subgroups were formed to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters. The present manuscript serves as the final report of the 2001 International Sepsis Definitions Conference. CONCLUSION: 1. Current concepts of sepsis, severe sepsis and septic shock remain useful to clinicians and researchers. 2. These definitions do not allow precise staging or prognostication of the host response to infection. 3. While SIRS remains a useful concept, the diagnostic criteria for SIRS published in 1992 are overly sensitive and non-specific. 4. An expanded list of signs and symptoms of sepsis may better reflect the clinical response to infection. 6. PIRO, a hypothetical model for staging sepsis is presented, which, in the future, may better characterize the syndrome on the basis of predisposing factors and premorbid conditions, the nature of the underlying infection, the characteristics of the host response, and the extent of the resultant organ dysfunction.

Humans↗
PubMed2003

A new paradigm for the treatment of sepsis: is it time to consider combination therapy?

Despite the advances in supportive care and the availability of potent antimicrobial agents, mortality from sepsis, a leading cause of death in intensive care units, has not improved. Over the last decade, clinical trials with numerous adjunctive therapies, including antiendotoxin antibodies and inhibitors of the inflammatory response, have yielded disappointing results. Recently, treatment with recombinant human activated protein C reduced mortality 6% compared with controls. Given the likelihood that many processes in the complex pathophysiology of sepsis are simultaneously activated, it is unlikely that therapy directed at any one of them, as has been done in the past, will dramatically improve survival. Rather, a combination of therapies directed at many arms of the septic process, much like the strategy used for cancer and HIV infection, is required. Given the likelihood that sepsis represents an excessive innate immune response to microbial products, vigorous attempts must be made to develop rapid assays that reflect the level of innate immune activation. Such assays could be used to identify patients who would benefit from therapy and to monitor their response so that overtreatment does not completely abrogate host defense mechanisms and render these patients susceptible to fatal infection. It is now time to test a new therapeutic paradigm based on an improved understanding of the pathophysiology of the septic process and the recognition that we may have reached the limits of adjunctive monotherapy.

Critical Care↗
PubMed2003

Endotoxin as a drug target.

OBJECTIVE: To review the preclinical and clinical evidence that antiendotoxin therapeutic strategies are potentially useful in the prevention and treatment of septic shock. STUDY DESIGN: A critical review of the literature over the past 30 yrs relating basic and clinical research on the therapeutic value of endotoxin as a target for the prevention and treatment of severe sepsis and septic shock. MAIN RESULTS: Bacterial endotoxin is a potent and predominant microbial mediator that induces an intense inflammatory and procoagulant response by elements of the innate immune response. This macromolecule is capable of inducing lethal septic shock in experimental animals, and a large number of preclinical studies consistently demonstrate the survival advantage of endotoxin inhibition in experimental models of sepsis. Clinical studies indicate that endotoxin may be found in the systemic circulation in the majority of humans with septic shock. Endotoxemia is largely independent of the nature of the infecting microorganism despite the fact that this molecule is specifically found in the outer membrane of Gram-negative bacteria only. Antiendotoxin strategies studied thus far have not provided reproducible survival benefits in clinical trials in septic patients. CONCLUSIONS: Despite compelling evidence of the critical importance of endotoxin in the pathogenesis of Gram-negative bacterial sepsis in preclinical investigations and numerous clinical interventional trials, the utility of antiendotoxin approaches to significantly reduce the mortality rate in human septic shock remains unproven. Ongoing clinical trials with specific endotoxin inhibitors should determine the potential value of this therapeutic approach to the management of septic shock.

Animals↗
PubMed2003

2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.

OBJECTIVE: In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were "to provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well." The general definitions introduced as a result of that conference have been widely used in practice and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes. DESIGN: Several North American and European intensive care societies agreed to revisit the definitions for sepsis and related conditions. This conference was sponsored by the SCCM, The European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). METHODS: The conference was attended by 29 participants from Europe and North America. In advance of the conference, five subgroups were formed to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters. The subgroups corresponded electronically before the conference and met in person during the conference. A spokesperson for each group presented the deliberation of each group to all conference participants during a plenary session. A writing committee was formed at the conference and developed the current article based on executive summary documents generated by each group and the plenary group presentations. The present article serves as the final report of the 2001 International Sepsis Definitions Conference. CONCLUSION: This document reflects a process whereby a group of experts and opinion leaders revisited the 1992 sepsis guidelines and found that apart from expanding the list of signs and symptoms of sepsis to reflect clinical bedside experience, no evidence exists to support a change to the definitions. This lack of evidence serves to underscore the challenge still present in diagnosing sepsis in 2003 for clinicians and researchers and also provides the basis for introducing PIRO as a hypothesis-generating model for future research.

Humans↗
PubMed2003

Effect of anti-CD14 monoclonal antibody on clearance of Escherichia coli bacteremia and endotoxemia.

OBJECTIVE: To determine the effects of an anti-CD14 monoclonal antibody on the clearance of a bacteremic Escherichia coli challenge in the presence or absence of antimicrobial agents. DESIGN: Prospective randomized animal study. SETTING: University-affiliated research laboratory. SUBJECTS: New Zealand White rabbits weighing 1.5-2.5 kg. INTERVENTIONS: Animals were pretreated with either an anti-lapine CD14 monoclonal antibody (immunoglobulin G2a, 5 mg/kg intravenously) or an isotype control monoclonal antibody. The animals then were challenged with 1 x 10(6) E. coli 018:K1 in the presence or absence of ceftazidime (50 mg/kg intravenously). There were four groups of six animals randomized to receive either anti-CD14 monoclonal antibody without ceftazidime, isotype control monoclonal antibody without ceftazidime, anti-CD14 monoclonal antibody with ceftazidime, or isotype control antibody with ceftazidime. MEASUREMENTS AND MAIN RESULTS: Serial measurement of quantitative bacteremia and endotoxemia was performed over 24 hrs after the administration of the bacterial challenge. Animals also underwent necropsy with quantitative bacterial cultures from multiple organ tissue samples. The anti-lapine CD14 monoclonal antibody significantly impaired the bloodstream clearance of E. coli (p <.01) and increased quantitative counts of E. coli in tissue culture samples when compared with isotype control antibody in the absence of simultaneous administration of ceftazidime. No differences in quantitative bacteremia, endotoxemia, or organ tissue counts were found after anti-CD14 antibody and control antibody-treated animals in the presence of ceftazidime treatment. CONCLUSIONS: Anti-CD14 monoclonal antibody has the capacity to interfere with the innate immune response and systemic microbial clearance in experimental animals with E. coli bacteremia. The concomitant administration of effective antimicrobial therapy eliminated differences in the rate of microbial clearance between the control antibody and the CD14 monoclonal antibody. These results indicate that care should be taken in clinical trials with anti-CD14 monoclonal antibodies to ensure that adequate antimicrobial therapy is administered in the presence of systemic bacterial infection.

Animals↗
PubMed2002

Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis.

The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review.

Animals↗
PubMed2002

Orally administered recombinant human interleukin-11 is protective in experimental neutropenic sepsis.

Recombinant human interleukin (IL)-11 is a multifunctional cytokine with hematopoietic, immunomodulatory, and epithelial cell protective activities. IL-11alpha receptors are expressed on the luminal surface of intestinal epithelial cells. It was hypothesized that orally administered IL-11 would prevent mucosal damage and protect against microbial invasion in a neutropenic rat model of gram-negative sepsis. IL-11 was administered daily by enteric, coated multiparticle pellets over the course of chemotherapy-induced neutropenia. Compared with the placebo group, IL-11-treated rats retained mucosal mass and had prolonged survival time, reduced pathologic changes, and reduced systemic levels of bacterial endotoxin and concentrations of Pseudomonas aeruginosa in target tissues. Enterocyte messenger RNA levels for tumor necrosis factor-alpha and interferon-gamma revealed that oral IL-11 reduced but did not prevent increased expression of these cytokine genes. These results indicate that orally administered IL-11 may preserve epithelial cell integrity in the presence of cytoreductive chemotherapy. This may represent a new treatment strategy for the prevention of infection in neutropenic hosts.

Administration, Oral↗
PubMed2002

Quality of life effects of antithrombin III in sepsis survivors: results from the KyberSept trial [ISRCTN22931023].

INTRODUCTION: Treatment of sepsis is aimed at increasing both the duration and quality of survival. A long-term focus on quality of life (QoL) in clinical trial evaluations of sepsis care should be a priority. METHOD: QoL data were used to evaluate the effects of intravenous antithrombin III treatment for severe sepsis measured for up to 90 days during the follow-up phase of the KyberSept phase III clinical trial. A visual analog scale and a Karnofsky scale were used to measure physical, psychologic, and social QoL at regular intervals. Changes from baseline between placebo and antithrombin III groups were assessed using Wilcoxon statistical tests, with additional analyses by severity of illness and admitting diagnosis. RESULTS: Among all sepsis survivors in the trial, there was a significant advantage on some attributes of QoL in the antithrombin III subgroup of patients who did not receive heparin as compared with the corresponding placebo group. DISCUSSION: The present study represents the first attempt to evaluate patient QoL over a relatively long period in a large, randomized, placebo-controlled sepsis trial. Over a 90-day period, survivors of severe sepsis receiving antithrombin III experienced significant improvements as compared with placebo on several attributes of QoL. In conclusion, the present study demonstrated that clinical improvements over an extended time period with antithrombin III were complemented by improvements in QoL, particularly in social and psychologic functioning, in many patients.

APACHE↗
PubMed2002

Bench-to-bedside review: Toll-like receptors and their role in septic shock.

The Toll-like receptors (TLRs) are essential transmembrane signaling receptors of the innate immune system that alert the host to the presence of a microbial invader. The recent discovery of the TLRs has rapidly expanded our knowledge of molecular events that initiate host-pathogen interactions. These functional attributes of the cellular receptors provide insights into the nature of pattern recognition receptors that activate the human antimicrobial defense systems. The fundamental significance of the TLRs in the generation of systemic inflammation and the pathogenesis of septic shock is reviewed. The potential clinical implications of therapeutic modulation of these recently characterized receptors of innate immunity are also discussed.

Animals↗
PubMed2002

Antithrombin, heparin, and heparan sulfate.

OBJECTIVES: To review the experimental and clinical evidence that antithrombin has multiple mechanisms for both its anticoagulant and anti-inflammatory properties. The interaction between antithrombin and specific polysulfated, acidic oligosaccharide moieties found on heparin and related proteoglycan molecules within the circulation and on endothelial surfaces will also be examined. DATA SOURCES: Review of the literature relating to antithrombin published during the past 25 yrs. DATA SUMMARY: Antithrombin is the most abundant endogenous anticoagulant circulating in human plasma. This serine protease inhibitor participates in the regulation of clotting in both physiologic and pathologic states. Reduced antithrombin activity in the early phases of sepsis contributes to a procoagulant state with excess activation of the innate immune response. Antithrombin binds to specific pentasaccharides expressed on heparin, glycosaminoglycans, and related proteoglycans within the circulation and along endothelial surfaces. The functions of neutrophils, monocytes, and endothelial cells are altered as a result of their interaction with antithrombin. These effects are mediated by the enzyme inhibitory action of antithrombin and its ability to function as a ligand for antithrombin receptors on cell surfaces. In addition, antithrombin exerts anti-inflammatory properties by both prostacyclin-dependent and prostacyclin-independent actions; heparin interferes with these anti-inflammatory properties. The role of antithrombin in sepsis, its therapeutic utility in severe sepsis, and its combination with heparin remain the subject of considerable debate. The results of a recent phase 3 clinical trials with high-dose antithrombin in sepsis suggested a beneficial effect in patients who did not concomitantly receive heparin, thereby generating new challenges in the understanding of interactions between antithrombin and heparin or heparin-like proteoglycans. CONCLUSIONS: Antithrombin has complex interactions with host coagulopathic and systemic inflammatory responses under physiologic conditions and in sepsis. The impact of these interactions in critically ill patients and the therapeutic implications of administration of antithrombin, and various doses and types of heparin in such patients, need further clarification.

Anticoagulants↗