Biomedical subjects

Edward Abraham

Publications and source records attributed to Edward Abraham.

At least 73 records · Page 4Linked to original sources

PubMed2004

The CRIT Study: Anemia and blood transfusion in the critically ill--current clinical practice in the United States.

OBJECTIVE: To quantify the incidence of anemia and red blood cell (RBC) transfusion practice in critically ill patients and to examine the relationship of anemia and RBC transfusion to clinical outcomes. DESIGN: Prospective, multiple center, observational cohort study of intensive care unit (ICU) patients in the United States. Enrollment period was from August 2000 to April 2001. Patients were enrolled within 48 hrs of ICU admission. Patient follow-up was for 30 days, hospital discharge, or death, whichever occurred first. SETTING: A total of 284 ICUs (medical, surgical, or medical-surgical) in 213 hospitals participated in the study. PATIENTS: A total of 4,892 patients were enrolled in the study. MEASUREMENTS AND MAIN RESULTS: The mean hemoglobin level at baseline was 11.0 +/- 2.4 g/dL. Hemoglobin level decreased throughout the duration of the study. Overall, 44% of patients received one or more RBC units while in the ICU (mean, 4.6 +/- 4.9 units). The mean pretransfusion hemoglobin was 8.6 +/- 1.7 g/dL. The mean time to first ICU transfusion was 2.3 +/- 3.7 days. More RBC transfusions were given in study week 1; however, in subsequent weeks, subjects received one to two RBC units per week while in the ICU. The number of RBC transfusions a patient received during the study was independently associated with longer ICU and hospital lengths of stay and an increase in mortality. Patients who received transfusions also had more total complications and were more likely to experience a complication. Baseline hemoglobin was related to the number of RBC transfusions, but it was not an independent predictor of length of stay or mortality. However, a nadir hemoglobin level of <9 g/dL was a predictor of increased mortality and length of stay. CONCLUSIONS: Anemia is common in the critically ill and results in a large number of RBC transfusions. Transfusion practice has changed little during the past decade. The number of RBC units transfused is an independent predictor of worse clinical outcome.

Adult↗

PubMed2004

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial.

OBJECTIVE: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DESIGN: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SETTING: One hundred forty-six intensive care units from nine countries. PATIENTS: Approximately 2,522 patients were planned to be enrolled < or =12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. MEASUREMENTS AND MAIN RESULTS: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p =.80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. CONCLUSIONS: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2004

Human models of endotoxemia and recombinant human activated protein C.

OBJECTIVES: To review human models of endotoxemia with an emphasis on the inflammatory and coagulopathic effects of lipopolysaccharide to describe the possible mechanisms of clinical benefit of recombinant human activated protein C (drotrecogin alfa [activated]) in severe sepsis. DATA SOURCE: A selected review of published literature in English on human endotoxemia models with special attention to studies using drotrecogin alfa (activated) in concert with endotoxemia. DATA EXTRACTION AND SYNTHESIS: After intravenous administration of purified lipopolysaccharide, subjects report constitutional influenza-like symptoms associated with an increase in temperature. Within 1 hr of lipopolysaccharide infusion, total leukocyte counts decline. Sustained leukocytosis, due to an increase in neutrophils counts, follows. An increase in markers of neutrophil activation (e.g., serum elastase) accompanies this leukocytosis. Production of tumor necrosis factor-alpha, interleukin-6, and interleukin-8 is also increased. In association with an inflammatory response, lipopolysaccharide administration also activates the coagulation system. Lipopolysaccharide infusion generates thrombin and initially activates fibrinolysis but subsequently generates inhibitors of the fibrinolytic system. Serum levels of endogenous inhibitors of coagulation (e.g., antithrombin, protein C, tissue factor pathway inhibitor) are not affected. Data are available for 40 subjects who have participated in placebo-controlled studies of drotrecogin alfa (activated) infusion before an intravenous dose of lipopolysaccharide. In these subjects, drotrecogin alfa (activated) has minimal effects on measured variables, including physiologic variables, markers of inflammation, and measures of sepsis-induced coagulopathy. CONCLUSION: Human endotoxemia is, at best, an incomplete model of human sepsis. In two studies using recombinant human activated protein C in the setting of human endotoxemia, there were minimal effects on hemodynamics, inflammation, thrombin generation, fibrinolysis, and markers of cellular activation. Other putative mechanisms of recombinant human activated protein C, such as inhibition of apoptosis and leukocyte recruitment, remain to be studied.

Anti-Infective Agents↗

PubMed2004

Immunomodulation and sepsis: impact of the pathogen.

Infection begins when microorganisms overcome host barriers and multiply within host tissues. To contain the infection, the host mounts an inflammatory response that mobilizes defense systems and kills the invading microorganisms. A focal inflammatory response is usually sufficient to eradicate the organisms. However, when it fails to contain the infection, the organisms, their toxins, and numerous host mediators are released into the bloodstream, producing a systemic inflammatory response and organ failure. Microorganisms have coevolved with their hosts, thereby acquiring means of overcoming host defense mechanisms or even taking advantage of innate host responses. Many pathogens avoid recognition by the host or dampen host immune responses via sophisticated pathogen-host interactions. Some pathogens benefit from the inflammatory response. According to current hypotheses regarding the pathogenesis of sepsis, the host generates both an innate immune response identical for all pathogens and an adaptive pathogen-specific response. Determining whether the innate response benefits the pathogen or the host is essential for understanding host-pathogen interactions. In this review, we discuss how pathogens interfere with innate and adaptive immune responses to escape eradication by the host.

Humans↗

PubMed2004

Bone transport in the management of posttraumatic bone defects in the lower extremity.

BACKGROUND: The aim of this study was to evaluate the clinical and functional outcomes of traumatic bone defects of the lower extremity managed by internal bone transport using the Ilizarov technique. METHODS: We retrospectively reviewed 19 patients who underwent internal bone transport for traumatic bone defects in the lower extremity. Mean follow-up was 68.7 months (5.7 years). Eighteen cases were open: grade IIIA, 10 cases; grade IIIB, 4 cases; and grade IIIC, 4 cases. RESULTS: Clinical outcome was 2 excellent, 11 good, 4 fair, and 2 poor. Eighteen of 19 patients reported being satisfied. The results of the SF-36 Health Survey showed a significant difference between the population norm and the mean of the study group in Physical Functioning, Bodily Pain, and Role-Emotional. The mean length of time in external fixation for all patients was 13.8 months. The mean length of regenerate was 5.7 cm (range, 0.8-20.4 cm). The total number of complications was 39 (20 minor and 19 major). Major complications included two transtibial amputations and four fractures at the docking site. CONCLUSION: Although the number of complications was high, the patients in this study were satisfied to have their limbs preserved. The SF-36 Health Survey showed that patients suffer mainly from physical and emotional consequences after these major injuries. Their general, social, and mental health is usually not affected. Infection significantly increased the healing index. The limb should be protected for a long time, with careful evaluation to avoid fracture at the docking site after fixator removal.

Adult↗

PubMed2003

Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein.

High mobility group box 1 (HMGB1) protein, originally described as a DNA-binding protein that stabilizes nucleosomes and facilitates transcription, can also be released extracellularly during acute inflammatory responses. Exposure of neutrophils, monocytes, or macrophages to HMGB1 results in increased nuclear translocation of NF-kappaB and enhanced expression of proinflammatory cytokines. Although the receptor for advanced glycation end products (RAGE) has been shown to interact with HMGB1, other putative HMGB1 receptors are known to exist but have not been characterized. In the present experiments, we explored the role of RAGE, Toll-like receptor (TLR) 2, and TLR 4, as well as associated kinases, in HMGB1-induced cellular activation. Culture of neutrophils or macrophages with HMGB1 produced activation of NF-kappaB through TLR 4-independent mechanisms. Unlike lipopolysaccharide (LPS), which primarily increased the activity of IKKbeta, HMGB1 exposure resulted in activation of both IKKalpha and IKKbeta. Kinases and scaffolding proteins downstream of TLR 2 and TLR 4, but not TLR/interleukin-1 receptor (IL-1R)-independent kinases such as tumor necrosis factor receptor-associated factor 2, were involved in the enhancement of NF-kappaB-dependent transcription by HMGB1. Transfections with dominant negative constructs demonstrated that TLR 2 and TLR 4 were both involved in HMGB1-induced activation of NF-kappaB. In contrast, RAGE played only a minor role in macrophage activation by HMGB1. Interactions of HMGB1 with TLR 2 and TLR 4 may provide an explanation for the ability of HMGB1 to generate inflammatory responses that are similar to those initiated by LPS.

Animals↗

PubMed2003

Modulation of bone marrow-derived neutrophil signaling by H2O2: disparate effects on kinases, NF-kappaB, and cytokine expression.

Reactive oxygen species (ROS), including hydrogen peroxide (H2O2), are generated in increased amounts in pathological, biological processes and can play a role in signal transduction. Neutrophils often accumulate in acute inflammatory reactions, at sites where elevated concentrations of ROS are present. ROS have been demonstrated to participate in the activation of intracellular signaling pathways, including those involved in modulating nuclear accumulation and transcriptional activity of NF-kappaB. However, the role of ROS in affecting such events in neutrophils has not been examined. Using exposure of murine bone marrow neutrophils to H2O2 as a model of oxidative stress, we found both strong and persistent activation of ERK1/2, p38, JNK, and PKB, but not the p21-activated kinase. Stimulating the bone marrow-derived neutrophils with H2O2 did not affect nuclear translocation of NF-kappaB. However, production and secretion of the proinflammatory cytokine TNF-alpha in LPS-stimulated neutrophils were inhibited by H2O2. Exposure of LPS- or TNF-alpha-stimulated neutrophils to H2O2 decreased nuclear translocation of NF-kappaB. LPS-induced activation of the transcriptional factor AP-1 was also inhibited by H2O2. This inhibition of nuclear accumulation of NF-kappaB by H2O2 was not caused by an impaired capacity of LPS to stimulate the IKK pathway or to direct oxidative effects on NF-kappaB but rather reflected diminished degradation of IkappaB-alpha. These results indicate that oxidative stress, despite being able to selectively activate intracellular kinases in bone marrow-derived neutrophils, also inhibits NF-kappaB activation and associated TNF-alpha expression. Such inhibitory effects on neutrophil activation may limit tissue damage produced by oxidative stress.

Animals↗

PubMed2003

Computational design of variant TNF molecules: a novel methodology for inhibition of proinflammatory cascades.

Site-directed mutagenesis of tumor necrosis factor (TNF) based on prediction of the interaction of specific residues with TNF receptors generated dominant-negative constructs, in which single- or double-amino acid changes result in decreased receptor binding and cellular activation. These dominant-negatives not only provide a novel manner to block the proinflammatory effects of TNF, but also can be used as a tool to examine ligand-receptor interactions and their importance in signaling. Because these TNF mutant molecules are smaller than those used for conventional anti-TNF therapies, such as etanercept or infliximab, they are likely to achieve greater tissue concentrations and may provide enhanced therapeutic effect. However, the immunogenicity, as well as efficacy, of the dominant-negative TNF constructs must be more completely examined.

Computational Biology↗

PubMed2003

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.

CONTEXT: The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation. OBJECTIVES: To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel. PATIENTS: The primary efficacy population consisted of 1754 patients (> or =18 years) with severe sepsis and a high INR (> or =1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo. MAIN OUTCOME MEASURE: All-cause 28-day mortality. RESULTS: Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively (P =.88, Pearson chi2 test; P =.75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P =.006, Pearson chi2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) (P =.051, Pearson chi2 test; P =.03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). CONCLUSIONS: Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.

Anticoagulants↗

PubMed2003

Nuclear factor-kappaB and its role in sepsis-associated organ failure.

Nuclear factor (NF)-kappaB is involved in regulating the transcription of many of the immunomodulatory mediators involved in the development of sepsis-induced organ failure. Kinase pathways involving p38 and Akt and initiated by engagement of Toll-like receptors modulate transcriptional activity of NF-kappaB, but apparently through different mechanisms. Increased activation of NF-kappaB occurs with sepsis, and greater levels of nuclear accumulation of NF-kappaB are associated with higher rates of mortality and worse clinical outcome. The percentage of apoptotic neutrophils is reduced in sepsis, and inhibition of nuclear translocation of NF-kappaB restores neutrophil apoptosis to baseline levels. In models of sepsis, suppression of NF-kappaB activation decreases acute inflammatory processes and organ dysfunction. Because NF-kappaB occupies a central role in signaling pathways important in sepsis, modulation of NF-kappaB activity may be an appropriate therapeutic target in patients with sepsis.

Animals↗

PubMed2003

Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation.

Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. Although increased circulating levels of uPA are present in endotoxemia and sepsis, conditions in which activated neutrophils contribute to the development of acute organ dysfunction, the ability of uPA to participate directly in LPS-induced neutrophil activation has not been examined. In the present experiments, we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS. In particular, uPA increased LPS-induced activation of intracellular signaling pathways, including Akt and c-Jun N-terminal kinase, nuclear translocation of the transcriptional regulatory factor NF-kappa B, and expression of proinflammatory cytokines, including IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha. There was no effect of uPA on LPS-induced activation of p38 mitogen-activated protein kinase in neutrophils. Transgenic mice unable to produce uPA (uPA(-/-)) were protected from endotoxemia-induced lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, lung IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha cytokine levels. These results demonstrate that uPA can potentiate LPS-induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil-mediated inflammatory responses, such as the development of acute lung injury.

Active Transport, Cell Nucleus↗

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

Early alterations in neutrophil activation are associated with outcome in acute lung injury.

Persistent elevations of proinflammatory cytokines in the lungs are associated with increased mortality from acute lung injury (ALI), suggesting that the degree of pulmonary inflammation is an important determinant of clinical course in ALI. The transcriptional regulatory factor nuclear factor-kappaB (NF-kappaB) is involved in modulating the expression of many cytokines and other proinflammatory mediators implicated in the development and progression of ALI. Because neutrophils appear to play a major role in the development of ALI, we examined the relationships between clinical outcome and activation of NF-kappaB in peripheral neutrophils from patients (n = 30) with sepsis-induced ALI. We found that nuclear translocation of NF-kappaB in this setting was dependent on the activation of p38 and Akt kinases. Diminished activation of NF-kappaB or Akt, but not p38, in the early postintubation period was associated with less time on the ventilator and improved survival in critically ill patients with ALI. These results suggest that early alterations in neutrophil activation patterns, particularly involving the ability to accumulate NF-kappaB to the nucleus after relevant stimuli, contribute to subsequent clinical course in ALI.

Adult↗

PubMed2003

Evidence for extracellular superoxide dismutase as a mediator of hemorrhage-induced lung injury.

Hemorrhage results in excessive production of superoxide that is associated with severe lung injury. We examined whether the superoxide dismutase (SOD) mimetic manganese(III) mesotetrakis (di-N-ethylimidazole) porphyrin (AEOL 10150) could attenuate this lung injury and whether extracellular (EC)-SOD-deficient mice would have increased hemorrhage-induced lung injury. Compared with wild-type mice, EC-SOD-deficient mice had increased lung neutrophil accumulation, a 3.9-fold increase in myeloperoxidase activity, a 1.5-fold increase in nuclear factor (NF)-kappaB activation, and a 1.5-fold increase in lipid peroxidation 1 h after hemorrhage. Pretreatment with AEOL 10150 did not attenuate neutrophil accumulation but significantly reduced NF-kappaB activation and lipid peroxidation in both wild-type and EC-SOD-deficient mice. The increase in hemorrhage-induced neutrophil accumulation in the lungs of EC-SOD-deficient mice suggests that EC-SOD might play a role in mediating neutrophil recruitment to the lung.

Aconitate Hydratase↗

PubMed2003

New approaches to the treatment of sepsis.

The clinical spectrum of sepsis, severe sepsis, and septic shock is responsible for a growing number of deaths and excessive health care expenditures. Until recently, despite multiple clinical trials, no intervention provided a beneficial outcome in septic patients. Within the last 2 years, studies that involved drotrecogin alfa (activated), corticosteroid therapy, and early goal-directed therapy showed efficacy in those with severe sepsis and septic shock. These results have provided optimism for reducing sepsis-related mortality.

Adrenal Cortex Hormones↗

PubMed2003

Involvement of phosphatidylinositol 3-kinase gamma in neutrophil apoptosis.

Although phosphoinositide 3-kinases (PI3-K) are known to participate in anti-apoptotic pathways, their importance in modulating neutrophil apoptosis in vivo has not been examined. In these studies, we used neutrophils from mice lacking the PI3-Kgamma isoform (PI3-Kgamma-/-) to determine the role that PI3-Kgamma occupies in neutrophil apoptosis under in vivo conditions. We found that neutrophil apoptosis under basal and LPS-stimulated conditions was increased in PI3-Kgamma-/- mice compared to that present in control PI3-Kgamma+/+ animals. Neutrophils from PI3-Kgamma-/- mice demonstrated decreased amounts of active, serine 473 phosphorylated Akt, phosphorylated CREB, and diminished nuclear translocation of NF-kappaB. Levels of the CREB-dependent anti-apoptotic protein Mcl-1 and of the NF-kappaB-dependent anti-apoptotic mediator Bcl-x(L) were significantly decreased in PI3-Kgamma-/- neutrophils. In contrast, PI3-Kgamma-/- neutrophils contained diminished amounts of phosphorylated, inactive forms of the pro-apoptotic mediators, Bad, FKHR, and GSK-3beta. These results demonstrate that PI3-Kgamma directly participates in multiple in vivo pathways involved in regulating neutrophil apoptosis.

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

Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure.

OBJECTIVE: Concentrations of group IIA secretory phospholipase A, an inflammatory response mediator, are increased in the plasma of patients with sepsis and septic shock, and the extent of elevation is correlated with mortality. LY315920Na/S-5920 is a selective inhibitor of group IIA secretory phospholipase A that has been shown to inhibit serum group IIA secretory phospholipase A enzyme activity in patients with severe sepsis. The primary objectives of this study were to determine whether there was a dose-response relationship between two doses of LY315920Na/S-5920 compared with placebo in the reduction of 28-day all-cause mortality in patients with severe sepsis and to determine whether LY315920Na/S-5920 had an acceptable safety profile.(2) (2) (2) DESIGN: Multicenter, double-blind, placebo-controlled trial of two doses of LY315920Na/S-5920 in a parallel design. PATIENTS: A total of 586 patients with severe sepsis at 72 institutions in the United States. INTERVENTIONS Patients enrolled within 72 hrs from onset of first sepsis-induced organ failure were randomized (1:1:1) to low-dose LY315920Na/S-5920 (target plasma concentration of 200 ng/mL, n = 196), high-dose LY315920Na/S-5920 (800 ng/mL, n = 194), or placebo (n = 196). Study medication was administered as a constant-rate intravenous infusion for 168 hrs. MEASUREMENTS AND MAIN RESULTS: The study was stopped prematurely because it was unlikely that a statistically significant difference in mortality between LY315920Na/S-5920 and placebo would be found. There was no effect of LY315920Na/S-5920 on the primary end point of 28-day all-cause mortality across the entire study population. The 28-day all-cause mortality was distributed as follows: placebo group, 33.2% (65/196 patients); low-dose LY315920Na/S-5920, 37.2% (73/196); and high-dose LY315920Na/S-5920, 36.1% (70/194); p = .525. However, in a prospectively planned analysis, there was a favorable overall dose-response effect on 28-day all-cause mortality in patients administered LY315920Na/S-5920 within 18 hrs of onset of the first sepsis-induced organ failure. Among these patients, 28-day all-cause mortality was distributed as follows: placebo group, 43.5% (20/46 patients); low-dose LY315920Na/S-5920, 31.4% (16/51); and high-dose LY315920Na/S-5920, 20.8% (10/48); p = .018. CONCLUSIONS: Administration of LY315920Na/S-5920 had an acceptable safety profile in patients with severe sepsis. There was no overall survival benefit associated with the use of LY315920Na/S-5920 in this study. However, prospectively planned secondary analyses suggested that treatment with LY315920Na/S-5920 was associated with an improvement in survival in patients treated within 18 hrs of the first sepsis-induced organ failure.

Acetates↗