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Edward Abraham

Publications and source records attributed to Edward Abraham.

At least 55 records · Page 3Linked to original sources
PubMed2005

Outcome measures for clinical research in sepsis: a report of the 2nd Cambridge Colloquium of the International Sepsis Forum.

BACKGROUND AND OBJECTIVES: Sepsis is the leading cause of morbidity and mortality for patients admitted to an intensive care unit. The evaluation of new therapies has been hampered by the underdevelopment of outcome measures used to detect biological activity and patient-centered benefit in a complex and highly heterogeneous patient population. We sought to evaluate existing approaches and to draw on insights from other disciplines to propose a comprehensive approach to outcome evaluation in sepsis clinical trials. METHODS: An expert colloquium organized by the International Sepsis Forum brought together sepsis researchers, clinical epidemiologists, and experts in the development and implementation of outcome measures in rheumatology, neurology, and oncology. RESULTS: The translation of an evolving understanding of the biology of sepsis into effective new therapies for critically ill patients requires a reevaluation of the end points used to determine response to intervention. These represent a continuum that measures biological activity against the target at one end and sustained improvement in survival or quality of life at the other. Early phase research should determine whether an intervention works in vivo, using measures that are responsive and informative to provide proof of principle, to aid in selecting optimal patient populations for study, and to gain insights into optimal dose and duration of therapy. After in vivo biology has been demonstrated and the possibility of efficacy inferred by plausible improvements in surrogate physiologic measures, definitive studies should seek robust evidence of benefit using end points that measure important, patient-centered benefit, including intermediate and longer term survival and health-related quality of life. Nonmortal measures of benefit assume particular importance for populations, such as children, whose mortality risk is low, or who have significant rates of comorbidities that independently limit survival. Composite measures that integrate morbidity and mortality effects may provide the most meaningful information about therapeutic efficacy. CONCLUSIONS: The development of explicit, hypothesis-driven, and iterative approaches to outcome measure development, patterned on approaches used in the fields of rheumatology and oncology, may improve the conduct of clinical studies in the critically ill.

Clinical Trials as Topic↗
PubMed2005

Genetic polymorphisms and sepsis.

Sepsis is a polygenic and complex syndrome that is initiated by infection and is characterized by a systemic inflammatory response. Genetic polymorphisms in the immune response to infection have been shown to be associated with clinical outcomes. Functional and association studies involving genetic polymorphisms in essential genes, including Toll-like receptors, cytokines, and coagulation factors, have provided important insights into the mechanisms involved in the pathogenesis of sepsis-induced organ dysfunction. The advancement of high-throughput single nucleotide polymorphism (SNP) genotyping will provide valuable information on the interaction of multiple allelic variants and clinical outcome. More precise categorization of patients based on genetic background is likely to lead to individualized targeted treatment. Future therapeutic trials as well as actual treatment regimens for patients with sepsis are likely to be designed to target specific genotypes and associated cellular responses, maximizing clinical response and patient safety.

Animals↗
PubMed2005

Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients.

The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n=6 patients) or hemodiafiltration (CVVHDF; n=6 patients). Patients (mean+/-standard deviation age, 50.9+/-15.9 years; weight, 98.5+/-15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t1/2) of imipenem were 145+/-18 ml/min and 2.7+/-1.3 h during CVVH versus 178+/-18 ml/min and 2.6+/-1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL(S), respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 microg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC=4 to 8 microg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.

Adult↗
PubMed2005

A descriptive evaluation of transfusion practices in patients receiving mechanical ventilation.

STUDY OBJECTIVES: To characterize and compare transfusion practices in a broad sample of patients receiving mechanical ventilation (MV) and not receiving MV in the ICU. DESIGN: Retrospective subgroup analysis from the prospective, multicenter, observational CRIT study. SETTING: Two hundred eighty-four medical, surgical, or medical/surgical ICUs. PATIENTS: Critically ill adults. MAIN RESULTS: Of the 4,892 patients enrolled in the CRIT study, 60% were receiving MV on ICU admission or within 48 h after admission for a median of 4 days. Patients receiving MV had higher baseline APACHE (acute physiology and chronic health evaluation) II scores than patients not receiving MV (22.8 +/- 7.8 and 14.9 +/- 6.4, respectively [mean +/- SD]; p < 0.0001). Despite similar baseline hemoglobin levels (11.0 +/- 2.3 g/dL and 10.9 +/- 2.5 g/dL, p = 0.17), more patients receiving MV underwent transfusions (49% vs 33%, p < 0.0001), and they received significantly more RBCs than patients not receiving MV (p < 0.0001). The principal reason for transfusion in both groups was low hemoglobin level (78.4% and 84.6%, respectively); however, patients receiving MV had higher pretransfusion hemoglobin levels (8.7 +/- 1.7 g/dL) than patients not receiving MV (8.2 +/- 1.7 g/dL, p < 0.0001). Notably, 40.1% of all transfusions in patients receiving MV were administered after day 3 of the ICU stay, compared to 21.2% in patients not receiving MV (p < 0.0001), and a higher percentage of patients receiving MV remaining in the ICU after day 3 underwent transfusions (33.4% vs 18.3%, p < 0.0001). Mortality was higher (17.2% vs 4.5%, p < 0.0001) and mean hospital (15 days vs 10 days, p < 0.0001) and ICU stays (9 days vs 4 days, p < 0.0001) were longer in the subgroup receiving MV. CONCLUSIONS: Mechanical ventilation appears to be an easily identifiable early marker for allogeneic blood exposure risk in ICU patients. While the longer ICU stays account for much of this risk, patients receiving MV also appear to undergo transfusions at higher hemoglobin thresholds than patients not receiving MV, at least early in the ICU stay. Justification of this relatively liberal transfusion practice in patients receiving MV will require further study.

APACHE↗
PubMed2005

Effects of recombinant human activated protein C in human models of endotoxin administration.

Alterations in the generation of activated protein C (APC) as well as in the interactions of APC with the endothelial protein C receptor are present in severe sepsis and acute lung injury. Administration of recombinant human activated protein C (rhAPC) improves the survival of critically ill patients with sepsis, but the mechanisms by which rhAPC produces benefit are not well defined. Human models of systemic and pulmonary endotoxin exposure may provide important insights into the mechanisms of action of rhAPC in critical illness. In volunteers given systemic endotoxin, rhAPC had minimal effects on physiologic parameters, including blood pressure, markers of inflammation, and measures of sepsis-induced coagulopathy. In contrast, in the setting of pulmonary endotoxin exposure, rhAPC decreased neutrophil migration into the airspaces and also diminished neutrophil chemotaxis. Administration of rhAPC did not affect other parameters of neutrophil function, including kinase activation, production of proinflammatory cytokines, or apoptosis. Such results indicate that the effects of rhAPC in inhibiting the infiltration of neutrophils into the lungs and other inflammatory sites may contribute to its beneficial effects in sepsis.

Endotoxemia↗
PubMed2004

Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis.

Recombinant human activated protein C (rhAPC) is a natural anticoagulant with potentially important anti-inflammatory properties. In humans with severe sepsis, rhAPC treatment reduces mortality, but mechanisms responsible have not been well characterized. Accumulation of activated neutrophils in the lungs and other organs during severe infection contributes to sepsis-induced organ dysfunction, including acute inflammatory lung injury. Because neutrophils express an APC receptor, we hypothesized that immunomodulatory effects of rhAPC occur, in part, via modulation of neutrophil responses. To examine this issue, we performed a double-blinded, placebo-controlled study of rhAPC in a human model of endotoxin-induced pulmonary inflammation. Administration of rhAPC significantly reduced leukocyte accumulation to the airspaces, independent of pulmonary cytokine or chemokine release. Neutrophils recovered from bronchoalveolar lavage fluid of volunteers receiving rhAPC demonstrated decreased chemotaxis ex vivo. Decreased neutrophil chemotaxis following exposure to rhAPC was confirmed in vitro. No differences were detected in gene expression, kinase activation, cytokine release, cell survival, or apoptosis of neutrophils recovered in the presence or absence of rhAPC. These studies demonstrate that rhAPC reduces both endotoxin-induced accumulation of leukocytes in the airspaces and neutrophil chemotaxis. These rhAPC-induced effects on neutrophil function may represent a mechanism by which rhAPC improves survival in patients with sepsis.

Adolescent↗
PubMed2004

Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study.

A novel assay for endotoxin, based on the ability of antigen-antibody complexes to prime neutrophils for an augmented respiratory burst response, was studied in a cohort study of 857 patients admitted to an intensive-care unit (ICU). On the day of ICU admission, 57.2% of patients had either intermediate (>or=0.40 endotoxin activity [EA] units) or high (>or=0.60 units) EA levels. Gram-negative infection was present in 1.4% of patients with low EA levels, 4.9% with intermediate levels, and 6.9% with high levels; EA had a sensitivity of 85.3% and a specificity of 44.0% for the diagnosis of gram-negative infection. Rates of severe sepsis were 4.9%, 9.2%, and 13.2%, and ICU mortality was 10.9%, 13.2%, and 16.8% for patients with low, intermediate, and high EA levels, respectively. Stepwise logistic regression analysis showed that elevated Acute Physiology and Chronic Health Evaluation II score, gram-negative infection, and emergency admission status were independent predictors of EA.

APACHE↗
PubMed2004

Phosphoinositide 3-kinase and Akt occupy central roles in inflammatory responses of Toll-like receptor 2-stimulated neutrophils.

Neutrophils are critical initiators and effectors of the innate immune system and express Toll-like receptor 2 (TLR2) and TLR4. Although signaling through pathways involving phosphoinositide 3-kinase (PI3-K) and the downstream kinase Akt (protein kinase B) plays a central role in modulating neutrophil chemotaxis and superoxide generation in response to engagement of G protein-coupled receptors, the importance of these kinases in affecting inflammatory responses of neutrophils stimulated through TLR2 has not been examined. In these experiments, we found activation of Akt in neutrophils stimulated with the TLR2-specific ligands peptidoglycan and the lipopeptide tri-palmitoyl-S-glyceryl-Cys-Ser-(Lys)(4) that occurred earlier and was of greater magnitude than that present after exposure to the TLR4 agonist LPS. The release of the proinflammatory mediators TNF-alpha and macrophage inflammatory protein-2 was inhibited in a dose-dependent manner by PI3-K blockade. The IC(50) for inhibition of peptidoglycan-stimulated Akt activation and macrophage inflammatory protein-2 release correlated closely, indicating linkage of these two events. PI3-K blockade did not inhibit nuclear translocation of NF-kappa B, but did prevent Ser(536) phosphorylation of the p65 subunit of NF-kappa B, an event required for maximal transcriptional activity of NF-kappa B. Inhibition of PI3-K also prevented activation of p38 mitogen-activated protein kinase and extracellular receptor-activated kinase 1/2 in TLR2-stimulated neutrophils. These results demonstrate that the PI3-K-Akt axis occupies a central role in TLR2-induced activation of neutrophils.

Animals↗
PubMed2004

Hemorrhage-induced acute lung injury is TLR-4 dependent.

Toll-like receptor 4 (TLR-4), initially identified as an LPS receptor, is critical to the signaling of a variety of danger signals, including heat shock protein 60, fibrinogen, and fibronectin. Recent data also suggest that TLR-4 plays a role in determining survival in both endotoxemia and hemorrhagic shock. We hypothesized that a functional TLR-4 would be required for hemorrhage and endotoxin-induced acute lung injury. Hemorrhage- and endotoxin-induced lung TNF-alpha mRNA and protein production, neutrophil accumulation, and protein permeability were dependent on a functional TLR-4. Hemorrhage-induced nuclear factor (NF)-kappaB activation was independent of functional TLR-4, whereas endotoxin-induced activation of NF-kappaB requires a functional TLR-4 for full response. Therefore, we conclude that 1) hemorrhage-induced acute lung injury is TLR-4 dependent and 2) hemorrhage has a different and distinct TLR-4-dependent intracellular activation mechanism compared with endotoxemia.

Acute Disease↗
PubMed2004

The decline and fate of an iron-induced subarctic phytoplankton bloom.

Iron supply has a key role in stimulating phytoplankton blooms in high-nitrate low-chlorophyll oceanic waters. However, the fate of the carbon fixed by these blooms, and how efficiently it is exported into the ocean's interior, remains largely unknown. Here we report on the decline and fate of an iron-stimulated diatom bloom in the Gulf of Alaska. The bloom terminated on day 18, following the depletion of iron and then silicic acid, after which mixed-layer particulate organic carbon (POC) concentrations declined over six days. Increased particulate silica export via sinking diatoms was recorded in sediment traps at depths between 50 and 125 m from day 21, yet increased POC export was not evident until day 24. Only a small proportion of the mixed-layer POC was intercepted by the traps, with more than half of the mixed-layer POC deficit attributable to bacterial remineralization and mesozooplankton grazing. The depletion of silicic acid and the inefficient transfer of iron-increased POC below the permanent thermocline have major implications both for the biogeochemical interpretation of times of greater iron supply in the geological past, and also for proposed geo-engineering schemes to increase oceanic carbon sequestration.

Alaska↗
PubMed2004

Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B.

Although oxidative stress has been thought to play a general role in the activation of NF-kappaB, the involvement of reactive oxygen species (ROS) in facilitating nuclear translocation of NF-kappaB in neutrophils has not been described. In addition, the mechanisms by which ROS modulate the transcriptional activity of NF-kappaB in response to Toll-like receptor 4 (TLR4)-dependent signaling are not well characterized. To examine these issues, oxidant-dependent signaling events downstream of TLR4 were investigated in neutrophils stimulated with LPS. Pretreatment of neutrophils with the antioxidants N-acetylcysteine or alpha-tocopherol prevented LPS-induced nuclear translocation of NF-kappaB. Antioxidant treatment of LPS-stimulated neutrophils also inhibited the production of proinflammatory cytokines (TNF-alpha, macrophage inflammatory protein-2, and IL-1beta), as well as activation of the kinases IkappaB kinase alpha, IkappaB kinase beta, p38, Akt, and extracellular receptor-activated kinases 1 and 2. The decrease in cytoplasmic levels of IkappaBalpha produced by exposure of neutrophils to LPS was prevented by N-acetylcysteine or alpha-tocopherol. Activation of IL-1R-associated kinase-1 (IRAK-1) and IRAK-4 in response to LPS stimulation was inhibited by antioxidants. These results demonstrate that proximal events in TLR4 signaling, at or antecedent to IRAK-1 and IRAK-4 activation, are oxidant dependent and indicate that ROS can modulate NF-kappaB-dependent transcription through their involvement in early TLR4-mediated cellular responses.

Acetylcysteine↗