intravenous-endotoxin-challenge-healthy-humans-an-experimental

Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation

Activation of inflammatory pathways represents a central mechanism in multiple disease states both acute and chronic. Triggered via either pathogen or ...

University College London

Paramedic tracheal intubation has been reported to carry a high failure rate and morbidity. A comparison between doctor and paramedic-led intubation at out-of-hospital cardiac arrests (OHCA) was conducted to assess whether this finding was observed in our clinical practice.

Can experienced paramedics perform tracheal intubation at cardiac arrests? Five years experience of a regional air ambulance service in the UK.

The role of e-learning in contemporary healthcare education is quickly developing. The aim of this study was to examine the relationship between the use of an e-learning simulation programme (Microsim, Laerdal, UK) prior to attending an Advanced Life Support (ALS) course and the subsequent relationship to candidate performance.

The effect of pre-course e-learning prior to advanced life support training: a randomised controlled trial.

The physiological and biochemical abnormalities that constitute multiple organ failure represent cellular perturbations that, importantly, need to be reconciled with a lack of significant cell death together with availability but impaired utilization of oxygen. In conjunction with the relatively rapid ability of the organ to recover in surviving patients, a paradigm of metabolic shutdown triggered by a decrease in mitochondrial energy production appears increasingly valid. This review discusses data demonstrating temporal changes in oxygen utilization through the septic process, evidence for mitochondrial derangements, and recovery of mitochondrial function preceding clinical recovery.

Organ failure in the ICU: cellular alterations.

Physiological track and trigger scores have an established role in enhancing the detection of critical illness in hospitalized patients. Their potential to identify individuals at risk of clinical deterioration in the pre-hospital environment is unknown. This study compared the predictive accuracy of the Modified Early Warning Score (MEWS) with current clinical practice.

Is the Modified Early Warning Score (MEWS) superior to clinician judgement in detecting critical illness in the pre-hospital environment?

Oxygen in resuscitation: a game of two halves.

Patients with critical illness, and in particular sepsis, are now recognized to undergo unifying, pathogenic disturbances of immune function. Whilst scientific and therapeutic focus has traditionally been on understanding and modulating the initial pro-inflammatory limb, recent years have witnessed a refocusing on the development and importance of immunosuppressive 'anti-inflammatory' pathways. Several mechanisms are known to drive this phenomenon; however, no overriding conceptual framework justifies them. In this article we review the contribution of pro-resolution pathways to this phenotype, describing the observed immune alterations in terms of either a failure of resolution of inflammation or the persistence of pro-resolution processes causing inappropriate 'injurious resolution'-a novel hypothesis. The dysregulation of key processes in critical illness, including apoptosis of infiltrating neutrophils and their efferocytosis by macrophages, are discussed, along with the emerging role of specialized cell subtypes Gr1(+) CD11b(+) myeloid-derived suppressor cells and CD4(+) CD25(+) FoxP3(+) T-regulatory cells.

Pathways mediating resolution of inflammation: when enough is too much.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) as immunomodulatory agents.

Sepsis, trauma, burns, and major surgical procedures activate common systemic inflammatory pathways. Nosocomial infection, organ failure, and mortality in this patient population are associated with a quantitatively different reprioritization of the circulating leukocyte transcriptome to the initial inflammatory insult, greater in both magnitude and duration, and secondary to multiple observed defects in innate and adaptive immune function. Dysregulation of inflammatory resolution processes and associated bioactive lipid mediators (LMs) mechanistically contribute to this phenotype. Recent data indicate the potential efficacy of therapeutic interventions that either reduce immunosuppressive prostaglandins (PGs) or increase specialized proresolving LMs. Here, we reassess the potential for pharmacological manipulation of these LMs as therapeutic approaches for the treatment of critical illness (CI).

Lipid mediators in immune dysfunction after severe inflammation.

Solid organ transplantation is a vital therapy for end stage diseases. Decades of research have established that components of the adaptive immune system are critical for transplant rejection, but the role of the innate immune system in organ transplantation is just emerging. Accumulating evidence indicates that the innate immune system is activated at the time of organ implantation by the release of endogenous inflammatory triggers. This review discusses the nature of these triggers in organ transplantation and also potential mediators that may enhance inflammation resolution after organ implantation.

Inflammatory triggers of acute rejection of organ allografts.

Liver disease is one of the leading causes of death worldwide. Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE2-dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE2-mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro. Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE2, reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus. Taken together, human albumin solution infusions may be used to reduce circulating PGE2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.

Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2.

3D printing for the many, not the few.

Increased mortality in "cold sepsis": the result of a frozen immune response?

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes - a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field.

Resolution of inflammation: a new therapeutic frontier.

Reduced ex vivo lipopolysaccharide (LPS) stimulated whole blood pro-inflammatory cytokine release is a hallmark of immunosuppression in the critically ill and predicts adverse clinical outcomes. No standard technique for performing the assay currently exists. The impact of methodological heterogeneity was determined.

Article	Year
Can experienced paramedics perform tracheal intubation at cardiac arrests? Five years experience of a regional air ambulance service in the UK. Resuscitation\| PubMed ID: 19733428	2009
The effect of pre-course e-learning prior to advanced life support training: a randomised controlled trial. Resuscitation\| PubMed ID: 20409627	2010
Organ failure in the ICU: cellular alterations. Seminars in respiratory and critical care medicine\| PubMed ID: 21989694	2011
Is the Modified Early Warning Score (MEWS) superior to clinician judgement in detecting critical illness in the pre-hospital environment? Resuscitation\| PubMed ID: 22248688	2012
Oxygen in resuscitation: a game of two halves. Resuscitation\| PubMed ID: 23523826	2013
Pathways mediating resolution of inflammation: when enough is too much. The Journal of pathology\| PubMed ID: 23794437	2013
Use of non-steroidal anti-inflammatory drugs (NSAIDs) as immunomodulatory agents. BMJ (Clinical research ed.)\| PubMed ID: 23935082	2013
Lipid mediators in immune dysfunction after severe inflammation. Trends in immunology\| PubMed ID: 24268519	2014
Inflammatory triggers of acute rejection of organ allografts. Immunological reviews\| PubMed ID: 24517430	2014
Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nature medicine\| PubMed ID: 24728410	2014
3D printing for the many, not the few. Nature biotechnology\| PubMed ID: 25380438	2014
Increased mortality in "cold sepsis": the result of a frozen immune response? Critical care medicine\| PubMed ID: 25978156	2015
Resolution of inflammation: a new therapeutic frontier. Nature reviews. Drug discovery\| PubMed ID: 27020098	2016
Stimulated Whole Blood Cytokine Release as a Biomarker of Immunosuppression in the Critically Ill: The Need for a Standardized Methodology. Shock (Augusta, Ga.)\| PubMed ID: 27089173	2016

James N. Fullerton

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