Evaluation of the efficacy and safety of TREM-1 inhibition with nangibotide in patients with COVID-19 receiving respiratory support: the ESSENTIAL randomised, double-blind trial.

Background: Activation of the TREM-1 pathway is associated with outcome in life threatening COVID-19. Data suggest that modulation of this pathway with nangibotide, a TREM-1 modulator may improve survival in TREM-1 activated patients (identified using the biomarker sTREM-1).

Methods: Phase 2 double-blind randomized controlled trial assessing efficacy, safety, and optimum treatment population of nangibotide (1.

Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial.

Background: Activation of the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway is associated with septic shock outcomes. Data suggest that modulation of this pathway in patients with activated TREM-1 might improve survival. Soluble TREM-1 (sTREM-1), a potential mechanism-based biomarker, might facilitate enrichment of patient selection in clinical trials of nangibotide, a TREM-1 modulator.

Rationale and protocol for the efficacy, safety and tolerability of nangibotide in patients with septic shock (ASTONISH) phase IIb randomised controlled trial.

Introduction: Septic shock is the subgroup of patients with sepsis, which presents as vasopressor dependence, an elevated blood lactate concentration and is associated with a mortality of at least 30%. Expression of the triggering receptor expressed on myeloid cells 1 (TREM-1) pathway, measured using a serum biomarker of pathway activation (soluble TREM-1, sTREM-1) has been associated with outcome in septic shock. Preclinical and early phase patient data suggest that therapeutic modulation of this pathway may improve survival.

Increased sTREM-1 plasma concentrations are associated with poor clinical outcomes in patients with COVID-19.

Patients with sepsis display increased concentrations of sTREM-1 (soluble Triggering Receptor Expressed on Myeloid cells 1), and a phase II clinical trial focusing on TREM-1 modulation is ongoing. We investigated whether sTREM-1 circulating concentrations are associated with the outcome of patients with coronavirus disease 2019 (COVID-19) to assess the role of this pathway in COVID-19. This observational study was performed in two independent cohorts of patients with COVID-19.

Endothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors.

Background: The vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role of the hypoxia-inducible factors, HIF-1α and HIF-2α in the pulmonary and systemic circulations as potential regulators of systemic vascular function in normoxic or hypoxic conditions and in response to inflammatory stress. We developed a series of transgenic mouse models, the HIF-1α Tie2Cre, deficient in HIF1-α in the systemic and pulmonary vascular endothelium and the L1Cre, a pulmonary endothelium specific knockout of HIF-1α or HIF-2α.

2-Hydroxyglutarate Metabolism Is Altered in an Model of LPS Induced Endotoxemia.

The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration , and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect.

Inhibition of Dimethylarginine Dimethylaminohydrolase 1 Improves the Outcome of Sepsis in Pregnant Mice.

Sepsis is one of the most important causes of maternal mortality. In our previous work, we established a polymicrobial sepsis (cecal ligation and puncture [CLP]) model in murine pregnancy and found that pregnant mice had a greater susceptibility to septic shock. In this model, mortality seemed to be associated with the development of early hemodynamic dysfunction and although circulating cytokine levels were similar, "off target" lung inflammatory cell numbers were greater in pregnant mice.

Bench to bedside review: therapeutic modulation of nitric oxide in sepsis-an update.

Nitric oxide is a signalling molecule with an extensive range of functions in both health and disease. Discovered in the 1980s through work that earned the Nobel prize, nitric oxide is an essential factor in regulating cardiovascular, immune, neurological and haematological function in normal homeostasis and in response to infection. Early work implicated exaggerated nitric oxide synthesis as a potentially important driver of septic shock; however, attempts to modulate production through global inhibition of nitric oxide synthase were associated with increased mortality.

The SOFA score-development, utility and challenges of accurate assessment in clinical trials.

The Sequential Organ Failure Assessment or SOFA score was developed to assess the acute morbidity of critical illness at a population level and has been widely validated as a tool for this purpose across a range of healthcare settings and environments.In recent years, the SOFA score has become extensively used in a range of other applications. A change in the SOFA score of 2 or more is now a defining characteristic of the sepsis syndrome, and the European Medicines Agency has accepted that a change in the SOFA score is an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis.

NMDA receptor modulation of glutamate release in activated neutrophils.

Background: Neutrophil depletion improves neurologic outcomes in experimental sepsis/brain injury. We hypothesized that neutrophils may exacerbate neuronal injury through the release of neurotoxic quantities of the neurotransmitter glutamate.

Methods: Real-time glutamate release by primary human neutrophils was determined using enzymatic biosensors.

Evidence for a protective role for the rs805305 single nucleotide polymorphism of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in septic shock through the regulation of DDAH activity.

Background: Dimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the synthesis of nitric oxide (NO) through the metabolism of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA). Pilot studies have associated the rs805305 SNP of DDAH2 with ADMA concentrations in sepsis. This study explored the impact of the rs805305 polymorphism on DDAH activity and outcome in septic shock.

Rapid onset of severe septic shock in the pregnant mouse†.

Aims: Globally, sepsis is a major cause of mortality through the combination of cardiovascular collapse and multiorgan dysfunction. Pregnancy appears to increase the risk of death in sepsis, but the exact reason for the greater severity is unclear. In this study, we used polymicrobial sepsis induced by cecal ligation and puncture (CLP) and high-dose intraperitoneal lipopolysaccharide (LPS; 10 or 40 mg, serotype 0111: B4) to test the hypotheses that pregnant mice are more susceptible to sepsis and that this susceptibility was mediated through an excessive innate response causing a more severe cardiovascular collapse rather than a reduction in microbe killing.

Definitions and pathophysiology of vasoplegic shock.

Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed.

Challenges in the Anesthetic and Intensive Care Management of Acute Ischemic Stroke.

Acute ischemic stroke (AIS) is a devastating condition with high morbidity and mortality. In the past 2 decades, the treatment of AIS has been revolutionized by the introduction of several interventions supported by class I evidence-care on a stroke unit, intravenous tissue plasminogen activator within 4.5 hours of stroke onset, aspirin commenced within 48 hours of stroke onset, and decompressive craniectomy for supratentorial malignant hemispheric cerebral infarction.

Dimethylarginine dimethylaminohydrolase 2 regulates nitric oxide synthesis and hemodynamics and determines outcome in polymicrobial sepsis.

Objective: Nitric oxide is a key to numerous physiological and pathophysiological processes. Nitric oxide production is regulated endogenously by 2 methylarginines, asymmetric dimethylarginine (ADMA) and monomethyl-L-arginine. The enzyme that specifically metabolizes asymmetric dimethylarginine and monomethyl-L-arginine is dimethylarginine dimethylaminohydrolase (DDAH).

Pharmacological inhibition of DDAH1 improves survival, haemodynamics and organ function in experimental septic shock.

The aim of the present study was to investigate the therapeutic effects of pharmacological inhibition of DDAH1 (dimethylarginine dimethylaminohydrolase 1), an enzyme that metabolizes endogenously produced nitric oxide synthase inhibitors, principally ADMA (asymmetric dimethylarginine). The present study employs a series of rodent models to evaluate the effectiveness a DDAH1-selective inhibitor (L-257). Short-term models involved the development of endotoxaemia using lipopolysaccharide and long-term models involved the intraperitoneal administration of faecal slurry.

The Imperial Paediatric Emergency Training Toolkit (IPETT) for use in paediatric emergency training: development and evaluation of feasibility and validity.

Aim: To develop and test the feasibility, reliability, and validity of a practical toolkit for the assessment and feedback of skills required to manage paediatric emergencies in critical care settings.

Methods: The Imperial Paediatric Emergency Training Toolkit (IPETT) was developed based on current evidence-base and expert input. IPETT assesses both technical and non-technical skills.

Unannounced in situ simulations: integrating training and clinical practice.

Simulation-based training for healthcare providers is well established as a viable, efficacious training tool, particularly for the training of non-technical team-working skills. These skills are known to be critical to effective teamwork, and important in the prevention of error and adverse events in hospitals. However, simulation suites are costly to develop and releasing staff to attend training is often difficult.

The use of computers for perioperative simulation in anesthesia, critical care, and pain medicine.

Simulation in perioperative anesthesia training is a field of considerable interest, with an urgent need for tools that reliably train and facilitate objective assessment of performance. This article reviews the available simulation technologies, their evolution, and the current evidence base for their use. The future directions for research in the field and potential applications of simulation technology in anesthesia, critical care, and pain medicine are discussed.

Acute intravascular haemolysis associated with intravenous administration of meropenem in a sixty four year old man.

We present the first reported case of severe intravascular haemolysis associated with the use of meropenem in a 64 year old man. The report highlights a further possible drug related cause of intravascular haemolysis. The patient, who had a background of dialysis dependent renal failure, epilepsy and learning difficulties, was admitted to the intensive care unit following laparotomy and large bowel resection.