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. Bacterial and direct protein-kinase C (Phorbol 12-myristate 13-acetate; PMA) activation of neutrophils in human whole blood, isolated neutrophils or human cell lines were compared in the presence/absence of N-Methyl-d-aspartic acid receptor (NMDAR) antagonists. Bacterial and direct activation of neutrophils from wild-type and transgenic murine neutrophils deficient in NMDAR-scaffolding proteins were compared using flow cytometry (phagocytosis, reactive oxygen species (ROS) generation) and real-time respirometry (oxygen consumption). FINDINGS: Both glutamate and the NMDAR co-agonist d-serine are rapidly released by neutrophils in response to bacterial and PMA-induced activation. Pharmacological NMDAR blockade reduced both the autocrine release of glutamate, d-serine and the respiratory burst by activated primary human neutrophils. A highly specific small-molecule inhibitor ZL006 that limits NMDAR-mediated neuronal injury also reduced ROS by activated neutrophils in a murine model of peritonitis, via uncoupling of the NMDAR GluN2B subunit from its' scaffolding protein, postsynaptic density protein-95 (PSD-95). Genetic ablation of PSD-95 reduced ROS production by activated murine neutrophils. Pharmacological blockade of the NMDAR GluN2B subunit reduced primary human neutrophil activation induced by Pseudomonas fluorescens, a glutamate-secreting Gram-negative bacillus closely related to pathogens that cause hospital-acquired infections. INTERPRETATION: These data suggest that release of glutamate by activated neutrophils augments ROS production in an autocrine manner via actions on NMDAR expressed by these cells. FUND: GLA: Academy Medical Sciences/Health Foundation Clinician Scientist. AVG is a Wellcome Trust Senior Research Fellow.

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. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition.

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. There is new class I evidence also demonstrating benefits of endovascular therapy on functional outcomes in those with anterior circulation stroke. In addition, the importance of the careful management of key systemic physiological variables, including oxygenation, blood pressure, temperature, and serum glucose, has been appreciated. In line with this, the role of anesthesiologists and intensivists in managing AIS has increased. This review highlights the main challenges in the endovascular and intensive care management of AIS that, in part, result from the paucity of research focused on these areas. It also provides guidelines for the management of AIS based upon current evidence, and identifies areas for further research.

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. These factors may restrict access to simulation training. We discuss our experiences of 'in situ' simulation for unannounced cardiac arrest training when the training is taken to the clinical environment. This has the benefit of decreasing required resources, increasing realism and affordability, and widening multidisciplinary team participation, thus enabling assessment and training of non-technical team-working skills in real clinical teams. While there are practical considerations of delivering training in the clinical environment, we feel there are many potential benefits compared with other forms of simulation training. We are able to tailor the training to the needs of the location, enabling staff to see a scenario that is relevant to their practice. This is particularly useful for staff who have less exposure to cardiac arrest events, such as radiology staff. We also describe the important benefit of risk assessment for a clinical environment. During our simulations we have identified a number of issues that, had they occurred during a real resuscitation attempt, may have led to patient harm or patient death. For these reasons we feel in situ simulation should be considered by every hospital as part of a patient safety initiative.