Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. Cell necroptosis features receptor-interacting protein (RIPK) 1 activation and necroptosome formation. This leads to loss of plasma membrane integrity, the release of cell contents into the extracellular space, and subsequent increased inflammation. ⋯ Using an in vivo mouse model of intratracheal injection (i.t.) of LPS and in vitro LPS stimulation of mouse PMN, we found that LPS-TLR4 signaling in PMNs activates and phosphorylates TBK1 and IKKε, which in turn suppress LPS-induced formation of the RIPK1-RIPK3-MLKL (necrosome) complex. TBK1 dysfunction by knockdown or inhibitor significantly increases the phosphorylation of RIPK1 (∼67%), RIPK3 (∼68%), and MLKL (∼50%) and promotes RIPK1-RIPK3 and RIPK3-MLKL interactions and increases PMN necroptosis (∼83%) in response to LPS, with subsequent augmented lung inflammation. These findings suggest that the LPS-TLR4-TBK1 axis serves as a negative regulator for PMN necroptosis and might be a therapeutic target for modulating PMN death and inflammation.
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One of the main contents of post-resuscitation care is to alleviate cardiac and neurological damage in cardiac arrest (CA) victims. Recently, dexmedetomidine pre- and post-conditioning have been shown to both effectively protect the heart and brain against regional ischemia reperfusion injury. In this study, we investigated the effects of dexmedetomidine post-conditioning on cardiac and neurological outcomes after CA and resuscitation in swine. ⋯ Dexmedetomidine post-conditioning dose-dependently improved post-resuscitation cardiac and neurological outcomes through the inhibition of tissue inflammation, oxidative stress, and cell apoptosis and necroptosis.
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The emerging concept of endovascular resuscitation applies catheter-based techniques in the management of patients in shock to manipulate physiology, optimize hemodynamics, and bridge to definitive care. These interventions hope to address an unmet need in the care of severely injured patients, or those with refractory non-traumatic cardiac arrest, who were previously deemed non-survivable. These evolving techniques include Resuscitative Endovascular Balloon Occlusion of Aorta, Selective Aortic Arch Perfusion, and Extracorporeal Membrane Oxygenation and there is a growing literature base behind them. This review presents the up-to-date techniques and interventions, along with their application, evidence base, and controversy within the new era of endovascular resuscitation.
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The coronavirus disease (COVID-19) pandemic has threatened millions of lives worldwide with severe systemic inflammation, organ dysfunction, and thromboembolic disease. Within our institution, many critically ill COVID-19-positive patients suffered major thrombotic events, prompting our clinicians to evaluate hypercoagulability outside of traditional coagulation testing. We determined the prevalence of fibrinolysis shutdown via rotational thromboelastometry (ROTEM, Instrumentation Laboratories, Bedford, Mass) in patients admitted to the intensive care unit over a period of 3 weeks. ⋯ Eight of 9 (73%) of the VTE patients met criteria for fibrinolysis shutdown. Given the high rate of fibrinolysis shutdown in these patients, our data support using viscoelastic testing to evaluate for the presence of impaired fibrinolysis. This may help identify patient subsets who might benefit from the administration of fibrinolytics.