Successful treatment for disseminated intravascular coagulation (DIC) corresponding to phenotype changes in a heat stroke patient

Abstract Background Heat stroke induces coagulofibrinolytic activation, which leads to life-threatening disseminated intravascular coagulation (DIC). However, treatment strategies for DIC in heat stroke have not yet been established, and also, the time course changes in coagulofibrinolytic markers have not been thoroughly evaluated. We report a severe heat stroke case with DIC who was eventually saved by anti-DIC treatments in accordance with changes in coagulofibrinolytic markers. Case presentation A 45-year-old man was found unconscious outside, and his body temperature was elevated to 41.9 °C. For heat stroke, we performed an immediate tracheal intubation under the general anesthesia along with cooling by iced gastric lavage, cold fluid administration, and an intravascular cooling using Thermogard™. About 4 h after admission, his core temperature fell to 37 °C. We assessed coagulofibrinolytic biomarkers and treated in accordance with changes in these parameters. This case exhibited a biphasic change varying from an enhanced to a suppressed fibrinolytic type of DIC depending on the relative balance between fibrinolytic activation and the level of plasminogen activator inhibitor-1 (PAI-1). In the early phase with consumption coagulopathy and enhanced fibrinolysis, we transfused a large amount of fresh frozen plasma (FFP) and platelets with tranexamic acid, an antifibrinolytic agent, possibly providing relief for the bleeding tendency. Anticoagulant therapy using recombinant human thrombomodulin-α (rh-TM-α) and antithrombin III (ATIII) concentrate was especially effective for DIC with a suppressed fibrinolytic phenotype in the later phase, after which organ failure that included severe hepatic failure was remarkably improved. Conclusion The present case may indicate the clinical significance of monitoring coagulifibrinolytic changes and the potential benefits of anticoagulants for heat stroke-induced DIC

Effects of hypnotic bromovalerylurea on microglial BV2 cells

An old sedative and hypnotic bromovalerylurea (BU) has anti-inflammatory effects. BU suppressed nitric oxide (NO) release and proinflammatory cytokine expression by lipopolysaccharide (LPS)-treated BV2 cells, a murine microglial cell line. However, BU did not inhibit LPS-induced nuclear translocation of nuclear factor-κB and subsequent transcription. BU suppressed LPS-induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF1). The Janus kinase 1 (JAK1) inhibitor filgotinib suppressed the NO release much more weakly than that of BU, although filgotinib almost completely prevented LPS-induced STAT1 phosphorylation. Knockdown of JAK1, STAT1, or IRF1 did not affect the suppressive effects of BU on LPS-induced NO release by BV2 cells. A combination of BU and filgotinib synergistically suppressed the NO release. The mitochondrial complex I inhibitor rotenone, which did not prevent STAT1 phosphorylation or IRF1 expression, suppressed proinflammatory mediator expression less significantly than BU. BU and rotenone reduced intracellular ATP (iATP) levels to a similar extent. A combination of rotenone and filgotinib suppressed NO release by LPS-treated BV2 cells as strongly as BU. These results suggest that anti-inflammatory actions of BU may be attributable to the synergism of inhibition of JAK1/STAT1-dependent pathways and reduction in iATP level

Abandon the mouse research ship? Not just yet!

Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leukocytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to discuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using animals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients