Shock

Sepsis-induced brain injury is associated with an acute deterioration of mental status resulting in cognitive impairment and acquisition of new functional limitations in sepsis survivors. However, the exact nature of brain injury in this setting is often subtle and remains to be fully characterized both in pre-clinical studies and at the bedside. Given the translation potential for the use of magnetic resonance imaging (MRI)1 to define sepsis-induced brain injury, we sought to determine and correlate the cellular changes with neuroradiographic presentations in a classic murine model of sepsis induced by cecal ligation and puncture (CLP)2...

BACKGROUND: Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. METHODS: In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis...

Mortalin/GRP75 (glucose regulated protein 75), a member of heat shock protein 70 (Hsp70) family of chaperones, is involved in several cellular processes including proliferation and signaling, and plays a pivotal role in cancer and neurodegenerative disorders. In this study, we sought to determine the role of mortalin/GRP75 in mediating vascular inflammation and permeability linked to the pathogenesis of acute lung injury (ALI). In an aerosolized bacterial lipopolysaccharide (LPS) inhalation mouse model of ALI, we found that administration of mortalin/GRP75 inhibitor MKT-077, both prophylactically and therapeutically, protected against PMN influx into alveolar airspaces, microvascular leakage and expression of pro-inflammatory mediators such as IL-1β, E-selectin and TNFα...

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) has the potential to diagnose infectious diseases. Due to the lack of reliable biomarkers and the importance of timely diagnosis for sepsis treatment, we conducted this systematic review and meta-analysis to evaluate the value of suPAR diagnosis and prognosis for sepsis. METHODS: PubMed, Embase, Web of Science and Cochrane Library databases were searched for studies, which reported the value of suPAR diagnosis and/or prognosis in patients with sepsis...

High levels of PGE2 have been implicated in the pathogenesis of intestinal inflammatory disorders such as necrotizing enterocolitis (NEC) and peritonitis. However, PGE2 has a paradoxical effect: its low levels promote intestinal homeostasis, whereas high levels may contribute to pathology. These concentration-dependent effects are mediated by four receptors, EP1-EP4. In this study, we evaluate the effect of blockade of the low affinity pro-inflammatory receptors EP1 and EP2 on expression of COX-2, the rate limiting enzyme in PGE2 biosynthesis, and on gut barrier permeability using cultured enterocytes and three different models of intestinal injury...

BACKGROUND: Vitamin D deficiency is associated with various cardiovascular diseases, including sudden cardiac arrest (SCA). Profound cardiogenic shock is associated with morbidity and mortality in patients with SCA. This study investigated the association of vitamin D deficiency with profound cardiogenic shock in patients resuscitated from SCA. MATERIALS AND METHODS: We enrolled patients who were successfully resuscitated from out-of-hospital cardiac arrests of a presumed cardiac cause...

This study aimed to assess the viability of using the venous-to-arterial carbon dioxide partial pressure difference (P(v-a)CO2) to predict clinical worsening of septic shock, depending on central venous oxygen saturation (ScvO2). The prospective, observational, multicentric study conducted in three intensive care units (ICU) included all patients with a septic shock episode during the first six hours, with 122 patients assessed. Clinical worsening was defined as an increase of sequential organ failure assessment (SOFA) scores ≥1 (ΔSOFA ≥1) within two days...

BACKGROUND: Resuscitation from hemorrhagic shock (HS) by blood transfusion restores oxygen (O2) delivery and provides hemodynamic stability. Current regulations allow red blood cells (RBCs) to be stored and used for up to 42 days. During storage, RBCs undergo many structural and functional changes. These storage lesions have been associated with adverse events and increased mortality after transfusion, increasing the need for improved RBC storage protocols. This study evaluates the efficacy of anaerobically stored RBCs to resuscitate rats from severe HS compared with conventionally stored RBCs...

Ischemia and reperfusion injury following severe trauma or cardiac arrest are major causes of organ damage in intensive care patients. The brain is particularly vulnerable because hypoxia rapidly damages neurons due to their heavy reliance on oxidative phosphorylation. Therapeutic hypothermia can reduce ischemia-induced brain damage, but cooling procedures are slow and technically difficult to perform in critical care settings. It has been previously reported that injection of naturally occurring adenosine 5'-monophosphate (AMP) can rapidly induce hypothermia in mice...

INTRODUCTION: Several disease processes trigger prolonged activation of the alternative complement pathway. Crosslinks between complement activation and physiologic changes in platelets and neutrophils have been identified, but how this interplay alters the hemostatic potential in humans remains undefined. We hypothesize that activation of the alternative pathway triggers a hypercoagulable state. METHODS: C3/C5 convertase Cobra Venom Factor (CVF, 10 Units/mL) was employed to activate the alternative complement pathway in whole blood...

INTRODUCTION: Suprarenal aortic cross clamping (SRACC) and reperfusion may cause acute pulmonary hypertension and multiple organ failure. HYPOTHESIS: The organic mononitrites of 1,2-propanediol (PDNO), an NO donor with a very short half-life, is a more efficient pulmonary vasodilator and attenuator of end-organ damage and inflammation without significant side effects compared to nitroglycerin and inorganic nitrite in a porcine SRACC model. METHODS: Anesthetised and instrumented domestic pigs were randomised to either of four IV infusions until the end of the experiment (n = 10 per group): saline (control), PDNO (45 nmol kg min), nitroglycerin (44 nmol kg min), or inorganic nitrite (a dose corresponding to PDNO)...

Extensive burn injuries promote an increase in the lipolysis of white adipose tissue (WAT), a complication that enhances post-burn hypermetabolism, contributing to hyperlipidemia and hepatic steatosis. The systemic increase of free fatty acids (FFA) due to burn-induced lipolysis and subsequent organ fatty infiltration may culminate in multiple organ dysfunction and ultimately, death. Thus, reducing WAT lipolysis to diminish the mobilization of FFAs may render an effective means to improve outcomes post-burn...

Pneumonia is the leading cause of sepsis and septic shock. Patients who survive pneumonia are vulnerable to long-term complications including increased risk of neurocognitive dysfunction. This study investigated the immune response and long-term complications of a non-surgical mouse model of Klebsiella pneumoniae pneumosepsis with antibiotic treatment. Pneumosepsis resulted in acutely enhanced expression of inflammatory cytokines, chemokines, and damage associated molecular patterns in the brain and spleen...

BACKGROUND: Whereas the circadian system controls the daily production of melatonin and the daily activity of the immune system, increasing evidences support the association between circadian misalignment with the alterations in the immune response and melatonin rhythm during sepsis. The aim of this study was to analyze the daily changes in clock genes expression and the urinary excretion of 6-SM (6-sulfatoxymelatonin, the major melatonin metabolite), and their connection with the innate immune activity, oxidative status in blood, and clinical outcome during sepsis...

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BACKGROUND: Cardiac dysfunction, a common complication from severe sepsis, is associated with increased morbidity and mortality. However, the molecular mechanisms of septic cardiac dysfunction are poorly understood. SIRT1, a member of the sirtuin family of NAD+-dependent protein deacetylases, is an important immunometabolic regulator of sepsis, and sustained SIRT1 elevation is associated with worse outcomes and organ dysfunction in severe sepsis. Herein, we explore the role of SIRT1 in septic cardiac dysfunction using a murine model of sepsis...

BACKGROUND: Endothelial dysfunction during hemorrhagic shock (HS), is associated with loss of cell-associated syndecan-1 (Sdc1) and hyperpermeability. Fresh frozen plasma (FFP) preserves Sdc1 and reduces permeability following HS, although the key mediators remain unknown. Antithrombin III (ATIII) is a plasma protein with potent anti-inflammatory and endothelial protective activity. We hypothesized that the protective effects of FFP on endothelial Sdc1 and permeability are mediated, in part, through ATIII...

INTRODUCTION: Tranexamic acid (TXA) improves survival in traumatic hemorrhage, but difficulty obtaining intravenous (IV) access may limit its use in austere environments, given its incompatibility with blood products. The bioavailability of intramuscular (IM) TXA in a shock state is unknown. We hypothesized that IM and IV administration have similar pharmacokinetics and ability to reverse in vitro hyperfibrinolysis in a swine controlled-hemorrhage model. METHODS: Twelve Yorkshire cross swine were anesthetized, instrumented, and subjected to a 35% controlled hemorrhage, followed by resuscitation...

Once thought of as an inert fatty tissue present only to provide insulation for the peritoneal cavity, the omentum is currently recognized as a vibrant immunologic organ with a complex structure uniquely suited for defense against pathogens and injury. The omentum is a source of resident inflammatory and stem cells available to participate in the local control of infection, wound healing, and tissue regeneration. It is intimately connected with the systemic vasculature and communicates with the central nervous system and the hypothalamic pituitary adrenal axis...