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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The purpose of this study was to evaluate the prognostic significance of classification of patients with septic shock into different critical illness-related corticosteroid insufficiency subgroups. A retrospective observational study was conducted in patients with septic shock who underwent a short corticotropin stimulation test within 72 h of the onset of shock. Patients were classified into normal adrenal function (NOM), low basal cortisol (LBC) (basal cortisol, <10 μg/dL), or low Δ cortisol (LDC) (basal cortisol, ≥10 μg/dL; cortisol, <9 μg/dL) groups. ⋯ The 28-day mortalities of the NOM, LBC, and LDC groups were 40.5%, 38.5%, and 63.2%, respectively (P = 0.007). Classification into the LDC group significantly increased the odds of 28-day mortality (odds ratio, 2.717; 95% confidence interval, 1.452-5.082; P = 0.002) and remained an independent risk factor for mortality even after controlling for all the other potential risk factors identified (odds ratio, 3.638; 95% confidence interval, 1.418-9.028; P = 0.006). Classification into the LDC group is an independent risk factor for mortality in hydrocortisone-treated septic shock patients.
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The contribution of the adaptive and innate immune systems to the pathogenesis and outcome of sepsis remains a fundamental yet controversial question. Here, we use mice lacking the recombination activating gene 1 (Rag-1) to study the role of T and B cells in sepsis after cecal ligation and puncture (CLP). Spleens of Rag-1 mice were atrophic and completely devoid of CD3 T cells and CD19 B cells. ⋯ Levels for most mediators were unaffected by the absence of T and B lymphocytes. Only the concentrations of IL-6 and IL-17 were found to be significantly lower in Rag-1 mice compared with wild-type mice. In conclusion, the absence of T and B cells in the CLP model used does not appear to affect the acute outcome of severe sepsis.
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The host inflammatory response in sepsis may be resolved by endogenous anti-inflammatory immune cell responses, avoiding fatal pathogenesis, organ injury, and death. The intracellular signaling mediator cyclic 3'5'-adenosine monophosphate is a potent modulator of inflammatory responses and initiates the polarization of immune cells in a direction that suppresses inflammatory activation. Cyclic 3'5'-adenosine monophosphate is enzymatically produced by adenylyl cyclases (ACs). ⋯ A correlation between increased miR142-3p and decreased AC9 expression was found in the liver, kidney, and spleen, and when hepatocytes, Kupffer cells (KCs), and liver sinusoidal endothelial cells were isolated after CLP, reduced AC expression and increased miR142-3p expression were found in KCs and liver sinusoidal endothelial cells. Transfecting a miR142-3p inhibitor probe in rat KCs abolished LPS-mediated AC9 inhibition in vitro. These results indicate that CLP leads to miR142-3p-mediated AC9 reduction in liver macrophages, which may further limit cyclic 3'5'-adenosine monophosphate signaling and the ability of macrophages to resolve the proinflammatory response.
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Intestinal ischemia-reperfusion (I/R) injury is a well-established animal model of systemic inflammation and can lead to multiple organ failure as well as severe and lasting morbidity and even death. It can occur in humans as a result of vascular surgery or as secondary sequelae to many common conditions including low blood pressure, myocardial infarction, and necrotizing enterocolitis. Systemic inflammation induced through kidney I/R injury has been shown previously to lead to encephalopathic adverse effects, and it was theorized that intestinal injury would also cause secondary central nervous system effects. ⋯ There was a significant increase in brain edema observed in sham-operated animals as well as in fasted and nonfasted I/R groups, but neurons were not apoptotic, in the 6-h time period. Conversely, Iba1-expressing activated microglia cells and glial fibrillary acidic protein-expressing astrocytes were found to be markedly increased in fasted and nonfasted I/R mice compared with controls and sham-operated animals. These data demonstrate that intestinal I/R injury induces inflammatory changes in the brain.
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Randomized Controlled Trial
Influence of severity of illness on the effects of eritoran tetrasodium (E5564) and on other therapies for severe sepsis.
Disease severity varies widely in patients with severe sepsis. Eritoran tetrasodium (E5564), a TLR4 antagonist, blocks the binding of endotoxin and is being evaluated as a novel therapy for severe sepsis. This analysis aimed to assess the efficacy of eritoran based on severity of illness and similar effects in other recent sepsis trials. ⋯ Potential survival benefits of eritoran in severe sepsis patients were associated with high severity of illness. These findings were used to design a phase 3 trial. Similar treatment by severity-of-illness interaction was found in most recent sepsis trials.