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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In clinical practice, prolonged occlusion of main arteries causes accumulation of metabolic waste and lactate. Reperfusion of blood flow is usually accompanied by circulatory shock. This study investigates the molecular mechanisms responsible for acidosis-induced hypotension and proposes therapeutic strategies for improving hemodynamic stability following ischemia-reperfusion acidosis. ⋯ Recording of electrocardiogram showed progressive development of bradyarrhythmia with ST-segment elevation in animals pretreated with PNU37883A before reperfusion. We demonstrate that acidosis-induced vasodilation is, in part, mediated by the activation of KATP channels through reduction of intracellular Ca in VSMCs. However, systemic antagonism of KATP channel significantly increases the overall mortality secondary to the development of cardiac dysrhythmia in animals with profound experimental metabolic acidosis, suggesting that activation of KATP channel is a protective response during reperfusion acidosis.
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Patients with crush injury often present systemic inflammatory response syndrome and fall into multiple organ failure. The mechanism by which the local tissue damage induces distant organ failure is still unclear. We focused on high-mobility group box 1 protein (HMGB1) as one of the damage-associated molecular pattern molecules that cause systemic inflammation in crush injury. ⋯ These results indicate that HMGB1 is released in response to damage immediately after crush injury and acts as a proinflammatory mediator. Administration of anti-HMGB1 antibody reduced inflammatory reactions and improved survival by blocking extracellular HMGB1. Thus, HMGB1 appears to be a therapeutic target, and anti-HMGB1 antibody may become a promising novel therapy against crush injury to prevent the progression to multiple organ failure.
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The management of severe traumatic brain injury (TBI) focuses on prevention and treatment of intracranial hypertension (ICH) and cerebral hypoperfusion (CH). Predicting which patients will develop these secondary insults is currently not possible. This study investigates the systemic manifestation of neuroinflammation and its role in helping to predict clinical deterioration following severe TBI. ⋯ Interleukin 8 and TNF-α demonstrate promise as candidate serum markers of impending ICH and CH. This suggests that we may be able to "predict" imminent events following TBI before clinical manifestations. Given the morbidity of ICH and CH, minimizing the effects of these secondary insults may have a significant impact on outcome and help guide decisions about timing of interventions.
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Gram-negative bacteria remain the leading cause of sepsis, a disease that is consistently in the top 10 causes of death internationally. Curing bacteremia alone does not necessarily end the disease process as other factors may cause inflammatory damage. Bacterial outer membrane vesicles (OMVs) are naturally produced blebs from the outer membrane of gram-negative bacteria, which contain various proteins and lipopolysaccharide (LPS). ⋯ Downstream events such as the recruitment of neutrophils into tissues due to the presentation of vascular adhesion molecules also occur in OMV-treated animals. Although soluble LPS elicits stronger responses than did OMVs, responses to the latter consistently exceeded those associated with lactated Ringer's infusion. These results indicate OMVs, independent of the parent bacteria, do initiate an inflammatory response; however, further studies are required to better characterize the temporal biomolecular interactions involved.
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Early detection and management of shock are important in optimizing clinical outcomes. One regional marker, sublingual capnography (SLCO2), is particularly appealing as redistribution of blood flow away from the sublingual mucosa can happen very early in the compensatory phase of hypovolemic shock. Our objective was to test the hypothesis that SLCO2 would detect early hypovolemia in a human laboratory model of hemorrhage: progressive lower body negative pressure until onset of cardiovascular collapse. ⋯ Average time to presyncope was 1,579 ± 72 s (mean ± SE). At the time of cardiovascular collapse, lower body negative pressure altered (P < 0.001) systolic blood pressure (mean ± SE: 130 ± 3 vs. 98 ± 2 mm Hg), pulse pressure (mean ± SE: 58 ± 2 vs. 33 ± 2 mm Hg), and heart rate (mean ± SE: 63 ± 3 vs. 102 ± 6 beats/min) when compared with baseline, whereas SLCO2 did not change (49.1 ± 1.0 vs. 48.6 ± 1.5 mm Hg, P = 0.624). In a model of progressive central hypovolemia in humans, we did not detect metabolic derangements in the sublingual mucosa as measured by SLCO2.