The Impact of Fluid Resuscitation on Glycocalyx Degradation in Septic Shock

尽管对脓毒症和脓毒症所致肺损伤的了解有所进展，但患者的发病率和 死亡率仍然高得令人无法接受。越来越多的人认识到，内皮细胞糖基化反应是一种 富含糖胺多糖的血管内膜是败血症预后的关键决定因素。糖基化花蕾 用于调节白细胞黏附、凝血、微循环流动和血管通透性-功能 对血管的动态平衡至关重要。新兴的临床前和小型人体研究表明，脓毒症介导的 病理障碍会使糖萼降解，导致血管功能障碍、肺损伤和死亡。 人们越来越多地认识到糖萼完整性的重要性，同时也认识到 静脉输液--长期以来被认为是败血症复苏的重要组成部分--可能 矛盾的是，脓毒症会加重器官损伤。有趣的是，临床前和小型临床研究表明 过度的液体复苏与病理性的血糖降解有关，提示了一种机制 静脉输液可能会导致肺损伤。相反，脓毒症前糖唇完整性丧失。 复苏可能有助于确定患者对液体有害影响的敏感性-代表 使液体复苏方法个性化的潜在机会。 晶体类自由或血管升压药早期复苏治疗脓毒症(三叶草)试验由美国国立卫生研究院资助2,320 ~50点防治所进行的多中心、随机、对照临床试验 比较不同的24小时液体复苏策略的急性肺损伤(PEAL)网络(自由 与限制性相比)在早期脓毒症中的作用以及对死亡率的影响。虽然在 最初的试验方案，三叶草是确定潜在的因果关系的理想位置 脓毒症的液体复苏策略、糖萼降解、ARDS和死亡率。 这项提议的广泛的长期目标是调查：1)不同的液体复苏策略 (限制性的或自由性的)影响败血症中的糖萼降解；2)糖萼的降解与 急性呼吸窘迫综合征(ARDS)的发展和/或死亡率，3)循环标志物 初始糖肾盏完整性可以预测患者对不同容量复苏策略的反应。 为了探讨这些假设，我们将利用三叶草研究提供的独特机会 执行一个全面的读数的糖萼损伤，不仅采用最先进的措施 糖基化降解(肝素等糖化裂解产物的质谱学检测 硫酸盐)，而且基于酶联免疫吸附试验(Syndecan-1)和护理点功能分析(例如 粘弹性凝血监测)，能够快速评估糖萼完整性。说明和说明 对这些机制的更好理解可能会导致预测结果的策略，为患者选择 量身定制的治疗方法，跟踪治疗反应，并开发针对脓毒症的新的糖萼导向疗法。

Despite advances in the understanding of sepsis and sepsis-induced lung injury, patient morbidity and mortality remain unacceptably high. There is increasing recognition that the endothelial glycocalyx, a glycosaminoglycan-enriched endovascular layer, is a critical determinant of sepsis outcomes. The glycocalyx serves to regulate leukocyte adhesion, coagulation, microcirculatory flow, and vascular permeability – functions vital to vascular homeostasis. Emerging preclinical and small human studies demonstrate that sepsis-mediated pathologic disturbances degrade the glycocalyx, leading to vascular dysfunction, lung injury and mortality. This increasing appreciation of the importance of glycocalyx integrity has coincided with recognition that intravenous fluid administration—long considered an essential component of sepsis resuscitation—may paradoxically worsen organ injury in sepsis. Interestingly, preclinical and small clinical studies suggest that excessive fluid resuscitation is associated with pathological glycocalyx degradation, suggesting a mechanism by which intravenous fluids may cause lung injury. Conversely, loss of glycocalyx integrity prior to sepsis resuscitation may help define a patient's susceptibility to the deleterious effects of fluids—representing a potential opportunity to personalize fluid resuscitation approaches. The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial is a NIH-funded 2,320 subject multi-center, randomized, controlled clinical trial conducted by the ~50-site Prevention and Treatment of Acute Lung Injury (PETAL) network comparing alternative 24-hour fluid resuscitation strategies (liberal versus restrictive) in early sepsis and the effect on mortality. While the glycocalyx was not addressed in the original trial protocol, CLOVERS is ideally positioned to determine the potential causal associations between fluid resuscitation strategies, glycocalyx degradation, ARDS, and mortality in sepsis. The broad, long-term objectives of this proposal are to investigate if: 1) different fluid resuscitation strategies (Restrictive or Liberal) impact glycocalyx degradation in sepsis; 2) glycocalyx degradation is associated with the development of acute respiratory distress syndrome (ARDS) and/or mortality, 3) circulating markers of initial glycocalyx integrity can predict patient responses to different volume resuscitation strategies. To pursue these hypotheses, we will leverage the unique opportunity provided by the CLOVERS study to perform a comprehensive readout of glycocalyx damage, employing not only state-of-the-art measures of glycocalyx degradation (mass spectrometry detection of glycocalyx breakdown products such as heparan sulfate), but also less expensive ELISA-based (syndecan-1) and point-of-care functional assays (e.g. viscoelastic coagulation monitoring) capable of rapid assessment of glycocalyx integrity. The elucidation and improved understanding of these mechanisms may lead to strategies to predict outcomes, to select patients for tailored therapy, to follow treatment response, and to develop novel glycocalyx-directed therapies in sepsis.