The Impact of Fluid Resuscitation on Glycocalyx Degradation in Septic Shock

液体复苏对感染性休克中糖萼降解的影响

• 批准号: 10004165
• 负责人: NATHAN I SHAPIRO
• 金额: $ 41.49万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004165
• 关键词: Acute Lung Injury; Adhesions; Adult Respiratory Distress Syndrome; Biological Assay; Biology; Blood Vessels; Cessation of life; Clinical Research; Coagulation Process; Collaborations; Colorado; Complex; Conduct Clinical Trials; Data; Detection; Development; Endothelium; Enzyme-Linked Immunosorbent Assay; Fluid Therapy; Functional disorder; Funding; Glycocalyx; Glycosaminoglycans; Heparitin Sulfate; Homeostasis; Hospitals; Hour; Human; Hypotension; IV Fluid; Iatrogenesis; Inflammation; Injury; Investigation; Israel; Laboratories; Lead; Leukocytes; Liquid substance; Mass Spectrum Analysis; Measures; Mediating; Monitor; Morbidity - disease rate; Outcome; Pathologic; Patient-Focused Outcomes; Patients; Positioning Attribute; Predisposition; Prevention; Protocols documentation; Randomized; Randomized Controlled Clinical Trials; Reporting; Research Infrastructure; Resuscitation; Role; Sepsis; Septic Shock; Site; United States National Institutes of Health; Universities; Vascular Diseases; Vascular Permeabilities; Vasoconstrictor Agents; base; circulating biomarkers; clinical decision-making; clinical investigation; crystalloid; improved; individualized medicine; lung injury; mortality; mortality risk; novel; organ injury; outcome prediction; patient response; point of care; pre-clinical; septic patients; syndecan; treatment effect; treatment response; treatment strategy; virtual; viscoelasticity

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.

尽管对脓毒症和脓毒症引起的肺损伤的认识有所进展，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，内皮糖萼， 富含糖胺聚糖的血管内层是脓毒症结局的关键决定因素。糖萼 用于调节白细胞粘附、凝血、微循环流动和血管通透性功能 对血管内环境稳定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 病理性紊乱使糖萼降解，导致血管功能障碍、肺损伤和死亡。 对糖萼完整性重要性的日益认识与以下认识相一致： 静脉输液-长期以来被认为是脓毒症复苏的重要组成部分-可能 反而加重了脓毒症中的器官损伤。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糖萼降解有关，提示其机制 静脉注射液体可能导致肺损伤。相反，脓毒症前糖萼完整性的丧失 复苏可能有助于确定患者对液体有害影响的易感性-代表一种 个性化液体复苏方法的潜在机会。 晶体自由或血管加压药早期复苏败血症（CLOVERS）试验是一项由NIH资助的2320 受试者多中心、随机、对照临床试验，由约50家研究中心的预防和治疗中心进行 急性肺损伤（PETAL）网络比较替代的24小时液体复苏策略（自由 与限制性）在早期脓毒症中的作用以及对死亡率的影响。虽然糖萼没有在 根据原始试验方案，CLOVERS是确定以下因素之间潜在因果关系的理想选择： 液体复苏策略、糖萼降解、ARDS和脓毒症死亡率。 本提案的广泛、长期目标是研究：1）不同的液体复苏策略 （限制性或自由性）影响脓毒症中的糖萼降解; 2）糖萼降解与 急性呼吸窘迫综合征（ARDS）和/或死亡率的发展，3） 初始糖萼完整性可以预测患者对不同容量复苏策略的反应。 为了实现这些假设，我们将利用CLOVERS研究提供的独特机会， 执行糖萼损伤的全面读出，不仅采用最先进的措施， 糖萼降解（糖萼分解产物如乙酰肝素的质谱检测 硫酸盐），而且还可以使用更便宜的基于ELISA的（syndecan-1）和即时功能测定（例如， 粘弹性凝固监测）能够快速评估糖萼完整性。说明和 对这些机制的进一步理解可能会导致预测结果的策略，选择患者进行治疗， 定制治疗，跟踪治疗反应，并开发新的脓毒症糖萼导向疗法。