Late cardiovascular consequences of septic shock

感染性休克的晚期心血管后果

基本信息

批准号：
8914853
负责人：
SACHIN YENDE
金额：
$ 24.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914853
关键词：
3-nitrotyrosine Accounting Acute Acute myocardial infarction Address Affect Aging Asses Back Biological Markers Blood C-reactive protein Cardiovascular Diseases Cardiovascular system Caring Cells Cessation of life Characteristics Clinical Clinical Trials Design Coagulation Process Critical Illness DNA Data Analyses Data Collection Deterioration Development E-Selectin Enrollment Epidemiology Epigenetic Process Event Exposure to F2-Isoprostanes Fibrin fragment D Fibrinolysis Frequencies Future Genes Goals Health Histone Acetylation Home visitation Hospital Records Hospitalization Hospitals House Call Immune Immune response Incidence Individual Infection Inflammation Inflammatory Interleukin-10 Interleukin-6 Intervention Interview Link Lipid Peroxidation Measures Morbidity - disease rate Myocardial Infarction Outcome Oxidative Stress Pathway interactions Patient Discharge Patients Pattern Peroxidases Plasminogen Activator Inhibitor 1 Pneumonia Prevention strategy Preventive Randomized Randomized Clinical Trials Recording of previous events Recovery Resolution Resuscitation Risk Sampling Sepsis Septic Shock Stroke Survivors TNFRSF5 gene Tail Techniques Testing Therapeutic Time Urine Work adjudicate antithrombin III-protease complex cardiovascular disorder risk design efficacy testing endothelial dysfunction follow-up high risk improved mortality novel response treatment planning treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Survivors of severe sepsis hospitalization have high long-term morbidity and mortality. More than one-half of all deaths that occur within one year after severe sepsis hospitalization happen after hospital discharge. Long-term consequences after sepsis will continue to increase with the rising incidence of sepsis and reduced short-term mortality after critical illness. An acute cardiovascular event, such as acute myocardial infarction and stroke, is an important long-term consequence of severe sepsis, occurring in 10% of patients discharged alive and accounting for one-third of deaths within one year. Of note, three-quarters of those who develop an acute cardiovascular event after severe sepsis do not have a prior history of cardiovascular disease and could be targeted for preventive therapies. However, the reasons for the link between sepsis and cardiovascular disease are not known. We recently showed that the immune response after pneumonia persists at hospital discharge despite clinical recovery, and higher circulating inflammatory and coagulation markers at discharge are associated with higher risk of subsequent cardiovascular deaths. The work proposed will extend our preliminary work and address four questions. First, with what frequency, and in which patients, does the immune response fail to resolve beyond discharge? Second, what might be the cause for delayed immune resolution? Third, are particular immune pathways more strongly associated with cardiovascular outcomes? Fourth, do early sepsis interventions have long-term beneficial effects? We will 'piggy-back' long-term follow-up in an ongoing randomized clinical trial designed to assess efficacy of Protocolized Care for Early Septic Shock, (ProCESS). We will enroll 600 ProCESS subjects who are alive at hospital discharge. We will conduct home visits to obtain blood and urine samples, and obtain all hospital records and conduct interviews with next of kin to determine fatal and non-fatal cardiovascular events over one year. Although many pathways are activated in sepsis, we will focus on 4 pathways (inflammation, coagulation-fibrinolysis, endothelial dysfunction, and oxidative stress) that are important in cardiovascular disease. For Aim #1, we will measure stable, well-validated circulating biomarkers in each pathway. We will test a novel hypothesis that the immune response initiated during severe sepsis will persist at discharge and at 3 weeks and 6 months after discharge, as evidenced by higher levels of biomarkers in these pathways. We will also conduct a small, exploratory study to asses if epigenetics will explain delayed resolution of the immune response. Aim #2 will determine whether unresolved immune response will increase the risk of acute cardiovascular events over 1 year after discharge. Aims #1 and #2 will identify biomarker patterns to target preventive therapies in future studies. Aim #3 will determine whether alternative cardiovascular resuscitation strategies that are known to affect the initial immune response will improve immune resolution after discharge and reduce late cardiovascular events. This work will result in one of the largest studies to date to assess recovery after sepsis, and the results will have immediate therapeutic implications to target patients with preventive strategies to reduce long-term consequences after sepsis.

描述（由申请人提供）：严重败血症住院的幸存者具有较高的长期发病率和死亡率。严重脓毒症住院一年内发生的所有死亡中，有一半以上发生在出院后。随着脓毒症发病率的上升和危重病后短期死亡率的降低，脓毒症后的长期后果将继续加剧。急性心血管事件，如急性心肌梗塞和中风，是严重脓毒症的一个重要的长期后果，10%的患者存活出院时发生，占一年内死亡人数的三分之一。值得注意的是，四分之三的严重脓毒症后发生急性心血管事件的人没有心血管疾病史，可以作为预防性治疗的目标。然而，脓毒症与心血管疾病之间存在联系的原因尚不清楚。我们最近表明，尽管临床已恢复，但肺炎后的免疫反应在出院时仍持续存在，出院时较高的循环炎症和凝血标记物与随后心血管死亡的较高风险相关。拟议的工作将扩展我们的前期工作并解决四个问题。首先，免疫反应在出院后未能解决的频率是多少？在哪些患者中？其次，免疫解决延迟的原因可能是什么？第三，特定的免疫途径是否与心血管结局密切相关？第四，脓毒症早期干预是否具有长期有益效果？我们将在一项正在进行的随机临床试验中“附带”长期随访，该试验旨在评估早期感染性休克方案化护理 (ProCESS) 的功效。我们将招募 600 名出院时仍活着的 ProCESS 受试者。我们将进行家访以获取血液和尿液样本，并获取所有医院记录并对近亲进行访谈，以确定一年内致命和非致命的心血管事件。尽管脓毒症中许多通路被激活，但我们将重点关注在心血管疾病中重要的 4 条通路（炎症、凝血纤溶、内皮功能障碍和氧化应激）。对于目标#1，我们将测量每个途径中稳定、经过充分验证的循环生物标志物。我们将测试一个新的假设，即严重败血症期间启动的免疫反应将在出院时以及出院后 3 周和 6 个月持续存在，这些途径中生物标志物水平较高就证明了这一点。我们还将进行一项小型探索性研究，以评估表观遗传学是否可以解释免疫反应的延迟解决。目标#2将确定未解决的免疫反应是否会增加出院后一年内发生急性心血管事件的风险。目标#1和#2将确定生物标志物模式，以在未来的研究中针对预防性治疗。目标#3将确定已知影响初始免疫反应的替代心血管复苏策略是否会改善出院后的免疫解决方案并减少晚期心血管事件。这项工作将成为迄今为止评估脓毒症后恢复情况最大规模的研究之一，其结果将对目标患者采取预防策略以减少脓毒症后的长期后果产生直接的治疗意义。