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很高的长期发病率和死亡率。出院后严重败血症住院后一年内发生的所有死亡中的一半以上发生。败血症后的长期后果将随着败血症发生率的上升和危重疾病后的短期死亡率降低而继续增加。急性心血管事件，例如急性心肌梗塞和中风，是严重败血症的重要长期后果，发生在10％的活着出院的患者中，占一年内死亡的三分之一。值得注意的是，在严重败血症后发生急性心血管事件的人中有四分之三没有心血管疾病的史，并且可以针对预防疗法。但是，败血症与心血管疾病之间联系的原因尚不清楚。我们最近表明，尽管临床恢复，肺炎后的免疫反应持续出院，并且出院时循环炎症和凝结标记的较高与随后的心血管死亡的风险更高有关。拟议的工作将扩大我们的初步工作，并解决四个问题。首先，以什么频率以及哪些患者在哪些患者中无法解决出排出的能力？其次，可能是延迟免疫分辨率的原因？第三，特定的免疫途径是否与心血管结局更强烈？第四，早期败血症的干预措施是否具有长期有益作用？我们将在正在进行的随机临床试验中“长期随访”，旨在评估协议护理对早期败血性休克的功效（过程）。我们将注册600名在出院时活着的过程受试者。我们将进行家庭探访以获取血液和尿液样本，并获得所有医院记录，并与亲属的近亲进行访谈，以确定一年内致命和非致命性心血管事件。尽管在败血症中激活了许多途径，但我们将专注于在心血管疾病中很重要的4种途径（炎症，凝结 - 纤维蛋白溶解，内皮功能障碍和氧化应激）。对于AIM＃1，我们将在每种途径中测量稳定，验证的循环生物标志物。我们将检验一个新的假设，即在出院时，在出院后的3周和6个月内，在严重败血症期间启动的免疫反应将持续存在，这证明了这些途径中较高水平的生物标志物。如果表观遗传学会解释免疫反应的延迟分辨率，我们还将进行一项小型的探索性研究，以进行评估。 AIM＃2将确定未解决的免疫反应是否会在出院后1年内增加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靶向预防疗法，以后的研究。 AIM＃3将确定已知会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分辨率并减少晚期心血管事件。这项工作将导致迄今为止最大的研究之一，以评估败血症后的恢复，结果将对具有预防策略的患者具有立即的治疗意义，以减少败血症后的长期后果。