PICS: A New Horizon for Surgical Critical Care

PICS：外科重症监护的新视野

基本信息

批准号：
8740713
负责人：
FREDERICK A MOORE
金额：
$ 225.79万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8740713
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Aging Anesthesiology Angiogenic Factor Angiotensin II Animals Bed rest Biological Markers Biometry Biostatistics Core Blood Caring Catabolism Cell physiology Cessation of life Chronic Clinical Cognitive Computerized Medical Record Consent Forms Critical Care Critical Illness Data Databases Development Diagnosis Dysmyelopoietic Syndromes Early Diagnosis Elderly Enrollment Epidemic Epidemiology Equilibrium Erythropoietin Exercise Florida Fostering Functional disorder Goals Health Health Occupations Hospital Mortality Hospitals Human Immunity Immunology Immunosuppression Incidence Inflammation Inflammatory Injury Institutes Intensive Care Units Intervention Intervention Studies Kidney Limb structure Lower Extremity Measures Mechanics Medical Medicine Methods Microbiology Modeling Molecular Biology Molecular Genetics Morbidity - disease rate Multiple Organ Failure Mus Muscle Muscle function Muscular Atrophy Myelogenous Myeloid Cells Myelopoiesis Newly Diagnosed Operative Surgical Procedures Outcome Outpatients Pathogenesis Patients Performance Phenotype Physical therapy Physiology Population Prevalence Process Protocols documentation Public Health Recovery Recovery of Function Rehabilitation therapy Research Research Subjects Resistance Respiratory Diaphragm Risk Factors Sampling Scientist Sepsis Severities Suppressor-Effector T-Lymphocytes Surgical Intensive Care Survivors Syndrome TNFRSF5 gene Technology Testing Therapeutic Intervention Tissues Training Programs Translational Research Trauma Universities Urine Vascular Endothelial Growth Factor Receptor Work aged aging population antiangiogenesis therapy college computerized cost cytokine data management evidence based guidelines experience human subject improved innovation mortality muscle strength novel novel therapeutic intervention prevent programs public health relevance response screening septic skeletal standard of care strength training therapy development wasting

项目摘要

DESCRIPTION (provided by applicant): Despite 30 years of intensive research, morbidity and mortality of sepsis in surgical intensive care unit (ICU) patients remain unacceptably high. Although recent advances in early ICU care have reduced in-hospital mortality, with the aging population a new epidemic of chronic critical illness (CCI) has emerged and its progression into what we call the persistent inflammation, immunosuppression and catabolism syndrome (PICS) has unacceptable morbid long-term consequences. Our overarching hypothesis is that PICS is now a predominant clinical trajectory in the surgical ICU patients after sepsis, and is the greatest, near-term clinical challenge in surgical ICUs. We further hypothesize that PICS is caused, at least in part, by dysregulated myelopoiesis and expansion of myeloid-derived suppressor cells (MDSCs), aggravated by aging and largely driven by acute kidney injury (AKI), resulting in imbalance of angiogenic and anti-angiogenic factors. This Sepsis and Critical Illness Research Center (SCIRC) application comprises four projects and five cores drawn from two colleges (Medicine and Public Health and Health Professions) and eight University of Florida Health departments (Surgery, Medicine, Anesthesiology, Biostatistics, Molecular Genetics and Microbiology, Aging and Geriatric Research, and Physical Therapy) and will address the following questions in four projects: #1a) What is the incidence and early risk factors for CCI in septic surgical ICU patients and what are the long-term cognitive and functional consequences? #1b) Can novel biomarkers predict, early, which patients will develop CCI, and, later, which CCI patients will have morbid long-term outcomes (i.e., PICS)? #2) Is PICS inherently driven by dysregulation in myelopoiesis and inappropriate MDSC expansion, promoting persistent inflammation, immunosuppression and catabolism?; #3) Does AKI, through dysregulation of anti-angiogenic and angiogenic cytokines, drive the expansion of MDSCs, inflammation, and anti-angiogenesis?; and #4) Does CCI contribute significantly to muscle atrophy, especially in mechanically ventilated patients' diaphragms and extremities, and will resistance exercise improve muscle strength, reduce inflammation, and alter the trajectory of CCI away from the PICS phenotype? We will study 400 surgical ICU patients who develop sepsis for at least one year, and use murine models of chronic polymicrobial sepsis for mechanistic studies and interventional methods. We recognize that no single therapeutic intervention will prevent PICS, but the SCIRC's overall goal is to understand the prevalence and pathogenesis of this new syndrome at a mechanistic level. Only through multi-disciplinary translational research by basic and clinical scientists with diverse expertise in critical care medicine, physical therapy, immunology, molecular biology, and understanding of muscle, kidney, and aging physiology, can CCI progression into PICS be understood and novel therapies developed.

描述（由申请人提供）：尽管经过 30 年的深入研究，外科重症监护病房 (ICU) 患者脓毒症的发病率和死亡率仍然高得令人无法接受。尽管早期 ICU 护理的最新进展降低了院内死亡率，但随着人口老龄化，出现了一种新的慢性危重病 (CCI) 流行病，并且其发展为我们所说的持续性炎症、免疫抑制和分解代谢综合征 (PICS)，这是不可接受的病态的长期后果。我们的总体假设是，PICS 现在是脓毒症后外科 ICU 患者的主要临床轨迹，也是外科 ICU 近期最大的临床挑战。我们进一步假设，PICS 至少部分是由骨髓生成失调和骨髓源性抑制细胞 (MDSC) 扩张引起的，衰老会加剧这种情况，很大程度上是由急性肾损伤 (AKI) 驱动的，导致血管生成和抗肾损伤不平衡。血管生成因子。该脓毒症和危重疾病研究中心 (SCIRC) 申请包括四个项目和五个核心，分别来自两所学院（医学、公共卫生和健康专业）和佛罗里达大学八个卫生部门（外科、医学、麻醉学、生物统计学、分子遗传学和微生物学）、衰老和老年研究以及物理治疗）并将在四个项目中解决以下问题：#1a）CCI 的发病率和早期风险因素是什么脓毒症手术 ICU 患者的长期认知和功能后果是什么？ #1b) 新的生物标志物能否早期预测哪些患者将发生 CCI，以及随后预测哪些 CCI 患者将出现病态的长期结果（即 PICS）？ #2) PICS 本质上是由骨髓生成失调和不适当的 MDSC 扩张驱动的，从而促进持续炎症、免疫抑制和分解代谢吗？； #3) AKI 是否通过抗血管生成和血管生成细胞因子的失调，驱动 MDSC 扩张、炎症和抗血管生成？和 #4) CCI 是否会显着导致肌肉萎缩，尤其是机械通气患者的膈肌和四肢，抗阻运动是否会改善肌肉力量、减少炎症并改变 CCI 远离 PICS 表型的轨迹？我们将研究 400 名发生脓毒症至少一年的外科 ICU 患者，并使用慢性多种微生物脓毒症的小鼠模型进行机制研究和介入方法。我们认识到，没有任何单一的治疗干预措施可以预防 PICS，但 SCIRC 的总体目标是从机制层面了解这种新综合征的患病率和发病机制。只有通过在重症监护医学、物理治疗、免疫学、分子生物学以及对肌肉、肾脏和衰老生理学的理解方面具有不同专业知识的基础和临床科学家进行多学科转化研究，才能理解 CCI 进展为 PICS 并开发出新的疗法。