PICS: A New Horizon for Surgical Critical Care

描述（由申请人提供）：尽管经过30年的深入研究，外科重症监护室（ICU）患者脓毒症的发病率和死亡率仍然高得不可接受。尽管最近ICU早期护理的进展降低了住院死亡率，但随着人口老龄化，出现了一种新的慢性危重病（CCI）流行病，其进展为我们所说的持续性炎症，免疫抑制和卡他综合征（PICS），具有不可接受的病态长期后果。我们的总体假设是，PICS现在是外科ICU患者脓毒症后的主要临床轨迹，并且是外科ICU中最大的近期临床挑战。我们进一步假设PICS至少部分是由骨髓生成失调和髓源性抑制细胞（MDSC）扩增引起的，由衰老加重，主要由急性肾损伤（阿基）驱动，导致血管生成和抗血管生成因子失衡。这个败血症和危重病研究中心（SCIRC）的应用程序包括四个项目和五个核心来自两个学院（医学和公共卫生和健康教育）和八个佛罗里达大学卫生部门（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）在脓毒症外科ICU患者中CCI的发病率和早期风险因素是什么，以及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展为CCI，以及随后哪些CCI患者将具有病态的长期结果（即，PICS）？#2）PICS是否由骨髓生成中的失调和不适当的MDSC扩增内在地驱动，从而促进持续性炎症、免疫抑制和catalysis？#3）阿基是否通过抗血管生成和血管生成细胞因子的失调驱动MDSC的扩增、炎症和抗血管生成？和#4）CCI是否显著促进肌肉萎缩，特别是在机械通气患者的横膈膜和四肢中，阻力锻炼是否会改善肌肉力量，减少炎症，并改变CCI的轨迹远离PICS表型？我们将研究400名外科ICU患者，这些患者发生脓毒症至少一年，并使用慢性多微生物脓毒症的小鼠模型进行机制研究和干预方法。我们认识到，没有单一的治疗干预将防止PICS，但SCIRC的总体目标是了解这种新的综合征的发病率和发病机制在一个机械水平。只有通过基础和临床科学家在重症监护医学，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多学科转化研究，才能理解CCI进展为PICS并开发新的治疗方法。

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.