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，外科重症监护病房(ICU)患者的脓毒症发病率和死亡率仍然高得令人无法接受。尽管ICU早期护理的最新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疾病(CCI)流行病，其进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)，具有不可接受的病态长期后果。我们的主要假设是，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至少部分是由髓系抑制细胞(MDSCs)的异常骨髓生成和扩张引起的，随着年龄的增长而加重，主要由急性肾损伤(AKI)驱动，导致血管生成和抗血管生成因子的失衡。脓毒症和危重疾病研究中心(SCIRC)的申请包括四个项目和五个核心，来自两个学院(医学和公共卫生与健康专业)和佛罗里达大学的八个卫生系(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疗法)，并将在四个项目中解决以下问题：#1a)败血症外科ICU患者CCI的发生率和早期风险因素是什么，以及长期的认知和功能后果是什么？#1b)新的生物标记物能否早期预测哪些患者将发展为CCI，并在以后哪些CCI患者会有病态的长期结果(即PICS)？#2)PICS是由骨髓生成失调和不适当的MDSC扩张所固有的，促进了持续性炎症、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来驱动MDSCs的扩张、炎症和抗血管生成？以及#4)CCI是否显著导致肌肉萎缩，尤其是在机械通气患者的横隔膜和四肢，阻力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名患有至少一年败血症的外科ICU患者，并使用慢性多菌败血症的小鼠模型进行机制研究和干预方法。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水平上了解这种新综合征的患病率和发病机制。只有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了解方面具有不同的专业知识，通过多学科的转化研究，才能了解CCI进入PICS的过程，并开发新的疗法。

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.