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.

Public Health Relevance

Mortality from sepsis has been declining due in part to early detection and improved, evidence-based guidelines for its treatment. However, with improved in-hospital survival, we are seeing an increasing number of sepsis patients who are becoming chronic critically ill (CCI) and expressing a persistent, inflammation, immunosuppression and catabolism syndrome (PICS) associated with morbid long-term outcomes. This Program proposes to investigate and describe the epidemiology of CCI and PICS in sepsis patients, identify early biomarkers that can predict its incidence and outcome, explore mechanisms that drive this process, and examine potential interventions to prevent the development of PICS in septic CCI patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
1P50GM111152-01
Application #
8740713
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Somers, Scott D
Project Start
2014-09-01
Project End
2019-05-31
Budget Start
2014-09-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Florida
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Mira, Juan C; Brakenridge, Scott C; Moldawer, Lyle L et al. (2017) Persistent Inflammation, Immunosuppression and Catabolism Syndrome. Crit Care Clin 33:245-258
Alamo, Ines G; Kannan, Kolenkode B; Loftus, Tyler J et al. (2017) Severe trauma and chronic stress activates extramedullary erythropoiesis. J Trauma Acute Care Surg 83:144-150
Loftus, Tyler J; Raymond, Steven L; Sarosi Jr, George A et al. (2017) Predicting appendiceal tumors among patients with appendicitis. J Trauma Acute Care Surg 82:771-775
Mathias, Brittany; Delmas, Amber L; Ozrazgat-Baslanti, Tezcan et al. (2017) Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock. Ann Surg 265:827-834
Mira, Juan C; Cuschieri, Joseph; Ozrazgat-Baslanti, Tezcan et al. (2017) The Epidemiology of Chronic Critical Illness After Severe Traumatic Injury at Two Level-One Trauma Centers. Crit Care Med 45:1989-1996
Loftus, Tyler J; Mira, Juan C; Ozrazgat-Baslanti, Tezcan et al. (2017) Sepsis and Critical Illness Research Center investigators: protocols and standard operating procedures for a prospective cohort study of sepsis in critically ill surgical patients. BMJ Open 7:e015136
Lysak, Nicholas; Bihorac, Azra; Hobson, Charles (2017) Mortality and cost of acute and chronic kidney disease after cardiac surgery. Curr Opin Anaesthesiol 30:113-117
Loftus, Tyler J; Jordan, Janeen R; Croft, Chasen A et al. (2017) Temporary abdominal closure for trauma and intra-abdominal sepsis: Different patients, different outcomes. J Trauma Acute Care Surg 82:345-350
Loftus, Tyler J; Brakenridge, Scott C; Dessaigne, Camille G et al. (2017) Antibiotics May be Safely Discontinued Within One Week of Percutaneous Cholecystostomy. World J Surg 41:1239-1245
Stortz, Julie A; Efron, Philip A (2017) Editorial: Myeloid-derived suppressor cells: a new therapeutic target in sepsis patients. J Leukoc Biol 102:185-187

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