Septic patients requiring 14 or more days of ICU care have been recently defined as chronically critically ill (CCI) patients. A subgroup of CCI patients develops persistent inflammation/immunosuppression and catabolism syndrome (PICS), and they have morbid long-term outcomes (Project #1). CCI patients with PICS often develop severe diaphragm and skeletal muscle atrophy and weakness. PICS patients also demonstrate diminished muscle mitochondrial function and accelerated protein catabolism. Muscle dysfunction in PICS is due to many factors including sarcopenia, sepsis/inflammation, proteolysis, apoptosis, and inactivity. Diaphragm weakness can delay patients'weaning from mechanical ventilation, and increase inflammation and the risk of nosocomial infection. Limb-muscle weakness prevents patients from reaching functional activity milestones, delaying their rehabilitation and return to normal function. Despite the seriousness of diaphragm weakness in CCI patients receiving mechanical ventilation, little is known about exercise strategies to treat this dysfunction. We also have limited knowledge about how strength training impacts inflammation, immunosuppression, and catabolism in CCI patients. In Project #4, we will conduct a Phase I/II randomized trial of specific inspiratory muscle strength training (IMST) for up to 28 days in 24 ventilated CCI patients to determine if they can respond to a training program that has previously shown to improve weaning outcome in chronically ventilated patients. Furthermore, because CCI patients also develop profound lower-extremity muscle weakness, for which little is known about the effectiveness of strength training, we propose to conduct a Phase I/II randomized trial of lower-extremity strength training in an additional 24 ventilated CCI patients for 28 days. Following training, muscle biopsies will be obtained from the quadriceps and contrasted between strength-trained and SHAM groups examining mitochondrial dysfunction, markers of anabolic and catabolic activity, and apoptosis. Both trials will also assess the effect of exercise on markers of inflammation, immunosuppression, and protein catabolism. Project #4's main functions will be the following: * Determine the effects of IMST on diaphragm strength in treated and control CCI patients. * Determine whether knee extension strengthening exercises induce changes in muscle properties including morphology, protein expression, and bioenergetics. * Determine the effects of knee extension strengthening exercises on the quadriceps muscle in CCI patients and on systemic inflammatory, immunosuppressive and catabolic markers. This project will further our understanding of how treating CCI-related muscle weakness with strength training can not only improve muscle function, but also potentially blunt the inflammation, immunosuppression, and catabolism of PICS.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
1P50GM111152-01
Application #
8740722
Study Section
Special Emphasis Panel (ZGM1)
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
Type
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
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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
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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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