Recent studies indicate that mechanically ventilated MICU patients develop severe respiratory and limb muscle weakness and that weakness is associated with poor clinical outcomes in these patients. As a result, administration of drugs that improve skeletal muscle strength should theoretically reduce the need for mechanical ventilation, shorten hospital stay, improve mortality, and increase exercise tolerance in this patient population. The purpose of the present proposal is to address this issue and evaluate the impact of anabolic agents on strength and outcomes in a large, diagnostically broad based MICU patient population. Two experiments are planned:
Aim 1 will test the hypothesis that limb and respiratory skeletal muscle weakness in critically ill patients can be attenuated by administration of hydroxymethylbutyrate (HMB) and/or eicosapentaenoic acid (EPA). We will first measure indices of muscle strength (magnetically stimulated diaphragm and quadriceps strength), muscle size (diaphragm and quadriceps thickness), and quadriceps muscle biopsy characteristics (force-pCa relationships, biomarker levels). We will next randomize mechanically ventilated MICU patients to receive either placebo, HMB, EPA, or both HMB+EPA for 10 days. We will then repeat parameter testing (muscle strength, size and biopsy characteristics) on days 11 and 21. Data will be analyzed to determine if anabolic treatments improve muscle strength, increase muscle size, alter muscle biomarker levels, and reduce the duration of mechanical ventilation.
Aim 2 will test the hypothesis that muscle training will augment the response to muscle strength enhancers (HMB+EPA) in mechanically ventilated MICU patients. We will measure muscle strength, size and biomarker levels. We will then randomize patients to either placebo, muscle strength enhancers (HMB+EPA) alone, targeted muscle training alone (loaded breathing, leg cycling exercise), or the combination of strength enhancers plus muscle training for 10 days. Parameter assessment will be repeated at days 11 and 21. We will determine if these treatments improve muscle strength, muscle size, alter biomarkers, and reduce the duration of mechanical ventilation. Our pilot study data suggest that both EPA and HMB can induce increases in both limb and respiratory muscle strength, shortening the duration of mechanical ventilation in critically ill patients. These data support our hypotheses and suggest that the proposed studies are likely to define a new treatment that will have an important impact on the care of critically ill patients.

Public Health Relevance

Skeletal muscle weakness is a major contributor to morbidity and mortality in critically ill MICU patients but currently there is no drug therapy available for his problem. The studies in this proposal are designed to identify a practical, safe, and potent therapy to prevent/reverse skeletal muscle weakness in these patients. We believe this work will define a new treatment that will have a major impact on the care of critically ill patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-A (02))
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Harabin, Andrea L
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University of Kentucky
Internal Medicine/Medicine
Schools of Medicine
United States
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Supinski, Gerald S; Morris, Peter E; Dhar, Sanjay et al. (2018) Diaphragm Dysfunction in Critical Illness. Chest 153:1040-1051
Supinski, Gerald S; Alimov, Alexander P; Wang, Lin et al. (2016) Calcium-dependent phospholipase A2 modulates infection-induced diaphragm dysfunction. Am J Physiol Lung Cell Mol Physiol 310:L975-84
Supinski, Gerald S; Westgate, Phillip; Callahan, Leigh A (2016) Correlation of maximal inspiratory pressure to transdiaphragmatic twitch pressure in intensive care unit patients. Crit Care 20:77
Callahan, Leigh A; Supinski, Gerald S (2016) Early Mobilization in the ICU: Help or Hype? Crit Care Med 44:1239-40
Supinski, Gerald S; Alimov, Alexander P; Wang, Lin et al. (2015) Neutral sphingomyelinase 2 is required for cytokine-induced skeletal muscle calpain activation. Am J Physiol Lung Cell Mol Physiol 309:L614-24
Supinski, Gerald S; Callahan, Leigh A (2015) How Important is Diaphragm Function as a Determinant of Outcomes for MICU Patients in Respiratory Failure? Physiology (Bethesda) 30:336-7
Supinski, Gerald S; Wang, Lin; Song, Xiao-Hong et al. (2014) Muscle-specific calpastatin overexpression prevents diaphragm weakness in cecal ligation puncture-induced sepsis. J Appl Physiol (1985) 117:921-9
Callahan, Leigh A; Supinski, Gerald S (2014) Hyperglycemia-induced diaphragm weakness is mediated by oxidative stress. Crit Care 18:R88
Supinski, Gerald S; Callahan, Leigh A (2014) ?-hydroxy-?-methylbutyrate (HMB) prevents sepsis-induced diaphragm dysfunction in mice. Respir Physiol Neurobiol 196:63-8
Supinski, Gerald S; Callahan, Leigh Ann (2013) Diaphragm weakness in mechanically ventilated critically ill patients. Crit Care 17:R120

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