Strategies to Reduce Organic Muscle Atrophy in the Intensive Care Unit (STROMA-ICU)

Acute muscle wasting occurs early and rapidly during the first week of critical illness and contributes substantially to weakness acquired in the ICU. Muscle wasting and subsequent weakness is associated with delayed liberation from mechanical ventilation, prolonged hospital length of stay, long-term functional disability, and worse quality of life. Moreover, low muscle volume as well as ICU-acquired weakness increases the risk of mortality in critically ill patients. Although several factors likely accelerate skeletal muscle wasting during critical illness (e.g., immobility, inflammation, multi-organ failure), the understanding of the underlying mechanisms remains limited and is reflected in the lack of effective interventions to prevent the loss of muscle mass in ICU patients. To-date, there is no known safe and effective pharmacological or nutritional intervention to attenuate the acute loss of muscle mass in ICU patients. Leucine is an amino acid widely regarded for its anabolic effects on muscle metabolism. However, the concentrations required to maximize its anti-proteolytic effects are far greater than the concentrations required to maximally stimulate protein synthesis. This has resulted in the search for leucine metabolites that may also be potent mediators of anabolic processes in skeletal muscle; one such compound is β-hydroxy-β-methylbutyrate (HMB). HMB is thought to primarily facilitate protein synthesis through stimulation of mammalian target of rapamycin (mTOR), a protein kinase responsive to mechanical, hormonal, and nutritional stimuli that plays a central role in the control of cell growth. Randomized, controlled trials to assess the effect of HMB supplementation on clinical outcomes in patients with chronic diseases are limited, and even fewer studies have assessed its effects on skeletal muscle metabolism during critical illness. Furthermore, despite compelling preclinical evidence, the exact mechanisms underlying the effect of HMB supplementation during acute catabolic stress in humans is not well defined. Therefore, the investigators goal is to study the impact of early HMB supplementation on skeletal muscle mass in ICU patients and to explore the mechanisms by which HMB may exert its effects on skeletal muscle metabolism during critical illness.

Acute muscle wasting occurs early and rapidly during the first week of critical illness and contributes substantially to weakness acquired in the ICU. Muscle wasting and subsequent weakness is associated with delayed liberation from mechanical ventilation, prolonged hospital length of stay (LOS), long-term functional disability, and worse quality of life. Moreover, low muscle volume and ICU-acquired weakness increases the risk of mortality in critically ill patients. Although several factors likely accelerate skeletal muscle wasting during critical illness (e.g., immobility, muscle unloading, inflammation, multi-organ failure), the understanding of the underlying mechanisms remains limited and is reflected in the lack of effective interventions to prevent the loss of muscle mass in ICU patients. Muscle mass is maintained through balanced protein breakdown and synthesis . As such, for wasting to occur, catabolic pathways must be increased relative to anabolic processes. In general, nutritional status is an important factor for maintaining skeletal muscle homeostasis. However, adequate caloric delivery is often challenging in ICU patients and recent data suggest that high protein delivery in early critical illness may adversely impact muscle protein synthesis. Moreover, randomized, placebo-controlled, clinical trials (RCTs) in ICU patients do not support the use of aggressive early macronutrient delivery. Such findings emphasize the need for targeted therapies to enhance anabolic pathways, which may improve clinical outcomes in critically ill patients. The amino acid leucine is widely regarded for its anabolic effects on muscle metabolism, but the concentrations required to maximize its anti-proteolytic effects are far greater than the concentrations required to maximally stimulate protein synthesis. This has resulted in the search for leucine metabolites that may also be potent mediators of anabolic processes in skeletal muscle -- one such compound is β-hydroxy-β-methylbutyrate (HMB). HMB is thought to primarily facilitate protein synthesis through stimulation of mammalian target of rapamycin (mTOR), a protein kinase responsive to mechanical, hormonal, and nutritional stimuli that plays a central role in the control of cell growth. Indeed, preclinical studies demonstrate that HMB supplementation increases phosphorylation of mTOR as well as its downstream targets. Preclinical data also suggest that HMB supplementation results in an increase in skeletal muscle insulin-like growth factor 1(IGF-1) levels, which may further stimulate mTOR. In addition, HMB may influence systemic levels of myostatin, a key negative regulator of mature skeletal muscle growth. Myostatin has been shown to reduce muscle protein synthesis by inhibiting mTOR signaling and by increasing proteolytic mechanisms. Recent preclinical data suggest that HMB may reduce myostatin levels and attenuate skeletal muscle atrophy. Furthermore, preclinical data has shown that HMB also stimulates the release of irisin, a newly discovered myokine, which up-regulates IGF-1 and inhibits myostatin. On the other hand, skeletal muscle proteolysis is thought to occur primarily through the ubiquitin-proteasome system, which is an energy-dependent proteolytic system that degrades intracellular proteins. The activity of this pathway is thought to be regulated through expression of nuclear factor kappa B (NF-κB), which is significantly increased in conditions such as fasting, immobilization, bed rest, and in various disease states. In preclinical studies, HMB has been shown to decrease proteasome expression and reduce activity of this pathway during catabolic states. Furthermore, caspase proteases (in particular, caspase protease-3 and caspase protease-9) are thought to induce skeletal muscle proteolysis through apoptosis of myonuclei. Preclinical data suggest that in catabolic states, HMB attenuates the up-regulation of caspases, which in turn, reduces myonuclear apoptosis and reduces skeletal muscle protein degradation. Randomized controlled trials (RCTs) that have assessed the effect of HMB supplementation on clinical outcomes in patients with chronic diseases are limited, and even fewer studies have assessed its effects on skeletal muscle metabolism during critical illness. Furthermore, despite compelling preclinical evidence, the exact mechanisms underlying the effect of HMB supplementation during acute catabolic stress in humans is not well defined. Therefore, the investigators goal is to study the impact of early HMB supplementation on skeletal muscle mass in surgical ICU patients and to explore the mechanisms by which HMB may exert beneficial effects on skeletal muscle metabolism during the course of critical illness.

GROUP 1 will receive Placebo (within 24 hours of ICU admission) and Vital HP ® (while on tube feeds). Vital HP® is on the Massachusetts General hospital formulary, but it is often restricted to patients with malabsorption due to its higher cost compared to other standard enteral nutrition formulas.

GROUP 2 will receive beta-hydroxy-beta-methylbutyrate (within 24 hours of ICU admission) and Vital HP ® (while on tube feeds). Vital HP® is on the Massachusetts General hospital formulary, but it is often restricted to patients with malabsorption due to its higher cost compared to other standard enteral nutrition formulas. The investigators will limit HMB dosing to 3g/day since this is the most widely studied dose.

HMB is a leucine metabolite that may also be a potent mediator of anabolic processes in skeletal muscle; subjects will not receive >3g of HMB/ day.

The placebo is cornstarch and will be mixed in with Vital HP. The solution will look identical to the intervention arm.

Time of admission to the ICU until the time of discharge from the intensive care unit, up to 100 weeks

number of days during ICU admission not requiring invasive mechanical ventilation support, or until study completion, up to 100 weeks

Inclusion Criteria: 18 years or older English-speaking Expected to require at least 72 hours of ICU care Able to provide written/verbal consent or have a suitable healthcare proxy Able to ultrasound the diaphragm and quadriceps muscles in a consistent location for 7 days Ability to take study drug orally vs. an indwelling nasogastric, orogastric, gastric, or gastrojejunostomy tube Exclusion Criteria: Pregnant or peri-partum female Baseline hemoglobin less than 8g/dL Not expected to survive beyond 72 hours Unable to provide a written/verbal consent or an available healthcare proxy Enrolled in another study which may interfere with the current study Prior ICU admission with 1 year of current admission or more than 7 days of hospital admission before transfer to the ICU Strict "nil per os" (NPO) status High output through naso/orogastric tube Clinically significant bowel obstruction Active cancer (except for actinic keratosis, squamous cell carcinoma, and basal cell carcinoma confined to the skin) Palliative care status Known or anticipated history of difficult blood draws History of elevated low density lipoprotein (LDL) and not on a stable treatment regimen Blood urea nitrogen (BUN): creatinine >20 without an underlying cause History of hypoglycemia

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