Ignite Creation Date:
2024-05-06 @ 8:36 AM
Last Modification Date:
2024-10-26 @ 12:02 PM
Study NCT ID:
NCT02773771
Status:
WITHDRAWN
Last Update Posted:
2021-05-05
First Post:
2016-05-05
Brief Title:
Strategies to Reduce Organic Muscle Atrophy in the Intensive Care Unit
Sponsor:
Massachusetts General Hospital
Organization:
Massachusetts General Hospital
Study Overview
Official Title:
Strategies to Reduce Organic Muscle Atrophy in the Intensive Care Unit STROMA-ICU
Status:
WITHDRAWN
Status Verified Date:
2021-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Per IRB submission history submission declined and withdrawn PI no longer at institution
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
STROMA-ICU
Brief Summary:
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 eg 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
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
Detailed Description:
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 eg 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 1IGF-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
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 1IGF-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None