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Winning the war against ICU-acquired weakness: new innovations in nutrition and exercise physiology.Critical Care (London, England) 2015Over the last 10 years we have significantly reduced hospital mortality from sepsis and critical illness. However, the evidence reveals that over the same period we have...
Over the last 10 years we have significantly reduced hospital mortality from sepsis and critical illness. However, the evidence reveals that over the same period we have tripled the number of patients being sent to rehabilitation settings. Further, given that as many as half of the deaths in the first year following ICU admission occur post ICU discharge, it is unclear how many of these patients ever returned home. For those who do survive, the latest data indicate that 50-70% of ICU "survivors" will suffer cognitive impairment and 60-80% of "survivors" will suffer functional impairment or ICU-acquired weakness (ICU-AW). These observations demand that we as intensive care providers ask the following questions: "Are we creating survivors ... or are we creating victims?" and "Do we accomplish 'Pyrrhic Victories' in the ICU?" Interventions to address ICU-AW must have a renewed focus on optimal nutrition, anabolic/anticatabolic strategies, and in the future employ the personalized muscle and exercise evaluation techniques utilized by elite athletes to optimize performance. Specifically, strategies must include optimal protein delivery (1.2-2.0 g/kg/day), as an athlete would routinely employ. However, as is clear in elite sports performance, optimal nutrition is fundamental but alone is often not enough. We know burn patients can remain catabolic for 2 years post burn; thus, anticatabolic agents (i.e., beta-blockers) and anabolic agents (i.e., oxandrolone) will probably also be essential. In the near future, evaluation techniques such as assessing lean body mass at the bedside using ultrasound to determine nutritional status and ultrasound-measured muscle glycogen as a marker of muscle injury and recovery could be utilized to help find the transition from the acute phase of critical illness to the recovery phase. Finally, exercise physiology testing that evaluates muscle substrate utilization during exercise can be used to diagnose muscle mitochondrial dysfunction and to guide a personalized ideal heart rate, assisting in recovery of muscle mitochondrial function and functional endurance post ICU. In the end, future ICU-AW research must focus on using a combination of modern performance-enhancing nutrition, anticatabolic/anabolic interventions, and muscle/exercise testing so we can begin to create more "survivors" and fewer victims post ICU care.
Topics: Body Composition; Critical Illness; Humans; Intensive Care Units; Muscle Weakness; Muscular Diseases; Nutritional Status; Patient Discharge; Patient Outcome Assessment; Survival Analysis
PubMed: 26728966
DOI: 10.1186/cc14724 -
International Journal of Clinical and... 2015For linear longitudinal bone elongation, the stem-like progenitor chondrocytes distributed in resting zone (RZ) of growth plate have a capacity to differentiate towards...
For linear longitudinal bone elongation, the stem-like progenitor chondrocytes distributed in resting zone (RZ) of growth plate have a capacity to differentiate towards the spindle chondrocytes in proliferative zone (PZ), then towards the columnar and tightly adjacent chondrocytes in hypertrophic zone (HZ). We hypothesized this process of endochondral ossification with cells morphological change was occurred along with the inter-conversion between epithelial to mesenchymal cell types. Consistent with this hypothesis, our study demonstrated the chondrocytes highly expressed mesenchymal-like biomarkers and loss of epithelial surface markers in PZ, while converse in RZ and HZ of the growth plate in mice distal tibia in vivo. To further determine these process and correlation regulatory pathway, the 4-week old male and female mice were treated with estradiol cypionate or oxandrolone, then investigated the response of epithelial- and mesenchymal biomarkers, and demonstrated that estrogen blocked the EMT process from RZ to PZ while androgen promoted MET from PZ to HZ. Our observations supported the hypotheses that the growth plate firstly go through EMT from RZ to PZ, then MET process from PZ to HZ during the epiphyseal fusion. Our results could interpret the different roles of estrogen and androgen in growth plate cartilage when endochondral ossification.
PubMed: 26550119
DOI: No ID Found -
Shock (Augusta, Ga.) Apr 2016Administration of oxandrolone, a nonaromatizable testosterone analog, to children for 12 months following severe burn injury has been shown to improve height, increase... (Randomized Controlled Trial)
Randomized Controlled Trial
Administration of oxandrolone, a nonaromatizable testosterone analog, to children for 12 months following severe burn injury has been shown to improve height, increase bone mineral content (BMC), reduce cardiac work, and augment muscle strength. Surprisingly, the increase in BMC persists well beyond the period of oxandrolone administration. This study was undertaken to determine if administration of oxandrolone for 2 years yields greater effects on long-term BMC and bone mineral density (BMD). Patients between 0 and 18 years of age with ≥30% of total body surface area burned were consented to an IRB-approved protocol and randomized to receive either placebo (n = 84) or 0.1 mg/kg oxandrolone orally twice daily for 24 months (n = 35). Patients were followed prospectively from the time of admission until 5 years postburn in a single-center, intent-to-treat setting. Height, weight, BMC, and BMD were recorded annually through 5 years postinjury. The long-term administration of oxandrolone for 16 ± 1 months postburn (range, 12.1-25.2 months) significantly increased whole-body (WB) BMC (p < 0.02) and lumbar spine (LS) BMC (p < 0.05); these effects were significantly pronounced for a longer time in patients who were in growth spurt years (7-18 years). When adjusted for height, sex, and age, LS BMD was found to significantly increase with long-term oxandrolone administration (p < 0.0009). Fewer patients receiving oxandrolone exhibited LS BMD z scores below -2.0 as compared with controls, indicating a significantly reduced risk for future fracture with oxandrolone administration. Long-term oxandrolone patients had significantly greater height velocity than controls throughout the first 2-year postburn (p < 0.05). No adverse side effects were attributed to the long-term administration of oxandrolone. A comparison of the current patients receiving long-term oxandrolone to previously described patients receiving 12 months of oxandrolone revealed that long-term oxandrolone administration imparted significantly greater increases in WB-BMC, WB-BMD, and LS-BMD (p < 0.05). In conclusion, the administration of oxandrolone for up to 24 months to severely burned pediatric patients significantly improves WB BMC, LS BMC, LS BMD, and height velocity. The administration of long-term oxandrolone was more efficacious than administration for 12 months. Additionally, fewer patients in the oxandrolone cohort met the diagnostic criteria for pediatric osteoporosis, pointing to a reduced risk for future bone fracture. This study demonstrates that administering oxandrolone for up to 2 years following severe burn injury results in greater improvements in BMC, BMD, and height velocity.
Topics: Administration, Oral; Bone Density; Burns; Child; Female; Follow-Up Studies; Humans; Male; Muscle Strength; Oxandrolone; Time Factors; Trauma Severity Indices
PubMed: 26506070
DOI: 10.1097/SHK.0000000000000517 -
The American Journal of Case Reports Oct 2015Anabolic steroids have the clinical effect of increasing protein synthesis in muscle and other tissues. The brain and spinal cord neurons have gonadal steroid receptors...
BACKGROUND
Anabolic steroids have the clinical effect of increasing protein synthesis in muscle and other tissues. The brain and spinal cord neurons have gonadal steroid receptors and various studies have shown at structural and molecular levels that androgenic steroids have a significant trophic effect on the brain and spinal cord.
CASE REPORT
We evaluated the effect of Oxandrolone (an FDA-approved anabolic steroid) at the dose of 20 mg/day for 3 months added to concomitant exercise strength training 3 times a week in a patient affected by a demyelinating disease, Charcot-Marie-Toot 1 (CMT1). After the treatment, an increase in muscular strength and walking capacity was observed. Muscle biopsy revealed a significant increase of type grouping of muscle fibers, an expression of regeneration and reinnervation processes.
CONCLUSIONS
Data ensuing from this single case-report suggest that anabolic androgenic steroids have a potential neuroregenerative effect, with an inherent improvement in neuromuscular efficiency through an increased myelin synthesis at peripheral nervous system site.
Topics: Adult; Androgens; Biopsy; Charcot-Marie-Tooth Disease; Humans; Male; Muscle, Skeletal; Nerve Regeneration; Oxandrolone
PubMed: 26502938
DOI: 10.12659/ajcr.893901 -
International Journal of Pediatric... 2015Turner syndrome is a chromosomal abnormality in which there is complete or partial absence of the X chromosome. Turner syndrome effects 1 in every 2000 live births....
Turner syndrome is a chromosomal abnormality in which there is complete or partial absence of the X chromosome. Turner syndrome effects 1 in every 2000 live births. Short stature is a cardinal feature of Turner Syndrome and the standard treatment is recombinant human growth hormone. When growth hormone is started at an early age a normal adult height can be achieved. With delayed diagnosis young women with Turner Syndrome may not reach a normal height. Adjuvant therapy with oxandrolone is used but there is no consensus on the optimal timing of treatment, the duration of treatment and the long term adverse effects of treatment. The objective of this review and meta-analysis is to examine the effect of oxandrolone on adult height in growth hormone treated Turner syndrome patients. Eligible trials were identified by a literature search using the terms: Turner syndrome, oxandrolone. The search was limited to English language randomized-controlled trials after 1980. Twenty-six articles were reviewed and four were included in the meta-analysis. A random effects model was used to calculate an effect size and confidence interval. The pooled effect size of 2.0759 (95 % CI 0.0988 to 4.0529) indicates that oxandrolone has a positive effect on adult height in Turner syndrome when combined with growth hormone therapy. In conclusion, the addition of oxandrolone to growth hormone therapy for treatment of short stature in Turner syndrome improves adult height. Further studies are warranted to investigate if there is a subset of Turner syndrome patients that would benefit most from growth hormone plus oxandrolone therapy, and to determine the optimal timing and duration of such therapy.
PubMed: 26322078
DOI: 10.1186/s13633-015-0013-3 -
Bone Research 2015Severe burn injury triggers the body's nonspecific adaptive responses to acute insult, including the systemic inflammatory and stress responses, as well as the... (Review)
Review
Severe burn injury triggers the body's nonspecific adaptive responses to acute insult, including the systemic inflammatory and stress responses, as well as the sympathetic response to immobilization. These responses trigger inflammatory bone resorption followed by glucocorticoid-induced apoptosis of osteoblasts and probably osteocytes. Because these patients are catabolic, they suffer concomitant muscle wasting and negative nitrogen balance. The use of anabolic agents such as recombinant human growth hormone and oxandrolone results in improved bone mineral content and muscle strength after approximately 1 year. Use of bisphosphonates within the first 10 days of a severe burn completely blocks the resorptive bone loss and has the added advantage of appearing to preserve muscle protein from excessive breakdown. The mechanism for the protective effect on muscle is not currently known. However, if the effect of bisphosphonates on muscle can be confirmed, it raises the possibility that bone communicates with muscle.
PubMed: 26273535
DOI: 10.1038/boneres.2015.2 -
The Cochrane Database of Systematic... Jul 2015Inclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness.... (Review)
Review
BACKGROUND
Inclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment.
OBJECTIVES
To assess the effects of treatment for IBM.
SEARCH METHODS
On 7 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials.
SELECTION CRITERIA
We considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodological procedures.
MAIN RESULTS
The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low-quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta-analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re-analysis. Other comparisons were also reported in single trials. An open trial of anti-T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events.
AUTHORS' CONCLUSIONS
Trials of interferon beta-1a and MTX provided moderate-quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures.
PubMed: 35658164
DOI: 10.1002/14651858.CD001555.pub5 -
Burns : Journal of the International... Jun 2015The pathophysiological response to burn injury disturbs the balance between skeletal muscle protein synthesis and breakdown, resulting in severe muscle wasting. Muscle... (Review)
Review
OBJECTIVE
The pathophysiological response to burn injury disturbs the balance between skeletal muscle protein synthesis and breakdown, resulting in severe muscle wasting. Muscle loss after burn injury is related to increased mortality and morbidity. Consequently, mitigation of this catabolic response has become a focus in the management of these patients. The aim of this review is to discuss the literature pertaining to pharmacological interventions aimed at attenuating skeletal muscle catabolism in severely burned patients.
DATA SELECTION
Review of the literature related to skeletal muscle protein metabolism following burn injury was conducted. Emphasis was on studies utilizing stable isotope tracer kinetics to assess the impact of pharmacological interventions on muscle protein metabolism in severely burned patients.
CONCLUSION
Data support the efficacy of testosterone, oxandrolone, human recombinant growth hormone, insulin, metformin, and propranolol in improving skeletal muscle protein net balance in patients with severe burns. The mechanisms underlying the improvement of protein net balance differ between types and dosages of drugs, but their main effect is on protein synthesis. Finally, the majority of studies have been conducted during the acute hypermetabolic phase of the injury. Except for oxandrolone, the effects of drugs on muscle protein kinetics following discharge from the hospital are largely unknown.
Topics: Adrenergic beta-Antagonists; Anabolic Agents; Androgens; Body Surface Area; Burns; Human Growth Hormone; Humans; Hypoglycemic Agents; Insulin; Metformin; Muscle Proteins; Muscle, Skeletal; Oxandrolone; Propranolol; Recombinant Proteins; Testosterone; Treatment Outcome
PubMed: 25468473
DOI: 10.1016/j.burns.2014.10.010 -
The Cochrane Database of Systematic... Sep 2014Recombinant human growth hormone (rhGH) increases protein synthesis, therefore it is used in burns with a total body surface area (TBSA) greater than 40%, where there is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recombinant human growth hormone (rhGH) increases protein synthesis, therefore it is used in burns with a total body surface area (TBSA) greater than 40%, where there is frequently an increase in protein breakdown and a decrease in protein synthesis. This change in protein metabolism correlates with poor wound healing of the burn and donor sites.
OBJECTIVES
To determine the effects of rhGH on the healing rate of burn wounds and donor sites in people with burns.
SEARCH METHODS
For this first update we searched the Cochrane Wounds Group Specialised Register (searched 04 September 2014); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 8); Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library 2014, Issue 3); Ovid MEDLINE (1950 to September Week 4 2014); Ovid MEDLINE (In-Process & Other Non-Indexed Citations September 8, 2014); Ovid EMBASE (1980 to 2014 Week 35); and EBSCO CINAHL (1982 to 8 September 2014).
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing rhGH with any comparator intervention, e.g. oxandrolone or placebo, in adults or children with burns.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies, assessed trial quality and extracted data. The primary outcomes were the healing of the burn wound and donor sites and the occurrence of wound infections. The secondary outcomes were mortality rate, length of hospital stay, scar assessment, and adverse events: hyperglycaemia and septicaemia.
MAIN RESULTS
We included 13 RCTs (701 people). Six of the RCTs included only children aged 1 to 18 years and seven involved only adults (from 18 to 65 years of age). The mean TBSA of the included participants was greater than 49%. Twelve studies compared rhGH with placebo and one study compared rhGH with oxandrolone. Two trials found that compared with placebo, burn wounds in adults treated with rhGH healed more quickly (by 9.07 days; 95% confidence interval (CI) 4.39 to 13.76, I² = 0%). The donor site healing time was significantly shorter in rhGH-treated adults compared with placebo-treated participants (by 3.15 days; 95% CI 1.54 to 4.75, I² = 0%). Two studies in children with the outcome of donor site healing time could be pooled and the donor site healing time was shorter in the rhGH-treated children (by 1.70 days; 95% CI 0.87 to 2.53, I² = 0%). No studies reporting the outcome of wound infection were found. The incidence of hyperglycaemia was higher in adults during rhGH treatment compared with placebo (risk ratio (RR) 2.43; 95% CI 1.54 to 3.85), but not in children. Pooling the studies of adults and children yielded a significantly higher incidence of hyperglycaemia in the rhGH-treated participants (RR 2.65; 95% CI 1.68 to 4.16).
AUTHORS' CONCLUSIONS
There is some evidence that using rhGH in people with large burns (more than 40% of the total body surface area) could result in more rapid healing of the burn wound and donor sites in adults and children, and in reduced length of hospital stay, without increased mortality or scarring, but with an increased risk of hyperglycaemia. This evidence is based on studies with small sample sizes and risk of bias and requires confirmation in higher quality, adequately powered trials.
Topics: Adolescent; Adult; Aged; Anabolic Agents; Body Surface Area; Burns; Child; Child, Preschool; Human Growth Hormone; Humans; Infant; Middle Aged; Oxandrolone; Randomized Controlled Trials as Topic; Recombinant Proteins; Transplant Donor Site; Wound Healing; Young Adult
PubMed: 25222766
DOI: 10.1002/14651858.CD008990.pub3