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ASSESSMENT
OF ANABOLIC AGENTS/EXERCISE
Specific Aims Linear growth and weight gain is often compromised after burn injury in children. These children also experience a significant muscular weakness that prevents them from returning to school and resuming normal activities. Previous work at our institution by investigators in this center project suggests that the use of anabolic hormones and a systematic exercise program can each positively affect these important outcomes. This center application will build on these findings in a comprehensive examination of the effects of anabolic agents (recombinant growth hormone and the oral testosterone Oxandralone), ketoconazole (an inhibitor of cortisol secretion), an exercise program, and amino acids on muscle, bone, and scar/skin tissues in recovering burned children. The measurements of tissue response will span the spectrum from histology to physiology to clinical assessment of outcomes of physical function. The specific aims are as follows: 1. To assess the effects of an 'in-house' exercise program on muscle protein metabolism, muscle function, lean body mass, bone density, and scar formation in recovering burned children. 2. To investigate the effects of recombinant growth hormone administration throughout rehabilitation on muscle protein metabolism, muscle function, lean body mass, bone density, and scar formation in recovering burned children. 3. To conduct studies investigating the mechanisms of muscle, bone, and skin collagen synthesis in response to anabolic agents and exercise. 4. To link basic mechanistic research on tissue physiology to clinical interventions intended to increase functional outcomes in burned children. 5. To evaluate and disseminate
information on interventions for improving functional outcomes in recovering
burned children to health care professionals and the public. We are uniquely qualified to answer
these specific aims as a research center 1. The survival rate for burned children at Shriners Burns Hospital - Galveston (SBH) is excellent. In over 50 recent cases of burns greater than 50% total body surface area, we have had only 2 deaths. As the survival of burn patients continues to improve, the crucial aspect of burn care becomes rehabilitation. For these children, the most important consideration is their return to school and the resumption of normal activities. We have recognized this need in burn care and have taken the initiative to develop a comprehensive and efficient rehabilitation program. Although in its embryonic stages, we have demonstrated encouraging pilot results and have an efficient multi-systems approach for tracking and rehabilitating our children. 2. We have an established and proficient system for conducting research on burned children. In many respects we have the functional aspects of a burns center already in place at SBH. The principal investigators of the various projects in this proposal have a history of cooperation dating back 6-15 years in most cases. We also have a 10-year history of post-doctoral burn training for research and clinical fellows. Clinical meetings dealing with patient research are conducted on a weekly basis and attended by all investigators and fellows. Experimental hypotheses and proposals are presented and discussed at weekly meetings of our scientific staff. The offices of all investigators, including the statisticians, are in close proximity. 3. A ground-breaking exercise program is already established at SBH and preliminary results are excellent. SBH offers a unique opportunity for investigating the effects of an exercise program in children recovering from burn injury. Children and their parents return for follow-up surgeries at 6 and 9 months post-burn. We can also provide for their return to participate in programmed exercise. Accommodations are available to house 14 children (and parents) for extended 'in-house' rehabilitation. The accommodations, and accompanying meals, are of no cost to the patient. We employ a staff exercise physiologist, Dr. Nick Cucuzzo, who has designed, established, and provides hands-on instruction for the in-house program. This represents a unique opportunity to study the rehabilitation process under carefully controlled circumstances. General Description of Projects: The focus of this
center proposal is to investigate the effects of exercise and anabolic
agents on muscle, skin, and bone in recovering burned children. The
sub-projects are interrelated and investigations will be concomitant with
each patient's return to SBH at 3, 6, 9, and 12 months post-injury.
The general outline and major hypotheses of each project follows:
Project 1 will test the hypothesis that an exercise program and the daily
administration of recombinant human growth hormone will promote recovery to
full physiological function in children after severe burn injury. An
intervention study will be performed in which clinically-relevant outcome
parameters will be quantified at 3-month intervals up to 1 year post-burn.
Half of the patients will be randomized to receive 0.5 mg/kg/d of rhGH or
placebo injection throughout the year. Each group will be further
randomized to participate in a 3 month 'in-house' exercise conditioning
program, or receive standard home rehabilitation. Thus, 4 groups of
patients will be studied. Endpoints of this study will be
determinations of resting energy expenditure, linear growth measurements and
standing height, weight and body composition, muscle strength, bone density,
bone histomorphometry, scar formation, and histology of skin biopsies.
The goal of Project 2 is to investigate the general hypothesis that recombinant growth hormone and/or oxandrolone (testosterone) will increase net skeletal muscle protein synthesis and decrease the net efflux of intracellular amino acids in recovering burned children. A further goal of this project is to investigate the hypothesis that the effects of these anabolic agents will be amplified by increased inward amino acid transport. Interventions promoting inward amino acid transport, such as amino acid infusion, or synthetic efficiency, such as exercise, will be investigated in conjunction with administration of these anabolic agents. Finally, we will investigate the hypothesis that amelioration of hypercoritsolemia will reduce muscle protein breakdown and result in a greater net protein balance with these anabolic agents. This proposal will evaluate the efficacy of these anabolic agents and determine the direction of future intervention studies.
It is the goal of Project 3 to investigate the effects of exercise and nutrition in promoting muscle anabolism in children recovering from severe burn injury. Our primary endpoint will be the rate of net muscle protein synthesis, which is the metabolic basis for increased muscle size and strength. Based on our experience in healthy normal adult volunteers, our general hypothesis is that exercise, amino acids and insulin all promote net muscle protein synthesis. We propose that exercise increases the efficiency of the protein synthetic process, while ingested amino acids stimulate amino acid transport, thereby providing precursors for synthesis. We propose that at rest insulin functions by similar mechanisms as exercise with regard to stimulating synthesis, but after exercise insulin functions primarily by preventing the increase in muscle protein breakdown that normally occurs after exercise. The results of this study, coupled with the results of Project 2, should form the basis for a subsequent intervention study in which the long-term effects of anabolic agents and an optimal nutritional supplement will be evaluated.
Project 4 will investigate the mechanisms responsible for arrested bone growth in recovering burned children. Bone collagen and calcium metabolism will be studied by stable isotope methodology in burned children and compared with values obtained from children with normal bone growth. Specifically, we will test the hypothesis that bone collagen synthesis is depressed and bone calcium resorption is increased in burned children when compared to age-matched controls. Further, we hypothesize that either rhGH or weight-bearing exercise will stimulate bone anabolism by increasing collagen synthesis and bone calcification. Finally, we hypothesize that the amelioration of hypercortisolemia with ketoconazole will restore bone collagen synthesis and diminish calcium resorption. Mass Spectrometry Core Stable isotope tracers have become invaluable tools with which to investigate human metabolism. This laboratory has been involved in the application and development of stable isotope tracer methods for the past 20 years. The specific goal of this core laboratory is to make available mass spectrometry analysis for all projects involved with the Burn Center. We have all the equipment necessary to perform stable isotope enrichment measurements, including five quadrupole gas chromatograph mass spectrometers, a gas chromatography-combustion-isotope ratio mass spectrometer, an isotope ratio mass spectrometer interfaced to an elemental analyzer, and an inductively coupled plasma mass spectrometer. We also have the necessary expertise to troubleshoot and to develop new analytical procedures. New kinetic models and analytical approaches have been developed in this lab to investigate various aspects of glucose, fat and protein metabolism. Our expertise in mathematical modeling will be central to the interpretation of resulting enrichment data. Training and education are also an aspect of the mass spectrometry core activity.
The general goal of the statistics and modeling core is to provide support in these areas for all of the projects in the center. The set of responsibilities of the core consists of four parts:
SITE SEARCH DISCUSSION FORUM |
Project 1. David
N. Herndon, M.D., P.I.
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