The metabolic basis for the increased REE in critically-burned patients as currently understood is summarized below. From this analysis, rational decisions can be made regarding the selection of pathways that appear to be major contributors to the catabolic, hypermetabolic response – based on current knowledge.

The MGH plan of research is based on evidence that severe burn injury initiates a unique series of changes in the homeostasis of nitrogen metabolism and that of the major energy-yielding substrates, glucose and lipids. Severe injury also profoundly alters the integration of inter-organ cooperation in the overall nitrogen and energy economy of the host. The net effect of these changes is an overall nitrogen catabolic state, which seriously compromises wound healing and recovery and is refractory to treat with current therapies. These changes lead to a functional redistribution of nitrogen (amino acids and proteins) and substrate metabolism among the wounded tissues and major body organs. This redistribution of substrate results in a quantitative reordering of the usual pathways of carbon and nitrogen flow within and among regions of the body with resulting depletion of required substrates and cofactors in important organs.

Increased Resting Energy Expenditure Among Organs

Before better nutritional, metabolic, or pharmacological therapies can be rationally designed to attenuate the catabolic and hypermetabolic response, we must better understand quantitatively the individual organ or tissue-specific substrate requirements and how they relate to the body as a whole. Although the whole-body metabolic rate, as measured by oxygen consumption, is increased as much as two-fold, these additional energy requirements are not simply distributed proportionately among the tissues and organs, but are focused in particular organs, the liver and skeletal muscle. The liver and skeletal muscle taken together increase from 37% of the oxygen consumption in normal healthy adults to represent nearly 60% of the oxygen consumption in the burned patient. This disproportionate redistribution could be considered controversial however, in that others have suggested that the redistribution of this increased REE is proportionately distributed among the various organs based upon weight (1). Therefore, it is important to clarify this most fundamental information about energy expenditure.

Increased Protein Turnover Among Organs

Regarding protein turnover, we know that both the liver and skeletal muscle are heavily involved in amino acid trafficking as well as protein turnover. Studies using 3-methyl histidine, which is not recycled after protein breakdown, suggest that protein degradation is high in skeletal muscle (2). From these facts and other data, we expect that the two-fold increases in whole body protein synthesis and degradation rates are not distributed uniformly from an organ perspective, and therefore that the individual organ-specific rates need to be determined directly in patients using noninvasive methodologies. For the most part, our current knowledge comes from a very limited data set of direct measurements of protein turnover derived from arterial-venous concentration differences and occasionally direct muscle biopsies in humans (3). Two of the projects are investigating skeletal muscle protein synthesis and degradation from different perspectives.

Oxygen Consumption and ATP

We know that after burn injury, patients overwhelmingly tend to oxidize fatty acids to generate the energy required for the greatly enhanced reaction rates of both ATP-consuming and non ATP-consuming reactions (4). This consumption of fatty acids as fuel is associated with a high rate of triglyceride synthesis (5-6). Although fatty acid oxidation serves as the primary fuel, it appears that the overall synthesis and degradation rates might exceed what might be necessary and lead to inefficiencies and “futile” recycling, which also consumes energy.

Energy Consumption

In normal healthy individuals, both ATP and non ATP-consuming reactions contribute to the whole body oxygen consumption. We estimate that non-mitochondrial oxygen consumption accounts for approximately 10% of the whole-body oxygen consumption. We also estimate that 70% of the body’s oxygen consumption is ATP-coupled with the remaining non-ATP-coupled (protein leaking and uncoupling with ATP formation). Importantly, however, it is not known how these proportions change with burn injury. It is possible that dissipating the mitochondrial proton gradient by uncoupling protein (UCP) and its homolog (UCPH or UCP-2) can alter the ratio of ATP synthesized to oxygen consumed, and this could have a major impact on energy economy.

Energy Consumption – ATP-Coupled Reactions

In normal healthy individuals, of the ATP-coupled reactions, the ATP-ase reactions account for approximately 26-34% of the oxygen consumption Of the other ATP-consuming reactions, protein turnover is a major contributor and accounts for a similar 20-30% of the whole-body oxygen consumption. Together with the protein leak, these two ATP-coupled reactions are potentially very important quantitatively to the consumption of ATP and worthy of further research. Our overall research program pursues this promising area of research in projects supported by non-NIH institutional funds.

The metabolic costs of the ATP-consuming reactions are increased two-fold with the exception of intracellular fatty acid cycling, which increases more than tenfold. To get a better understanding of how these various reactions contribute quantitatively to the overall 20 kcal/kg/d increase in REE, assumptions were made based on classical biochemical relationships.

In these estimates, approximately 57% of the increased energy consumption has been accounted. Approximately 22% of the increased energy consumption is related to protein synthesis and another 21%, which is likely to be a low estimate because of our assumptions, is accounted to fatty acid cycling and gluconeogenesis-glycolytic (ggc) cycling. Of these, we will be evaluating aspects of individual organ contributions to the fatty acid and ggc cycling pathways in Project 2. We also recognize that the glutamine and alanine contributions to the gluconeogenic pathways are crucial to the ggc cycling reactions and we are developing improved methodologies to evaluate this important contribution.

Drivers of the Catabolic, Hypermetabolic Response

As mentioned above, one possible hypothesis regarding the drivers of this hypermetabolic response identifies neurohormonal alterations as the cause for the increases in metabolic rate, glucose turnover, lipolysis, whole body protein turnover, negative nitrogen balance, and insulin resistance. However, when the counter-regulatory hormones of stress, which include glucagon, hydrocortisone, and epinephrine, were infused in normal human volunteers, the responses in metabolic rate, urinary nitrogen loss, and amino acid fluxes were only modest (7). It is likely that counter-regulatory hormones, although prominent contributors, are not the sole cause of the hypermetabolic response (8). It is far more likely that there are additional but potentially more complex factors, which lead to the hypermetabolic response to stress and selected candidates including TNF, IL-6, and NO• are evaluated in Projects 3 and 4. As previously mentioned, these factors may include tissue factors, bacterial products, central nervous system response to pain and emotional stress, fever, production of prostaglandins and cytokines, and potentially environmental factors of heat, cold, or noise. As mentioned previously, the fact that the counter-regulatory hormones often peak and return to normal in the ebb phase of trauma, prior to development of the hypercatabolic phase, provides additional challenge to the counter-regulatory hormone hypothesis. It is our hope that, since it is likely that multiple factors have roles to feed this fire or catabolic, hypermetabolic process, considerable efforts will eventually allow all the pieces to be understood and fitted together. With this additional information, we may be able to “normalize” the hypermetabolic response to stress by blocking or modulating factors, which will allow appropriate nutritional support and medical management to reverse the dramatic wasting and thus significantly improve the likelihood of the patient’s survival.

Discovery of additional potential drivers of this complex process requires a larger-scale effort than this P50 program. In coordinated but separately funded research entitled "Inflammation and the Host Response to Injury" at http://www.gluegrant.org, additional drivers of this complex metabolic system are being sought using discovery-driven methodology. In that project, the genes, which are highly regulated in the post-injury response, together with their protein products are identified in a high throughput, systematic fashion. It is anticipated that several of these highly regulated genes and gene products will intensely affect the metabolic pathways in the post-injury state.

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6. Hart DW, Wolf SE, Mlcak R, Chinkes DL, Ramzy PI, Obeng MK, Ferrando AA, Wolfe RR, Herndon DN. Persistence of muscle catabolism after severe burn. Surgery. 2000 Aug;128(2):312-9.

7. Wolfe RR, Herndon DN, Jahoor F, Miyoshi H, Wolfe M. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N Engl J Med. 1987 Aug 13;317(7):403-8.

8. Klein S, Peters EJ, Shangraw RE, Wolfe RR. Lipolytic response to metabolic stress in critically ill patients. Crit Care Med. 1991 19:776-9.