The Biological Problem of Burns

Based on the measurements in our burn patients, burn injury triggers a two-fold increase (20 kcal/kg/day) in resting energy expenditure (REE) of our patients (1) . Compared to other processes such as sepsis, peritonitis, skeletal trauma and elective surgery, this increase in REE from burn injury is the most dramatic. However, one should remain optimistic that this severe, damaging phenotype can be controlled, since the overall magnitude of this response appears to have diminished since the 1970s and this is likely, at least in part, to be related to improvements in modern comprehensive burn care (2).

In addition to the hypermetabolic increase in REE, a more problematic metabolic feature is self-catabolism, or wasting of muscle tissue, which routinely follows a burn injury, and this catabolic response is presumably a consequence of the increase in REE or is related to it. The self-catabolism, which is manifested by a two-fold increase in protein degradation with a lesser increase in synthesis, persists despite state-of-the-art nutritional care. As a result, the rate of protein degradation continues to exceed that of synthesis by 1.3 g/kg/day in our patients. The driver(s) for the catabolic, hypermetabolic response, which are considered below, remain fundamentally unknown.

Current consensus supports the concept that at least one set of drivers of the hypermetabolic response is the counter-regulatory hormones (glucagon, cortisone, and epinephrine). These hormones are an excellent possibility because they naturally antagonize insulin, which is a very potent anabolic agent. Secondly in human studies, their short-term infusion recreates a significant, albeit modest, increase in REE (3). On the other hand, it is also apparent that the counter-regulatory hormones do not persist during the entire hypermetabolic response period and therefore, they may not and probably are not the only drivers of this response. Because they do not persist during the entire post-injury period, one possibility is that they serve as a switch, which initiates the cascade of events resulting in the catabolic, hypermetabolic process.

However, it is not only possible, but also highly probable, that there are additional initiators or drivers involved both in the initiation as well as continuation of the hypermetabolic, catabolic response (4). These other drivers may be neurohumoral factors including 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. In particular as one example, the cytokines clearly have metabolic effects as well as regulatory effects on key metabolic systems such as the Na-K ATPase enzyme systems, which is likely to be highly dysregulated in the post-injury period (5-6).

Manipulation of the Hypermetabolic Response

Unfortunately, there has been very limited success in directly attenuating this catabolic, hypermetabolic response thus far. Anabolic hormones (rhGH, IGF-1/bp 3, insulin, testosterone, and oxandrolone) promised to raise the rate of protein synthesis while lowering the rate of net protein loss (7-8). These agents, however, do not appear to affect the rate of protein degradation, although they do increase protein synthesis substantially. Therefore, the net effect of these agents only serves to potentially increase REE. Similarly, the inhibition of cytokines has not favorably influenced the catabolic, hypermetabolic response (9). On the other hand, propranolol, which is a nonspecific beta-blocker, has been successful, at least in part (10). Although the overall metabolic rate has been decreased with propranolol, it is not likely to be adopted as standard treatment in modern burn care because of its broad and nonspecific effects on the cardiovascular and metabolic systems. Therefore broadly interpreted, our Center research focuses on key amino acids in their role to regulate protein synthesis and degradation and on insulin receptor function. Project 1 focuses on the amino acids, glutamine and arginine, to include key aspects of their role in the production of glutathione and nitric oxide respectively. Project 2 focuses on the key amino acid tracer, methionine, as a tool to determine the individual organ contributions to protein synthesis and degradation within the context of blood flow, oxygen consumption, as well as glucose and fatty acid substrate cycling.

In Projects 3 and 4, we have chosen insulin receptor function as a key regulatory pathway not only because it is critical to maintain glucose tolerance, but also because normal insulin receptor function is probably critical to maintain a vigorous, anabolic state. It is possible, or perhaps even probable, that downstream, post-receptor components substantially regulate skeletal muscle wasting and apoptosis as well as abnormalities of ATP-coupling with oxygen consumption and normal mitochondrial function. Project 3 focuses on the proximal post-receptor regulation as well as stress kinase activities and the insulin receptor substrate (IRS-1). Project 4 focuses upon more distal key post-receptor events including the activation of Akt/PKB as a pivotal regulator of insulin’s effect on glycogen and protein synthesis as well as maintenance of mitochondrial integrity.

The Center has focused much of its investigational effort on modulating the individual nutrient components in a shared hope of improving efficiencies in utilization, compensating for energy losses and improving nitrogen economies. This approach has been based on the hypothesis that by meeting the needs of stress, the catabolic fire could be turned off and there would no longer be a need for proteolysis (enhanced rates of protein degradation). This hope was buoyed by the development of greatly improved methods to provide energy, amino acids, and other nutrients by enteral as well as intravenous routes. Unhappily, meeting the needs of the catabolic fire, at least as currently understood, has not attenuated the catabolic, hypermetabolic response. Currently, we feed the fire and hope for resolution of the stress process, which will eliminate the process driver(s) and allow metabolic recovery. Succinctly stated, limited if any, survival benefit has been observed despite aggressive nutritional support during the peak of catabolic hypermetabolism except perhaps for a potential benefit of enteral over parenteral nutrition administration (11). On the other hand in fact, harmful effects of aggressive nutritional support have been observed and include hepatic steatosis, suppression of the immune response, and excessive carbon dioxide production (11).

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2. Carlson DE, Cioffi WG, Mason AD Jr, et al. Resting energy expenditure in patients with thermal injuries. Surg Gynecol Obstet 174:270-6, 1992

3. Bessey PQ, Watters JM, Aoki TT, Wilmore DW. Combined hormonal infusion simulates the metabolic response to injury. Ann Surg. 1984 Sep;200(3):264-81

4. Watters JM, Bessey PQ, Dinarello CA, Wolff SM, Wilmore DW. Both inflammatory and endocrine mediators stimulate host responses to sepsis. Arch Surg. 1986 Feb;121(2):179-90

5. Ewart HS, Klip A.. Hormonal regulation of the Na(+)-K(+)-ATPase: mechanisms underlying rapid and sustained changes in pump activity. Am J Physiol. 1995 Aug;269(2 Pt 1):C295-311

6. Middleton JP. Direct regulation of the Na,K pump by signal transduction mechanisms. Miner Electrolyte Metab. 1996;22(5-6):293-302

7. Herndon DN, Pierre EJ, Stokes KN, Barrow RE. Growth hormone treatment for burned children. Horm Res. 1996;45 Suppl 1:29-31

8. Byrne TA, Morrissey TB, Gatzen C, Benfell K, Nattakom TV, Scheltinga MR, LeBoff MS, Ziegler TR, Wilmore DW. Anabolic therapy with growth hormone accelerates protein gain in surgical patients requiring nutritional rehabilitation. Ann Surg. 1993 Oct;218(4):400-16; discussion 416-8

9. Ling PR, Istfan NW, Colon E, Bistrian BR. Differential effects of interleukin-1 receptor antagonist in cytokine- and endotoxin-treated rats. Am J Physiol. 1995; 268:E255-61

10. Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of catabolism by beta-blockade after severe burns. N Engl J Med. 2001: 345 :1223-9

11. Souba WW. Nutritional support. N Engl J Med. 1997;336:41-8