Current status of anabolic hormone administration in human burn injury
Ramzy, Peter I
ABSTRACT. Survival after massive burns has increased due to advances in critical care and wound closure techniques. Because of the ravages of hypermetabolism that is so prevalent in these patients, survivors are left with significant lean body mass losses that correspond to decreased strength with which to begin the rehabilitation phase. Efforts to decrease lean body mass catabolism by environmental regulation, early wound closure, and sufficient caloric provision modify the hypermetabolic response to
an extent; however, further manipulations are required to optimize recovery fully. Pharmacologic intervention with hormone agonists and antagonists holds this promise. This article reviews some of the current investigations in this area and points out the future work that needs to be done to elucidate the field of anabolic hormones after severe injury. (Journal of Parenteral and Enteral Nutrition 23:5190-5194, 1999)
Severe burn is associated with persistent hypermetabolic responses characterized by accelerated breakdown of skeletal muscle protein, increased peripheral lipolysis, impaired wound healing, fatty infiltration of the liver, and a hyperdynamic circulation. These effects result in loss of lean body mass and accumulation of fat, making rehabilitation from these devastating injuries more difficult. As critical care management and wound coverage techniques for these patients have improved, survival of severely burned patients has increased to the extent that almost all young patients with severe burns should be expected to survive, regardless of the extent of the burns. 12,3 These survivors then present further challenges for the burn care team in terms of rehabilitation from the injury to enable an effective reentry into the workplace and society. Efforts to preserve strength and lean body mass during the ravages of hypermetabolism are then warranted.
Three strategies can be used to inhibit hypermetabolism after severe burn. The first is to diminish the hypermetabolic signal through occlusive dressings for open burn wounds, appropriate ambient temperature control, and rapid closure of the burn wound through modern wound care techniques. The second is to provide sufficient caloric intake to “feed the fire” during the acute phase of recovery such that further catabolism is diminished. The third is to pharmacologically manipulate the hypermetabolic response with hormones and hormone antagonists.
Anabolic agents serve as an important adjunct to nutrition support of critically ill patients who are hypermetabolic after severe thermal injury. Nutritional management of severely burned patients poses a challenge to even the most experienced clinicians and requires a multidisciplinary approach aimed at optimizing caloric utilization and preserving lean body mass. It is essential for an experienced dietitian to work in close conjunction with the physician team in order to formulate a nutritional strategy that is tailored to the needs of the individual burn patient. The use of anabolic hormones to attenuate the hypermetabolic response has significant implications for treatment of the severely burned. The ultimate goals are to increase muscle strength, accelerate healing of the burn wound, maintain immune function, and improve long-term functional rehabilitation, These goals are best achieved using a two-pronged therapeutic approach involving pharmacologic intervention with anabolic agents in combination with early enteral feeding to bolster nutrition support of the hypermetabolic response.4 THE HYPERMETABOLIC RESPONSE IN BURNS Severe burns represent the most extreme end point on the spectrum of traumatic injury, and patients manifest a dramatic increase in basal metabolic rate and resting energy expenditure. Stress-induced catabolism is the hallmark of a severe burn, and its magnitude is generally commensurate with burn size. Although patients suffering from other forms of traumatic stress and critical illness are also often hypermetabolic, they are usually not so profoundly affected. For patients with large cutaneous burns, the basal metabolic rate may be increased by as much as 200%, to 300%.
In 1974, Wilmore et al5 demonstrated that thermal injury is associated with increased circulating levels of catecholamines, glucagon, and cortisol. Although many potential mediators have been postulated to have a role in generating the hypermetabolic response, current opinion is that these are most important. Catabolic hormones initiate a massive increase in metabolic demand manifested by heightened fuel consumption and huge increases in substrate flux. Hepatic glycogen stores are depleted as hypercortisolemia and elevated catecholamines cause rapid glycogenolysis. Once these stores are depleted, the skeletal muscle compartment becomes a depot of amino acid precursors to fuel the hypermetabolic response. Ultimately, wasting of peripheral skeletal muscle ensues as protein turnover is increased and amino acids from structural proteins are utilized to provide the precursors for hepatic gluconeogenesis. Rampant proteolysis continues as the muscle is consumed.
In addition to increased breakdown of skeletal muscle protein, burn patients also experience a significant increase in catecholamine-induced peripheral lipolysis as fat stores are depleted to provide substrate to feed the response. This dramatic increase in peripheral lipolysis results in hepatic fatty infiltration, as the normal hepatic-fat export mechanisms are overwhelmed.6
Clinically, patients who have endured the ravages of profound catabolism will present with spindly extremities and increased liver span secondary to severe skeletal muscle wasting and hepatic fatty infiltration. It is also imperative to realize that the effects of the hypermetabolic response are long lasting. Children are especially vulnerable because they are still growing and a massive burn can retard linear growth and decrease growth velocity for several years. The devastating effects of the hypermetabolic response on long-term functional rehabilitation are what make proper nutrition support and adjunctive pharmacologic support during the acute phase of injury so critical. An aggressive nutritional approach can sustain the hypermetabolic response to an extent; however, it is insufficient by itself, therefore making anabolic agents that abrogate catabolism of structural protein a necessary linchpin of effective therapy. NUTRITION SUPPORT Nutrition support of the burn patient during the acute phase is best accomplished through early enteral feeding. This provides adequate nutrition, improves intestinal motility, and preserves gut mucosal integrity. A common misconception is that burn patients experience a severe ileus that precludes enteral feeding. On the contrary, early enteral feedings are generally well tolerated in most patients, and the use of total parenteral nutrition (TPN) has been almost totally abandoned as viable alternative in the nutrition management of the burn patient. Although TPN may at first appear to be an ideal way to supplement enteral feedings, it is fraught with complications that argue against its use. It has been shown that TPN is associated with fatty infiltration of the liver, gut mucosal atrophy, and septic morbidity from increased bacterial translocation and catheter-related infection. In several prospective trials, our group clearly demonstrated that TPN was associated with increased mortality in severely burned patients.7,’ Elemental feedings via the enteral route, therefore, are the mainstay of treatment. In pediatric burn patients, we generally recommend feeding according to the formula of 1800 kcal/m2 body surface area per day plus 1300 kcal/m2 total body surface area burned per day in order to maximize efficient caloric utilization.9
Anabolic agents have emerged as important adjuncts that help to preserve lean body mass, improve nitrogen balance, and decrease the breakdown of skeletal muscle protein. A pantheon of anabolic agents exists, and while several are closely related, each one has its own unique characteristics. Although some have an established role in thermal injury, others are still being actively investigated. The majority of experience with the anabolic agents has been during the acute phase of injury, although long-term administration of certain agents is currently under investigation as well. The anabolic agents can be broadly classified according to their structure and mechanism of action into proteins, steroids, and antagonists. THE SPECIFIC ANABOLIC AGENTS The Protein Agents Growth hormone. The pioneering work by Sir David Cuthbertson in 1941 laid the foundation for the current rationale for the use of anabolic agents in human burn injury. Cuthbertson et all used anterior lobe extracts of the pituitary gland and demonstrated increased nitrogen retention in an animal model of traumatic injury. Based on these early studies, the potential of growth hormone as an anabolic agent in human stressinduced catabolism began to be explored. Unfortunately, cost was extremely prohibitive and it was not until the 1980s when a recombinant form of human growth hormone (rhGH) became available that the anabolic effects of this hormone could be harnessed for more widespread clinical use.” 2 Initial experience with rhGH at a dose of 0.2 mg/kg/d during the acute phase after severe burn demonstrated improved isolated limb protein kinetics and whole-body nitrogen balance. It was further shown that rhGH exerted these effects by decreasing amino acid efflux from the skeletal muscle compartment.13 In addition to improving net nitrogen balance and preserving lean body mass, rhGH also increased expression of structural proteins in the skin such as collagen and cytokeratin, which are important in the wound healing process.15 In fact, this agent has been shown to decrease donor site wound healing times by as much as 2 to 4 days.14 Clinically, this allows more frequent grafting procedures and earlier burn wound coverage. This effect might also be extrapolated to second-degree wounds, which might heal faster under the influence of rhGH therapy. These effects on wound healing were culminated by the finding of significantly decreased length of hospital stay for patients receiving rhGH when compared with randomized and blinded controls.16
Recently, the use of growth hormone in the treatment of the critically ill has been criticized. Studies in critically ill, nonburned adults showed a significant increase in mortality after administration of human growth hormone.17 This caused some concern and prompted a reassessment of the use of this anabolic agent in the pediatric burn population. In a large series of severely burned children, however, no difference in mortality could be found between blinded placebo and growth hormone-treated patients.18 This study also demonstrated that rhGH therapy was associated with a decreased need for albumin replacement, which was the standard practice at the study institution. It is likely that differences in the populations under study are responsible for the opposite mortality findings, but notwithstanding, rhGH remains a safe and effective agent for management of the hypermetabolic response in the pediatric burn population. The major side effect of growth hormone therapy found in this study was hyperglycemia requiring increased amounts of exogenous insulin to maintain euglycemia in treated patients compared with controls. Induction of peripheral insulin resistance is thought to be the responsible mechanism. Other less common side effects include transient sodium and fluid retention.
In light of the adverse effects of growth hormone therapy on glucose metabolism, investigators sought another agent with effects on protein metabolism. The somatomedin hypothesis holds that growth hormone effects are partially mediated by a family of proteins known as insulin-like growth factors. The most important of these is insulin-like growth factor 1 (IGF-1).
IGF-1. IGF-1 serum levels are decreased after burn. Administration of recombinant human growth hormone to severely burned patients has been shown to increase serum levels of IGF-1.19 Initial studies by Strock et al20 in a small-animal model of thermal injury demonstrated that IGF-1 treatment decreased oxygen consumption and increased body weight compared with control animals. Later, Cioffi and others 21 studied the effects of IGF-1 in adult burn patients and found significant decreases in whole-body protein oxidation. Unfortunately, because of cross-reactivity with the insulin receptor, the doses of IGF-1 that were used mandated constant clinical vigilance to avoid symptomatic hypoglycemia. Less commonly, peripheral neuropathies have been documented after administration of IGF-1 in other catabolic states.
In order to better modulate the bioavailability of IGF-1 and avoid potential hypoglycemia and other adverse side effects, IGF-1 has recently become available in a recombinant form in combination with its principal binding protein, insulin-like growth factor binding protein 3 (IGFBP-3).
IGF-1/IGFBP-3. Our group first studied IGF1/IGFBP-3 in an effort to determine its effect on net protein balance after severe burns. This study demonstrated for the first time that at a dose of 1 mg/kg/d to 4 mg/kg/d, IGF-1/IGFBP-3 attenuated protein catabolism across the leg in severely burned children. The most marked effects were observed in patients who were most catabolic at the time therapy was initiated. This effect appeared to be mediated through increased fractional synthetic rate of skeletal muscle protein. Glucose metabolism and substrate utilization were not altered, and there were negligible clinical side effects. In no case was symptomatic hypoglycemia observed. Recent experience with IGF-1/IGFBP-3 in adults also showed promising results.23 It thus appears that IGF1I/IGFBP-3 has relatively specific effects on protein kinetics, with little to no effect on glucose metabolism, thus offering a new alternative for patients in whom more traditional agents such as growth hormone may not be as well tolerated.
The use of IGF-1/IGFBP-3 was also associated with improved Thl immune responses after injury. Investigators showed that isolated lymphocytes from severely burned children had diminished Thl cytokine production with markedly increased Th2 cytokine production, indicating a shift to the Th2 phenotype. This shift has been associated with decreased cell-mediated immune defenses. When IGF-1/IGFBP-3 was given to these patients, the Thl response was stimulated to compare with the normal range (Wolf SE, Ramirez RJ, Kobayashi M, et al, unpublished data). Further work to determine the clinical significance of this finding is ongoing.
Insulin. Insulin can be thought of as the prototypical protein anabolic hormone. Endogenous insulin has remarkable effects on inward transport of substrate for intracellular consumption, including both glucose and amino acids. It serves to reason, then, that the use of exogenous insulin as a means of ameliorating the postburn hypermetabolic response and other forms of stress-induced catabolism might be the most efficacious. To investigate this hypothesis, Sakurai et al demonstrated that maximal doses of a prolonged (> 48 hours) continuous exogenous insulin infusion in severely catabolic burn patients improved negative nitrogen balance by stimulating skeletal muscle protein synthesis up to 350%. It was also shown to increase the fractional synthetic rate of protein in the wound by 50%Ic. In this initial study, increased protein synthesis was associated with a sixfold increase in inward amino acid transport after insulin administration.24 Another interesting finding was an increase in protein breakdown with insulin treatment. It was proposed that this increase in protein breakdown was an effort to provide substrate for stimulated protein synthesis. The doses of insulin used in this study required constant clinical vigilance, with an average of 5000 kcal given in addition to required calculated needs to maintain euglycemia. In a more recent study, prolonged insulin infusion was successfully used at submaximal doses to achieve an anabolic effect, which did not require increased glucose supplementation to maintain euglycemia.25 The effects on stimulation of protein synthesis were maintained; however, the dramatic increases in inward transport of amino acids into the muscle cells and increases in protein breakdown were not seen. It was concluded then, that prolonged insulin treatment at submaximal doses improved intracellular utilization of amino acids from protein breakdown, resulting in improved protein balance. In another study, Pierre et a126 demonstrated beneficial effects of insulin on donor site healing time. As with growth hormone, these effects on donor site healing allow more frequent reharvesting and earlier closure of the burn wound, resulting in decreased sepsis and death. The Corticosteroid Agents Testosterone. The anabolic effects of testosterone during adolescence in males are well known; however, the role of testosterone as an anabolic agent for use in severely traumatized patients is still a subject of debate. Unlike protein agents, which bind to cytoplasmic receptors, corticosteroid hormones are translocated to the nucleus of the cell where they modulate transcription. A recent study in healthy, nonburned adult males showed a twofold increase in muscle protein synthesis after administration of 200 mg of intramuscular testosterone. This study also revealed that testosterone at these doses, unlike maximal doses of insulin, does not appear to affect inward transport of amino acids, but rather exerts its effects on protein synthetic rate through more efficient reutilization of the available intracellular amino acid pool.27 Investigators are currently examining the effects of testosterone in critically ill patients; however, it will be sometime before testosterone is widely available for this purpose.
Oxandrolone. Another corticosteroid hormone that offers potential therapeutic benefit for severely burned patients is oxandrolone. Oxandrolone is an analogue of testosterone and is a potent anabolic agent with minimal androgenic side effects. It has been used to cause weight gain in patients who have suffered extensive weight loss secondary to chronic debilitating illnesses. Experience with its use in human burn injury is limited, and it is currently being investigated as an anabolic agent for chronic administration. Its primary advantage is oral administration, which does not require injections as do long-term growth hormone administration and testosterone. It also has the advantage of diminished androgenic effects, making it possible for use in females and males. Demling and DeSanti28 have reported on a small series of adult burn patients to whom oxandrolone was administered during the rehabilitation phase and who have shown significant improvement in weight gain. Further prospective randomized studies looking directly at protein kinetics are necessary, however, to establish the role of oxandrolone in supporting the hypermetabolic response. The Antagonists Another group of compounds that have the potential to modify hypermetabolic responses to burn include agents that block the signals causing the effect. Putative mediators that could be blocked include the glucocorticoids and catecholamines. Glucocorticoids can be hindered either through modifying synthesis with agents such as ketoconazole, or with competitive antagonists, such as the abortifacient drug RU-486. Studies are currently under way to determine if glucocorticoid levels can be decreased with ketoconazole to the extent that metabolism is altered. Current regulatory difficulties with the availability of RU-486 have hampered the investigation of this agent in modifying hypermetabolism.
Antagonists to the increased catecholamine response to burn may also have utility in decreasing catabolism after injury. One agent that has been studied is the nonselectiveBblocker, propranolol. P-blockade has been shown to decrease cardiac work in catabolic burn patients with hyperdynamic circulation,29 and lower rates of peripheral lipolysis.30 Other benefits may include a decrease in anxiety and improved hemodynamics, particularly in the older burned patients. Further work in this area is required. CONCLUSION Successful management of burn-induced hypermetabolism requires a synergistic approach based on aggressive nutrition support in combination with anabolic agents to preserve lean body mass and enhance nitrogen retention. With increased survival of patients with even 80% or greater total body surface area burns,3 it is becoming increasingly important to be cognizant of long-term functional debilitation secondary to profound catabolism. Although previous studies have been done with several agents during the acute phase of injury, future research endeavors should focus on investigating agents that can be used for long-term administration to improve muscle strength, facilitate functional rehabilitation, and reintegrate burn survivors back into society as fully productive members.
`Presented at the 23rd Clinical Congress of the American Society for Parenteral and Enteral Nutrition, January 31-February 3, 1999, San Diego, CA.
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Peter I. Ramzy, MD; Steven E. Wolf, MD; and David N. Herndon, MD
From the Department of Surgery, University of Texas Medical Branch and Shriners Burns Hospital, Galveston, Texas
Correspondence and reprint requests: Steven E. Wolf, MD, Shriners Burns Hospital, 815 Market Street, Galveston, TX 77550.
Copyright American Society for Parenteral and Enteral Nutrition Nov/Dec 1999
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