WHAT, HOW, AND HOW MUCH SHOULD BURN PATIENTS BE FED?

SYNOPSIS

The hypermetabolic response to severe burn injury is characterized by hyperdynamic circulation, profound metabolic, physiologic, catabolic and immune system derangements. Failure to satisfy overwhelming energy and protein requirements after, and during severe burn injury, results in multi-organ dysfunction, increased susceptibility to infection, and death. Attenuation of the hypermetabolic response by various pharmacologic modalities is emerging as an essential component of the management of severe burn patients. This review focuses on the more recent advances in therapeutic strategies to attenuate the hypermetabolic response and its post-burn associated insulin resistance. Modulation of the response by early excision and grafting of burn wounds, environmental thermoregulation, early and continuous enteral feeding with high protein-high carbohydrate feedings and pharmacologic treatments that stimulate anabolism and oppose catabolism have markedly decreased morbidity in the acute phase post severe burn injury.

INTRODUCTION

Severe burn injury represents a significant problem worldwide. More than 1 million burn injuries occur annually in the United States. Although most of these burn injuries are minor, approximately 10% of burn patients require admission to a hospital or major burn center for appropriate treatment every year¹. Recent reports revealed a 50% decline in burn-related deaths and hospital admissions in the USA over the last 20 years, mainly due to effective prevention strategies, decreasing the number and severity of burns^{2, 3}. Advances in therapeutic strategies, including advances in resuscitation, wound coverage, better support of hypermetabolic response to injury, more appropriate infection control and improved treatment of inhalation injury, have further improved the clinical outcome of this unique patient population over the past years. However, severe burns remain a devastating injury affecting nearly every organ system and leading to significant morbidity and mortality⁴.

METABOLIC CHANGES FOLLOWING SEVERE BURN INJURY

Severe burns covering more than 40% total body surface area (TBSA) are typically followed by a period of stress, inflammation and hypermetabolism, characterized by a hyperdynamic circulatory response with increased body temperature, glycolysis, proteolysis, lipolysis and futile substrate cycling.^5–7 These responses are present in all trauma, surgical, or critically ill patients, but the severity, length and magnitude is unique for burn patients^{4, 8}. Marked and sustained increases in catecholamine, glucocorticoid, glucagon and dopamine secretion are thought to initiate the cascade of events leading to the acute hypermetabolic response with its ensuing catabolic state^{5, 9–16}. The response is characterized by supraphysiologic metabolic rates, constitutive muscle and bone catabolism, growth retardation, insulin resistance, and increased risk for infection^{5–7, 17, 18}. If untreated, physiologic exhaustion ensues, and the insult becomes fatal^19–22. This period is characterized by profoundly accelerated glycolysis, lipolysis, proteolysis, insulin resistance, liver dysfunction, and decreases of lean body mass and total body mass^23–29. A ten percent loss of total body mass leads to immune dysfunction; 20% leads to decreased wound healing; 30% leads to severe infections; and a 40% loss leads to death³⁰. Severely burned, catabolic patients can lose up to 25% of total body mass after acute severe burn injury²⁵.

The cause of this complex response is not well understood. However, it is hypothesized that interleukins 1 and 6, platelet-activating factor, tumor necrosis factor (TNF), endotoxin, neutrophil-adherence complexes, reactive oxygen species, nitric oxide and coagulation as well as complement cascades have also been implicated in regulating this response to burn injury³¹. Once these cascades are initiated, their mediators and by-products appear to stimulate the persistent and increased metabolic rate associated with altered glucose metabolism seen after severe burn injury³². The primary mediators of this response after severe burn injury are catecholamines, corticosteroids, and inflammatory cytokines³³. There is a 10 to 50-fold elevation of plasma catecholamines and corticosteroid levels that last up to 12 months post-burn^{34, 35}. Inflammatory cytokine levels, serum hormones, acute proteins and constitutive proteins are altered immediately post-burn and remain abnormal throughout the acute hospitalization up to 2 months post-burn compared with normal levels³⁴.

Several studies have indicated that these metabolic phenomena post-burn occur in a timely manner, suggesting two distinct patterns of metabolic regulation following injury³⁶. The first phase occurs within the first 48 hours of injury and has classically been called the “ebb phase,”^{36, 37} characterized by decreases in cardiac output, oxygen consumption, and metabolic rate as well as impaired glucose tolerance associated with its hyperglycemic state. These metabolic variables gradually increase within the first five days post-injury to a plateau phase (called the “flow” phase), characteristically associated with hyperdynamic circulation and the above mentioned hypermetabolic state.

Multi-organ dysfunction is the hallmark of the acute phase response post-burn⁸. Immediately post-burn, patients may have low cardiac values characteristic of early shock³⁸. However, by four days post-burn, at the onset of shock, they have cardiac outputs greater than 150% compared with non-burned, healthy volunteers³⁴. Heart rates of our patients approach 160% compared with non-burned, healthy patients²⁸. Post-burn, patients have increased cardiac work that lasts well into the rehabilitation phase^4,39. Myocardial oxygen consumption values far surpass values of marathon runners and are sustained well into the rehabilitation phase^{39, 40}. Profound hepatomegaly occurs after burn injury. The liver increases its size by 225% by two weeks post-burn and remains increased at discharge by 200%³⁴.

Insulin release during this time period was found to be twice that of controls in response to glucose load^{41, 42} and plasma glucose levels are markedly elevated, indicating the development of an insulin-resistance^{42, 43}. Current understanding has been that these metabolic alterations resolve soon after complete wound closure. However, recent studies found that the hypermetabolic response to burn injury may last for more than 12 months after the initial event^{5, 9, 16, 44}. We found in a recent study that sustained hypermetabolic alterations post-burn, indicated by persistent elevations of total urine cortisol levels, serum cytokines, catecholamines and basal energy requirements, were accompanied by impaired glucose metabolism and insulin sensitivity that persisted for up to three years after the initial burn injury⁴⁵.

Glucose metabolism in severely burned patients is dramatically deranged. In order to provide glucose, a major fuel source to vital organs, release of the above mentioned stress mediators oppose the anabolic actions of insulin⁴⁶. By enhancing adipose tissue lipolysis⁴⁷ and skeletal muscle proteolysis⁴⁸, they increase gluconeogenic substrates, including glycerol, alanine and lactate, thus augmenting hepatic glucose production in burned patients^49–51. In healthy subjects glucose metabolism is tightly regulated, and under normal circumstances, a postprandial increase in blood glucose concentration stimulates release of insulin from pancreatic β-cells. Insulin mediates peripheral glucose uptake into skeletal muscle and adipose tissue and suppresses hepatic gluconeogenesis, thereby maintaining blood glucose homeostasis^{49, 50}. In severe burns, however, metabolic alterations can cause significant changes in energy substrate metabolism. Hyperglycemia fails to suppress hepatic glucose release during this time,⁵² and the suppressive effect of insulin on hepatic glucose release is attenuated, significantly contributing to post-trauma hyperglycemia⁵³. Catecholamine-mediated enhancement of hepatic glycogenolysis, as well as direct sympathetic stimulation of glycogen breakdown, can further aggravate the hyperglycemia in response to stress⁴⁹. Catecholamines have also been shown to impair glucose disposal via alterations of the insulin signaling pathway and GLUT-4 translocation in muscle and adipose tissue, resulting in peripheral insulin resistance^{50, 54}. Researchers have shown an impaired activation of Insulin Receptor Substrate-1 at its tyrosine binding site and an inhibition of AKT in muscle biopsies of children at seven days post-burn⁵³. There is a link between impaired liver and muscle mitochondrial oxidative function, altered rates of lipolysis, and impaired insulin signaling post-burn, attenuating the suppressive actions of insulin both on hepatic glucose production and on the stimulation of muscle glucose uptake^{42, 47, 52, 53}. Another counter-regulatory hormone of interest during stress of the critically ill is glucagon. Glucagon, like epinephrine, leads to increased glucose production through both gluconeogenesis and glycogenolysis⁵⁵. The action of glucagon alone is not maintained over time; however, its action on gluconeogenesis is sustained in an additive manner by the presence of epinephrine, cortisol, and growth hormone^{46, 55}. Similarly, epinephrine and glucagon have an additive effect on glycogenolysis⁵⁵. Pro-inflammatory cytokines contribute indirectly to post-burn hyperglycemia by enhancing the release of the aforementioned stress hormones^56–58. Other groups showed that inflammatory cytokines, including tumor necrosis factor (TNF), interleukin (IL) -6 and monocyte chemotactic protein (MCP) -1 also act via direct effects on the insulin signal transduction pathway through modification of signaling properties of insulin receptor substrates, contributing to post-burn hyperglycemia via liver and skeletal muscle insulin resistance^59–61. Alterations in metabolic pathways as well as pro-inflammatory cytokines, such as TNF, have also been implicated in significantly contributing to lean muscle protein breakdown, both during the acute and convalescent phases in response to burn injury^{62, 63}. In contrast to starvation, in which lipolysis and ketosis provide energy and protect muscle reserves, burn injury considerably reduces the ability of the body to utilize fat as an energy source.

Skeletal muscle is thus the major source of fuel in the burned patient, which leads to marked wasting of lean body mass (LBM) within days after injury^{4, 64}. This muscle breakdown has been demonstrated with whole body and cross leg nitrogen balance studies in which pronounced negative nitrogen balances persisted for 6 and 9 months after injury⁶⁵. Since skeletal muscle has been shown to be responsible for up to 80% of whole body insulin-stimulated glucose uptake, decreases in muscle mass may significantly contribute to this persistent insulin resistance post-burn⁶⁶. The correlation between hyperglycemia and muscle protein catabolism has been also supported by Flakoll and others⁶⁷, in which an isotopic tracer of leucine was utilized to index whole-body protein flux in normal volunteers. The group showed a significant increase in proteolysis rates occurring without any alteration in either leucine oxidation or non-oxidative disposal (an estimate of protein synthesis), suggesting that hyperglycemia induced increased protein breakdown. Flakoll and others⁶⁷ further demonstrated that elevations of plasma glucose levels resulted in a marked stimulation of whole body proteolysis during hyperinsulinemia. Net loss of protein leads to loss of lean body mass, and severe muscle wasting leads to decreased strength and failure to rehabilitate fully. The resultant muscle weakness was further shown to prolong mechanical ventilatory requirements, and delay mobilization in protein-malnourished patients, thus markedly contributing to the incidence of mortality in these patients⁶⁸. This loss of protein is directly related to increases in metabolic rate and may persist up to 9 months after critical burn injury, often resulting in significantly negative whole-body and cross-leg nitrogen balances. Severely burned patients have a nitrogen loss of 20–25 g/m²TBSA/day, and if unattended, lethal cachexia becomes imminent in less than 30 days. Persistent protein catabolism may also account for the delay in growth frequently observed in our pediatric patient population for up to 2 years post-burn¹⁷.

Perturbations, such as sepsis, increase metabolic rates and protein catabolism up to 40% compared with patients with like-size burns that do not develop sepsis^{5, 69}. A vicious cycle ensues, as patients that are catabolic are more susceptible to sepsis due to changes in immune function and immune response. The emergence of multi-resistant organisms have led to increases in sepsis related infections and death overall^70–72. Inflammatory cells, in response to burn wounds and burn wound infections metabolize glucose anaerobically to pyruvate and lactate⁷³. These are returned to the liver for gluconeogenesis which produces recycled energy for use by leukocytes and fibroblasts in the burn wound^{74, 75}.

In past years, therapeutic approaches therefore, have, mainly focused on reversing the hypermetabolic response, with its ensuing catabolic state post-burn, using a large number of different strategies.

Nutritional Support of the Severely Burned Patient

The hypermetabolic response for a severely burned patient far surpasses that in any other disease state¹⁴. Determinants of successful initial burn treatment include early aggressive resuscitation (including nutrition), control of infection, and early closure of the burn wound. Aggressive, early enteral feeding improves outcomes in the burned patient by mitigating the degree and extent of catabolism^76,77. Attempting to overcompensate by providing excess calories and/or protein is ineffective and likely to increase such complications as hyperglycemia, carbon dioxide retention (CO2), and azotemia⁶⁴. Thus, the primary goal of nutritional support in burn patients is to satisfy acute, burn-specific requirements, and not to overfeed.

Patients with 40% TBSA treated with vigorous oral alimentation alone can lose a quarter of their preadmission weight by 3 weeks after injury²⁵. Attempts to feed severely burned patients orally failed due to altered mental status, inhalation injuries that compromised pulmonary function, gastrointestinal dysfunction, and/or feeding intolerance²⁵. The amount of nutrition necessary to provide adequate support and prevent severe catabolism was intolerable for these patients. Inanition proved fatal as severely burned victims succumbed to severe systemic infections and respiratory failure^{25, 78}. Thus, the primary goal of nutritional support, is to address the ever-evolving metabolic needs in severely burned patients. Nutrition should be tailored to promote wound healing, to increase resistance to infection, and to prevent persistent loss of muscle protein. During the acute hospitalization of severely burned patients, attempts to optimize nutrition are countered by immobility and evolving catabolic responses to injury; attempts to achieve a positive nitrogen balance are repeatedly thwarted.

Total parenteral nutrition (TPN) for the nutrition and rehabilitation of severely burned patients surfaced in the 1970's^{79, 80}. TPN allows for the provision of elemental components that do not require digestion or a functioning alimentary tract. Dextrose is the main calorie source in TPN, and protein is supplied as crystalline amino acid solutions. Lipid emulsions can comprise a significant proportion of the calories in TPN. Use of TPN has now been largely replaced by enteral nutrition (EN) in burn patients.

Adults can maintain body weight after severe burn injury only with aggressive, continuous nutrition of 25 kilocalories per kilogram body weight per day plus 40 kilocalories per percent total body surface area burn per day^81,82. Children require 1,800 kilocalories per square meter of body surface plus 2,200 kilocalories per square meter of burn area per day to maintain body weight⁸³. The mechanism by which patients are fed affects outcomes. Research shows that parenteral nutrition alone or even in combination with enteral nutrition could lead to overfeeding, liver failure, impaired immune response and increased mortality by 3-fold^84–86. Enteral nutrition reduces translocation bacteremia and sepsis, maintains gut motility, and preserves `first pass' nutrient delivery to the liver⁷⁶. For these patients, parenteral nutrition should be reserved primarily for those who have enteral feeding intolerance or prolonged ileus.

Timing of Nutrition

Advances in burn care have altered the magnitude of the post-burn hypermetabolic response, but not the nature of the response⁶⁴. A major determinant of outcome for severe burn patients is time to treatment. Any delays in resuscitation lead to poorer outcomes⁸⁷. In the acute phase, in the unfed patient, there is significant gut mucosal damage and increased bacterial translocation that collectively lead to decreased nutrient absorption^{88, 89}. Therefore, optimal nutritional support for the severely burned patient is best accomplished by early initiation of enteral nutrition. Moreover, multiple studies demonstrate that early institution of enteral feeding can significantly modulate the hypermetabolic response to severe burn^{76, 77}. Laboratory studies showed significant decreases in metabolic rates by two weeks post-burn in animals enterally fed continuously by two hours post-burn compared with animals fed 3 days post-burn, indicating the benefits of early initiation⁷⁶. Significant modulation of catecholamine levels and support of gut mucosal integrity have been shown with early enteral nutrition⁹⁰. In human studies, early continuous enteral nutrition delivered calculated caloric requirements (resting energy expenditure) by post-burn day three, nearly prevented the hypermetabolic response, and significantly decreased circulating levels of catecholamines, cortisol and glucagon^{90, 91}. Early enteral feeding preserved gut mucosal integrity, motility and intestinal blood flow⁷⁶. Intestinal hypoperfusion or ileus, secondary to delays in resuscitation can be reversed by reperfusion or adequate resuscitation. Post-burn ileus spares the small bowel and primarily affects the stomach and colon⁹². Patients with severe burn injury can be safely enterally fed in the duodenum or jejunum 6 hours post-burn, whether or not they have total gastroduodenal function⁹³. Nasojejunal, or nasoduodenal feeding should be initiated as soon as possible to facilitate the full resuscitation of the severely burned patient.

The Nutritional Requirements

Actual caloric requirements can be accurately determined by measuring resting energy expenditures with bedside carts.^94,95. Preservation of lean body mass should be a nutritional goal for severe burn victims, as a major consequence of the hypermetabolic response is severe total body catabolism. Appropriate nutrient delivery can be accomplished by feeding 1.2 to 1.4 times the measured resting energy expenditures (in kilocalories per square meter per day). Goran et al⁹⁴ found that by feeding patients 1.2 times the measured resting energy expenditures, body weight may be maintained, but with a loss of 10% of lean body mass. While others found an increase in body weight by feeding 1.4 times the resting energy expenditure, the gains, however, were in fat deposition, not lean body mass^{95, 96}.

The major energy source for burn patients should be carbohydrates which serve as fuel for wound healing, provide glucose for metabolic pathways, and spare the amino acids needed for catabolic burn patients. It is estimated that critically ill, burned patients have caloric requirements that far exceed the body's ability to use glucose, which is approximately 7 grams per kilogram per day (gm/kg/day) (2,240 kcal for an 80 kilogram man)⁹⁷. Providing a limited amount of dietary fat reduced requirements for carbohydrates and can improve glucose tolerance significantly.

The hypermetabolic, catabolic response to severe burns suppresses lipolysis and limits the extent to which lipids can be utilized for energy. Thus, fat should comprise no more than about 30% of non-protein calories, or about 1 gm/kg/day of intravenous lipids in TPN⁹⁸. Thirty percent may be overwhelming in burned patients. In an animal model, immune function was further compromised with diets containing more than even 15% lipids, advocating the use of low-fat diets in severely burned patients^{99, 100}. The composition of administered fat is more important than the quantity. Most common lipid sources contain omega-6 free fatty acids (ω-6 FFA's) such as linoleic acid which are metabolized through synthesis of arachidonic acid, a precursor of pro-inflammatory cytokines such as Prostaglandin E2. Omega-3 fatty acids (ω-3 FFA's) are metabolized without provoking pro-inflammatory compounds. Diets high in ω-3 FFA's have been associated with an improved inflammatory response, improved outcomes, and reduced incidences of hyperglycemia^{101, 102}.

Proteolysis is another hallmark of the hypermetabolic response after severe burn injury. Protein catabolism in burn patients can exceed 150 grams/day, or almost a half-pound of skeletal muscle⁶⁴. Increased protein catabolism leads to decreased wound healing, immuno-incompetence, and loss of lean body mass⁶⁴. There is some evidence that increased protein replacement for severely burned patients may be beneficial^103,104. Healthy individuals require 1 gram per kilogram body weight per day of protein intake^105,106. However, based on in vivo kinetics studies measuring oxidation rates of essential and non-essential amino acids, burn patients have 50% higher utilization rates than healthy individuals in the fasting state^103,107,¹⁰⁴. Thus, burn patients require a minimum of 1.5 to 2 grams per kilogram body weight per day protein intake^{16, 64, 108}. Any higher amount of supplementation in burned children, however, leads to increased urea production without improvements in lean body mass or muscle protein synthesis¹⁰⁹.

Amino acids have a key role in recovery following injury. Alanine and glutamine (GLU) are important transport amino acids, created in skeletal muscle to supply energy to the liver and to aid in wound healing¹¹⁰. GLU serves as a primary fuel for enterocytes and lymphocytes, and aids in maintaining small bowel integrity, preserving gut-associated immune function, and limiting intestinal permeability following acute injury^{111, 112}. GLU is rapidly depleted from both serum and muscle following severe burn injury, limiting visceral protein synthesis, and underscoring the importance of glutamine replacement after severe burn injury^{110, 113}. When GLU was given at 25 gm/kg/day, severely burned patients had a decrease in incidence of infections, improved visceral protein levels, decreased length of stay, and reduced mortality^114–116. Replacement of branched-chain amino acids led to improvements in nitrogen balance, but no effect on survival¹¹⁷.

Vitamins and other micronutrients are also profoundly affected by the hypermetabolic – catabolic response post-burn¹¹⁸ (Table 1)^119,120,166. Decreased levels of Vitamins A, C, and D, iron, zinc, and selenium have been implicated in decreased wound healing and immune dysfunction post severe burn injury^{118, 121}. Vitamin A replacement is important for wound healing and epithelial growth^{120, 122}. Vitamin C is paramount for synthesis and the cross-linking of collagen post-burn, and burn patients often require up to 20 times the recommended daily allowance^{120, 121}. Vitamin D is essential in the prevention of further bone catabolism post-burn¹²¹. Iron is an important cofactor in oxygen-carrying proteins⁶⁴. Zinc supplementation contributes to improvements in wound healing, DNA replication, and lymphocyte function¹²³. Selenium replacement improves cell-mediated immunity¹²⁴. Collectively, replacement of these micronutrients has contributed to the improvement in morbidity of severely burned patients.

Table 1.

Summary of the main effects of various pharmacologic interventions to alter the hypermetabolic response to burn injury.

Drug	Inflammatory Response	Stress Hormones	Body Composition	Net Protein Balance	Insulin Resistance	Hyperdynamic Circulation
rhGH	Improved	No Difference	Improved	No Difference	Hyperglycemia	No Difference
IGF1	Improved	No Difference	Improved	Improved	Improved	No Difference
Oxandrolone	Improved	No Difference	Improved	Improved	No Difference	No Difference
Insulin	Improved	No Difference	Improved	Improved	Improved	No Difference
Propranolol	Improved	Improved	Improved	Improved	Improved	Improved
Oxandrolone + Propranolol	Improved (Preliminary)	Improved (Preliminary)	Improved (Preliminary)	Improved (Preliminary)	Improved (Preliminary)	Improved (Preliminary)

The data summarized in the table is extrapolated from previously published data^{23, 28, 30, 53, 137, 140, 142, 148, 149, 151, 152, 155, 157, 166, 185–200} and has been previously published in Williams FN, Herndon DN, Jeschke MG. The Hypermetabolic Response to Burn Injury and Interventions to Modify this Response. Clinics in Plastic Surgery. Oct 2009;36(4):583-596, with permission.

Milk, traditionally an isocaloric-isoprotein, but high fat diet, consisting of 44% fat, 42% carbohydrate and 14% protein, became standard of care for the pediatric burned patient¹²⁵,¹²⁶. Although it was well-tolerated, fat did not serve as the optimal energy source for these patients. There was continued protein degradation, and lean body mass gains paled in comparison with high carbohydrate diets – consisting of 3% fat, 15% protein and 82% carbohydrate¹²⁶. The high carbohydrate diet increased protein synthesis, increased effective endogenous insulin production, and improved lean body mass. Increased endogenous insulin levels, stimulated by high carbohydrate delivery, may have contributed to improved muscle protein synthesis¹²⁶. Parenteral formulas which are traditionally 70% dextrose, 15% amino acids and 20% lipids, can be manipulated and adjusted to meet patients' caloric needs. However, TPN is associated with increased pro-inflammatory cytokines, increased pulmonary dysfunction, and increased mortality^{84, 85, 127, 128}. Thus, all TPN formulas containing currently available fat emulsions should be reserved for patients that cannot tolerate EN.

Overfeeding

The overfeeding of severely burned patients can lead to major complications. Overfeeding with carbohydrates results in elevated respiratory quotients, increased fat synthesis, and increased CO2 elimination. Ventilated patients become more difficult to manage and to wean from support¹²⁹. Excess carbohydrate or fat can also lead to fat deposition in the liver¹³⁰. Excess protein replacement leads to elevations in blood urea nitrogen (BUN), which could lead to acute renal failure, increased propensity to sepsis, and death¹³⁰. Overfeeding can lead to hypergycemia, which is already present in up to 90% of all critically ill patients – leading to increased morbidity and mortality¹³¹. This iatrogenic hyperglycemia is even harder to treat as both endogenous and exogenous insulin effects are often countered by the surge of catabolic hormones^{33, 132}. These complications are not specific to parenteral or entereal feedings, but are manifestations of attempts to over-compensate for the tremendous losses suffered by severely burned patients.

Positive changes in body weight are among the best predictors of overall nutritional status. Significant weight loss, particularly rapid and unplanned, is a predictor of mortality¹³³. However, it should be noted that resuscitation and maintenance fluid increases may mask ongoing loss of lean body mass so that patients can suffer significant inanition and still weigh more than they did at the time of admission. In addition, fluid shifts associated with infections, ventilator support, hypoptroteinemia, and elevations in aldosterone and antidiuretic hormone lead to wide fluctuations in weight that have little to do with nutritional status¹³⁴. Judicious monitoring of long-term trends is paramount in the clinical management of severely burned patients.

Determination of nitrogen balance, serum proteins, and abnormalities of immune function will also aid the assessment of nutritional supplementation post-burn^{121, 135, 136}. While no single laboratory test is fully reliable in nutritional monitoring, regular metabolic assessment is paramount in the ever-evolving physiologic response post-burn.

The Hormonal Response in Severe Burns

Elevated levels of catecholamines, cortisol, and glucagon perpetuate the profound changes in metabolic rates, growth, and physiology observed in the burn patient population. Anabolic agents such as recombinant human growth hormone (rhGH), insulin, insulin-like growth factor (IGF-1), and insulin-like growth factor binding protein-3 (IGFB-3) in combination with testosterone and oxandrolone have been shown to abate post-bun metabolism. To counter elevated levels of catecholamines, the adrenergic antagonist, propranolol, has been used with profound results. Other glucose modulators, besides insulin, have also been shown to attenuate post-burn metabolic derangements. The use of anabolic or anti-catabolic agents in severely burned children, in addition to standard of care, have led to significant decreases in protein catabolism.

PHARMACOLOGIC MODALITIES

Recombinant human Growth hormone

Intramuscular administration of recombinant human growth hormone (rhGH) at doses of 0.2 mg/kg as a daily injection during the acute burn phase favorably influenced the hepatic acute phase response^{137, 138}, increased serum concentrations of its secondary mediator IGF-I¹³⁹, improved muscle protein kinetics, maintained muscular growth^{140, 141}, decreased donor site healing time by 1.5 days¹⁴², improved resting energy expenditure, and attenuated hyperdynamic circulation¹⁴³. These beneficial effects of rhGH are mediated by insulin-like growth factor (IGF) -I, and patients receiving treatment demonstrated 100% increases in serum IGFI and IGF-binding protein (IGFBP) -3 relative to healthy individuals^{144, 145}. However, in a prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 247 patients and 285 critically ill non-burned patients, Takala and others found that high doses of rhGH (0.10 +/− 0.02 mg/kg BW) were associated with increased morbidity and mortality¹⁴⁵. Others demonstrated growth hormone treatment to be associated with hyperglycemia and insulin resistance^{146, 147}. However, neither short nor long-term administration of rhGH was associated with an increase in mortality in severely burned children^{143, 148}.

Insulin-like Growth Factor

IGF-I mediates the effects of GH. the infusion of equimolar doses of recombinant human IGF-1 and IGFBP-3 to burned patients has been demonstrated to be effective in improving protein metabolism in catabolic pediatric subjects and adults with significantly less hypoglycemia than rhGH alone^{149, 150}. It attenuates muscle catabolism and improves gut mucosal integrity in children with severe burns¹⁵⁰. Immune function is effectively improved by attenuation of the type 1 and type 2 hepatic acute phase responses, increased serum concentrations of constitutive proteins, and vulnerary modulation of the use of body protein resulting from hypercatabolism^150–153. However, studies by van den Berghe and colleagues¹⁵⁴ indicate that the use of IGF-1 alone is not effective in non-burned critically ill patients.

Oxandrolone

Treatment with anabolic agents such as oxandrolone, a testosterone analog which possesses only 5% of its virilizing androgenic effects, improves muscle protein catabolism via enhanced protein synthesis efficiency¹⁵⁵, reduces weight loss, and increases donor site wound healing¹⁵⁶. In a large prospective, double-blinded, randomized single-center study, oxandrolone given at a dose of 0.1 mg/kg every 12 hours shortened length of acute hospital stay, maintained LBM, and improved body composition and hepatic protein synthesis¹⁵⁷. These effects were independent of age¹⁵⁸. Long-term treatment with this oral anabolic during rehabilitation in the outpatient setting is more favorably regarded by pediatric subjects than parenteral anabolic agents. Oxandrolone use in children successfully abates the effects of burn associated hypermetabolism on body tissues and significantly improves body mass over time, increasing lean body mass at 6, 9, and 12 months after burn, and bone mineral content by 12 months after injury in comparison with unburned controls¹⁵⁹. Patients treated with oxandrolone experience few complications relative to those treated with rHGH. However, it must be noted that although anabolic agents can increase lean body mass, exercise is essential to developing strength¹⁶⁰.

Propranolol

Beta-adrenergic blockade with propranolol probably represents the most efficacious anti-catabolic therapy in the treatment of burns.⁸ Long-term use of propranolol during acute care in burn patients, at a dose titrated to reduce heart rate by 15 to 20%, was noted to diminish cardiac work³⁹. It also reduced fatty infiltration of the liver, which typically occurs in these patients as the result of enhanced peripheral lipolysis and altered substrate disposition. Reduction of hepatic fat results from decreased peripheral lipolysis and reduced palmitate delivery and uptake by the liver^{161, 162}, resulting in smaller livers and avoiding the hepatomegaly that frequently adversely affects diaphragmatic function.. Stable isotope serial body composition studies showed that administration of propranolol reduces skeletal muscle wasting and increases lean body mass post-burn^{28, 163}. The underlying mechanism of action of propranolol is still unclear, however, its effects appear to occur due to increased protein synthesis in the presence of persistent protein breakdown and reduced peripheral lipolysis¹⁶⁴. Recent data suggest that administration of propanolol at 4 mg/kg BW/q24 also markedly decreased the amount of insulin necessary to reduce elevated blood glucose levels post-burn.⁴⁰ Propranolol may thus constitute a promising approach to overcoming post-burn insulin resistance.

ATTENUATION OF HYPERGLYCEMIA POST-BURN

Insulin

Insulin probably represents one of the most extensively studied therapeutic agents and novel therapeutic applications are continually being explored. Insulin decreases blood glucose levels by mediating increased peripheral glucose uptake by skeletal muscle and adipose tissue, and suppressing hepatic gluconeogenesis. It also increases DNA replication and protein synthesis via control of amino acid uptake, increases fatty acid synthesis and decreases proteiolysis¹⁶⁵. The latter action makes insulin particularly attractive for the treatment of hyperglycemia in severely burned patients since insulin given during acute hospitalization has been shown to improve muscle protein synthesis, accelerate donor site healing, and attenuate lean body mass loss and the acute phase response^166–173. In addition to its anabolic actions, insulin was shown to exert totally unexpected anti-inflammatory effects, potentially neutralizing the pro-inflammatory actions of glucose^{170, 171, 174}. These results suggest a dual benefit of insulin administration: reduction of pro-inflammatory effects of glucose by restoration of euglycemia, and a possible additional insulin-mediated anti-inflammatory effect¹⁷⁵. Van den Berghe and colleagues confirmed the beneficial effects of insulin in a large recent milestone study. Insulin administered to maintain glucose at levels below 110 mg/dl decreased mortality, incidence of infections, sepsis, and sepsis-associated multi-organ failure in critically ill surgical patients¹³¹. Intensive insulin therapy also significantly reduces newly acquired kidney injury, accelerating weaning from mechanical ventilation and accelerating discharge from the ICU and the hospital¹⁷⁶. The ideal target blood glucose range for the severely burned patient has not been identified unequivocally, and several groups are currently undertaking clinical trials in order to define ideal blood glucose levels for the treatment of ICU and burned patients: A study by Finney and colleagues suggests maintaining blood glucose levels of 140 mg/dl and below¹⁷⁷, while the Surviving Sepsis Campaign recommends maintenance of blood glucose levels below 150 mg/dl¹⁷⁸. However, maintaining a continuous hyperinsulinemic, euglycemic clamp in burn patients is particularly difficult since these patients are being continuously fed large caloric loads via enteral feeding tubes. Since burn patients require weekly operations and daily dressing changes, enteral nutrition occasionally needs to be stopped, which may lead to disruption of gastrointestinal motility and increased risk of hypoglycemia⁴.

Metformin

Metformin (Glucophage), a biguanide, has recently been suggested as an alternative means to correct hyperglycemia in severely injured patients¹⁷⁹. By inhibiting gluconeogenesis and augmenting peripheral insulin sensitivity, metformin directly counters the two main metabolic processes which underlie injury-induced hyperglycemia^180–182. In addition, metformin has only rarely been associated with hypoglycemic events, thus possibly minimizing this concern which is associated with the use of exogenous insulin¹⁸³. In a small randomized study reported by Gore and colleagues, metformin reduced plasma glucose concentration, decreased endogenous glucose production, and accelerated glucose clearance in severely burned patients¹⁷⁹. A follow-up study evaluating the effects of metformin on muscle protein synthesis, confirmed these observations and demonstrated an increased fractional synthetic rate of muscle protein and improvement in net muscle protein balance in metformin treated patients¹⁸². Thus, metformin, analogous to insulin, may have efficacy in critically injured patients as both an antihyperglycemic and a muscle protein anabolic agent. On the other hand despite the advantages and potential therapeutic uses, treatment with metformin, or other biguanides, has been associated with lactic acidosis^{183, 184}. To avoid metformin-associated lactic acidosis, the use of this medication is contraindicated in certain diseases or illnesses in which there is a potential for impaired lactate elimination (hepatic or renal failure) or tissue hypoxia – and it should be used with caution in acute burn patients.

Novel therapeutic options

Other ongoing trials, with the goal of decreasing post-burn hyperglycemia, include the use of Glucagon-Like-Peptide (GLP)-1 and PPAR-γ agonists (e.g., pioglitazone, thioglitazones) or the combination of various anti-diabetic drugs. PPAR-γ agonists, such as fenofibrate, have been shown to improve insulin sensitivity in patients with diabetes. Cree and colleagues found in a recent double-blind, prospective, placebo-controlled, randomized trial that fenofibrate treatment significantly decreased plasma glucose, concentrations by improving insulin sensitivity and mitochondrial glucose oxidation⁵³. Fenofibrate also led to significantly increased tyrosine phosphorylation of the insulin receptor (IR) and IRS-1 in muscle tissue after a hyperinsulinemic-euglycemic clamp when compared with placebo treated patients, indicating improved insulin receptor signaling⁵³.

SUMMARY AND CONCLUSION

Severely burned patients have profound nutritional requirements secondary to the prolonged post-burn hypermetabolic, hypercatabolic response. Enteral nutritional support should be initiated early to optimize total burn care and decrease long-term morbidity. Neither non-pharmacologic nor pharmacologic strategies are sufficient to abate completely the catabolic response to severe burn injury. All therapeutic strategies have contributed to some extent to the improvements in morbidity and mortality (Table 1). Early enteral nutrition has contributed to the significant decline in lean body mass loss of severely catabolic patients^{34, 44}. Modulation of the hypermetabolic response is paramount in the optimal restoration of structure and function of severely burned patients and remains an elusive completely fulfilled goal despite the significant advances made in this area in the past few decades.