History of Metabolic Treatments in Burn Care

Throughout the latter portion of the 20th century, major developments and advances within the specialty of burn care have been made. Several interventions and developments in reducing energy demands following burns have played a role in attenuating the metabolic response and reducing energy requirements. As a result, long-term function and prognosis have greatly improved. These interventions include early burn excision and wound closure with skin grafts or substitutes, early and aggressive enteral feeding, elevating environmental temperature to thermal neutrality, and pharmacological therapies to modulate the hypermetabolic response. Other developments include improved antimicrobial agents and treatment rationales, as well as efficacious topical antimicrobials and burn dressings that have led to prevention, earlier recognition, and treatment of sepsis.
Severe burn injuries induce an array of metabolic and physiologic processes to activate and respond in an attempt to restore homeostasis. The stress response following severe burns (approximately ≥ 40% total body surface area [TBSA]) is exaggerated and manifests detrimentally as hypermetabolism and associated profound catabolism. Features of the hypermetabolic response are known to include prolonged elevation in circulating catecholamines, cortisol, and glucagon.¹ This results in associated elevation in gluconeogenesis, glycogenolysis, and muscle catabolism as well as other features including insulin resistance and impairment of lipolysis. Metabolic disturbances continue well past the acute phase following severe burns and may persist for more than a year after injury.
A large study from a burn unit in the United Kingdom covering the decade prior to 1954 showed 50% mortality in children with a burn of 50% TBSA.² The authors later compared burn units from 1918–1948 and found that overall mortality was 50% in the 0–14 year age group of patients with 30% TBSA burns, and more than 90% mortality in patients with 40% surface area burns. Bull and Fisher² of the UK Medical Research Council attributed the observed improvements at Jackson’s Birmingham unit in 1954 to factors including recognition of the value of transfusion for shock, control of infection, and early surgery. By the late 1990s, pediatric burn mortality in specialized burn units was less than 50% for 91%–95% TBSA burns.³ Factors that remain associated with poor outcomes include very young age, inhalation injury, delayed resuscitation, sepsis, and multi-organ failure.
The primary mediators of the catabolic response following burns are catecholamines,⁴ which rise up to 10-fold following burns with greater than 40% TBSA.⁵ Wilmore et al^4,6 showed in 1974 and 1975 that following severe burns, metabolism and catecholamine levels could also be reduced by increasing ambient temperature to 33˚C, and also be modulated with alpha- and beta-adrenergic antagonists. They found the hypermetabolic response directly correlated with elevated catecholamine levels, which routinely increased 5-fold above normal following severe burns, and hence, promoted muscle catabolism and lipolysis. Wilmore and colleagues⁷ affirmed that burned extremities display increased glucose uptake and lactate production, and suggested that systemic responses act to increase peripheral blood flow in an attempt to supply the energy needs of the healing burn wound, thus, promoting hypermetabolism.
Hart et al⁸ more recently demonstrated that increasing burn surface area up to 40% consistently increased catabolism but did not increase directly thereafter. Delay to surgery, increasing age, and sepsis are associated with increased protein catabolism. Persistence of muscle catabolism and proteolysis following severe burns persists beyond 9 months such that strategies to modulate hypermetabolism should also extend well into the rehabilitation phase of the patient.⁹
 

Pharmacological Modulators of Hypermetabolism

Beta-adrenergic blockade (Propranolol). In 1974, Wilmore et al⁴ reported on the use of a beta-adrenergic blockade to significantly reduce metabolism by attenuating the massive rise in catecholamine levels, which can be as much as 10-fold following severe burns. The systemic response to this rise is characterized by a hyperdynamic circulation, elevated resting energy expenditure, and stimulation of peripheral lipolysis and muscle catabolism.
Attempting to modulate the actions of catecholamines by beta-adrenergic blockade with drugs such as propranolol, a nonselective beta-1 and 2 antagonist, has been shown to be effective in reversing many of the features of hypermetabolism and catabolism following severe burns.^4,10–13 Over the last 20 years, treatment with beta-blockers has been shown to reduce cardiac workload and heart rate by 20% in children when prescribed long-term,¹⁰ to reduce tachycardia,¹³ metabolic rate,⁴ and modulate the severe catabolic response and aid in diminishing muscle protein breakdown.¹²
The reduction in metabolic rate is associated with reduced heart rate, blood pressure, minute ventilation, and free fatty acid release. Studies at the authors’ unit, the Shriners Burns Institute for Children (Galveston, Tex), over this period have shown that propranolol is safely used to attenuate hypermetabolism and reverse muscle-protein catabolism.^12,13 Fatty-infiltration of the liver, a significant complication of major burns that is believed to occur due to elevated peripheral lipolysis as well as altered hepatic substrate handling, has been found to reduce following propranolol treatment.^14,15 Hepatomegaly following burns can impair ventilation by diaphragmatic impingement. Propranolol has also been shown not to increase inflammation, sepsis, or infectious episodes in severely burned children.¹⁶

Anabolic Agents

Endogenous anabolic hormone levels have been found to be depressed for an extended period in children following severe burns.¹⁷ Recent studies have shown beneficial effects following the administration of anabolic agents in children to attenuate catabolism. The most common and cost effective of these agents include human growth hormone, exogenous insulin infusion, and the synthetic anabolic testosterone analogue, oxandrolone.
Recombinant Human Growth Hormone (rhGH). Human growth hormone is a potent anabolic agent with a wide array of actions. The possible benefits of growth hormones and their impact on nitrogen balance and catabolism were recognized in the late 1950s.¹⁸ In the early 1970s, Wilmore et al¹⁹ investigated the anabolic effects of growth hormone following burns in and went on to later report together with Knox et al²⁰ in 1995 the results of their retrospective review of growth hormone supplementation between 1989–1993, which suggested mortality reduction.
Although increased mortality has been reported in adult critical-care patients, growth hormone appears safe in a pediatric burn population. Negative effects potentially include promotion of hyperglycemia and lipolysis. However, in a pediatric population following severe burns, long-term supplementation studies at the authors’ unit have shown rhGH to decrease catabolism, increase protein synthesis, promote muscle and bone growth, and shorten hospital stay.²¹ Skin-graft donor site healing in 40% TBSA and greater burns in children was shown to improve by 20%–30%.^22,23 Improved growth and recovery time were demonstrated, following long-term administration of rhGH over a 12-month period.²⁴ Concern that treatment with growth hormone could potentially increase scarring prompted a study that showed that severely burned children who received rhGH during the acute hospital course did not develop increased scarring.²⁵
Oxandrolone. The synthetic anabolic testosterone analog, oxandrolone, had been shown to improve muscle mass in other catabolic disorders including alcoholic hepatitis and AIDS before trials in burn patients.^26,27 It has 5% of the virilizing activity compared to testosterone and is preferable for use in children and women. Fewer side effects are also seen in comparison with rhGH. In 1997, Demling et al²⁸ discovered that oxandrolone administration during the acute recovery phase of burn patients, combined with a high protein diet, improved both weight gain and exercise function. Hart et al²⁹ showed that oxandrolone was stimulating protein synthesis rather than inhibiting muscle breakdown and was efficient at improving overall protein net balance following severe burns in children. The authors’ group recently demonstrated that oxandrolone administration in both the acute and long-term phases following pediatric major burns improved body composition and hepatic protein synthesis over 1 year.¹⁷

Insulin

In a non-burn, critical-care setting, tight blood glucose control through the use of intensive insulin protocols together with dextrose infusion to maintain euglycemia has emerged as an important factor in reducing infection and mortality rate, as shown in the 2001 study by van den Berghe et al.³⁰ Insulin is also an anabolic agent that stimulates protein synthesis in severely burned patients³¹ without increasing hepatic triglyceride production.³²
Wolfe et al³³ showed that patients with burns are glucose-intolerant and insulin-resistant. Hyperglycemia occurs due to impaired utilization of glucose. The severe stress response and high-energy demands of patients with burns are usually satisfied by supplied carbohydrate sources, which also cause a tendency towards hyperglycemia.

Nonpharmacological Modulators of Hypermetabolism

Early burn excision and wound closure. Early excision of full-thickness burn wounds has likely had the greatest impact on mortality over the past few decades. Tompkins et al³⁴ reported findings from their 19-year review of mortality in 1988. Mortality due to burn injuries had markedly reduced from 9% in the late 1960s to 1% in the early 1980s. They attributed this reduction to improvements in burn care over this period. Children and infants now survived burn injuries at a similar rate as young adults, with the most significant reductions in mortality seen in patients with burns covering more than 50% of the body surface area.
Later studies found that early wound excision together with early feeding in severe burns markedly attenuated muscle catabolism and improved infectious outcomes when compared with delayed treatment. Wound colonization and sepsis were diminished with early treatment as well.³⁵
Early excision and grafting as part of aggressive treatment for burn patients had been pioneered by Jackson at his unit in Birmingham, England in the 1950s. By 1953, he had devised the “pin-prick” test to differentiate partial from full-thickness skin loss. Janzekovic³⁶ in Maribor, Slovenia in the 1960s, developed the concept of removing deep partial-thickness burns by tangential excision with a simple uncalibrated knife and covering the wounds with autografts. Her technique was implemented by Jackson at his unit with impressive results and is presently the method of choice worldwide.
In 1983, Engrav et al³⁷ compared early tangential excision and grafting against nonoperative treatment of burns of indeterminate depth. Compared to nonoperative treatment with silver sulfadiazine cream, early excision and grafting of deep partial-thickness burns of less than 20% TBSA resulted in shorter hospitalization, earlier return to work, lower cost, and reduced hypertrophic scarring.
In 1989, Herndon et al³⁸ showed a decrease in mortality in massively burned adults with third-degree burns when treated with early excision as opposed to conservative treatment. Children over the period 1982–1986 now had a 50% survival rate with burns of 95% TBSA^39,40 in contrast to a similar survival rate seen with 50% TBSA burns in the era 30 years prior.²
Further studies have shown attenuation of the hypermetabolic response in burn patients of all ages.^38,41 Using stable isotope studies to measure protein kinetics, Hart et al⁸ in 2000 investigated factors affecting the degree of catabolism after severe burns. Resting metabolic rate was reduced by 40% in patients who had large burn wounds excised and covered with either autograft, allograft, or skin-substitute, within 2 to 3 days of injury compared to patients whose surgery was delayed until day 7 post-injury.
Early wound excision remains a safe therapeutic approach that modulates the hypermetabolic response after burn injury and is superior to conservative treatment with silver sulfadiazine and delayed excision; therefore, it should be considered when treating all severe full-thickness burns.⁴²

Prevention and Early Treatment of Sepsis

Septic patients with burns have a 40% increase in metabolic rate and protein catabolism compared to nonseptic patients with a similar burn size.⁸ Therefore, preventing and treating sepsis plays a major role in controlling the metabolic response following burns. Invasive burn wound sepsis caused a mortality of up to 80% in the era before the introduction of efficacious silver-containing topical antimicrobials in the mid-1960s when burn wound sepsis rapidly decreased following their introduction. Early excision and grafting further decreased morbidity and mortality from burn wound sepsis during this period. In 1965, Moyer et al⁴³ reported use of 0.5% silver nitrate soaks as a potent topical antibacterial agent for burn wounds. Mafenide acetate (Sulfamylon®, UDL Laboratories, Rockford, Ill) was adapted for treating burns by Lindberg et al⁴⁴ in the same period. This penetrates third-degree eschar and is extremely effective against a wide spectrum of pathogens. Fox et al⁴⁵ developed silver sulfadiazine cream (Silvadene®, King Pharmaceuticals, Inc., Bristol, Tenn), which was almost as efficacious as mafenide acetate. Silver sulfadiazine has become the mainstay of topical antimicrobial therapy because of its success in controlling infection in burns combined with its minimal side effects.

Thermally Neutral Ambient Temperature

Evaporation at the burn eschar causes heat loss, which contributes to the energy requirements of the already hypermetabolic burn patient. Water loss can be as much as 4 L per m² TBSA burn per day.^46,47 Similar to cold acclimatization mediated by the hypothalamus, core and skin temperatures are reset to 2˚C above normal in patients with severe burns. In 1975, Wilmore et al⁶ showed hypermetabolism following large burns could be significantly reduced by warming to a thermally neutral ambient temperature of 33˚C at which point the heat required for evaporation derives from the environment rather than the patient.

Nutritional Support of Hypermetabolism

Nutritional support is vitally important to improve outcomes following major burn injury and to meet the demands of the metabolic response. In the early 1970s before routine nutritional support via enteral or parenteral feeding, patients with severe burns could be expected to lose 15% of their lean body mass within a few weeks of injury due to severe catabolism, a major factor contributing to the prevailing mortality rates.^48,49
Severe burn injury results in a catabolic state, increasing proteolysis by up to 50%, and results in profound loss of muscle mass.⁵⁰ The hypermetabolic response that follows severe burn trauma causes an elevation in energy expenditure of up to 100% above normal. Shaffer and Coleman⁵¹ had advocated high caloric feeding for burn patients as early as 1909. In 1971, Wilmore et al⁵² supported feeding regimens with caloric intake as high as 8000 kcal/day. In 1974, Curreri et al⁵³ quantified the calories required to maintain body weight over time, and developed a formula specific to burn patients to calculate energy requirements based on burn size.
Current guidelines recommend a rise in protein provision of at least 50% to 1.5–2.0 g/kg/day for adults and up to 3 g/kg/day for pediatric patients to match the rise in proteolysis.^54,55 The increased intake helps to reduce the negative nitrogen balance but does not prevent catabolism.⁵⁶ Excess provision of protein above the suggested levels has been shown not to block protein breakdown or enhance synthesis, and can result in overfeeding and its associated complications. Improved survival, immune function, and lower rates of bacteremia have also been demonstrated in pediatric burn patients who were fed a diet containing 23% protein.⁵⁷
Energy and protein demands are greatly elevated in burn patients and this should be addressed by calculation of individual requirements and tailoring supplementation to adapt to changing needs. Early and aggressive support with enteral nutrition (EN) has been shown to improve outcomes and should be considered the first choice in suitable patients without contraindications.⁵⁸ Total parenteral nutrition (TPN) involves intravenous infusion of elemental components and bypasses the usual processes of digestion. A central line is required for delivery of hyperosmolar feeding regimens. TPN has declined from its previous popularity and should now be reserved for patients in whom contraindications to EN exist, due to the advantages of EN in terms of cost, reduced complications, and improved outcomes. Supplementation with additional TPN as an adjunct has been associated with substantially increased mortality in patients with burns.^59,60 In contrast to EN, TPN has been associated with increased rates of bacterial translocation.⁶¹

Resistive Exercise

Supplementation with the anabolic agents described may augment loss of lean body mass but resistive exercise is also required to preserve and develop strength post-burn.⁶² Significant improvements in muscle strength, power, and lean body mass, were recently observed among children enrolled in a supervised in-hospital 12-week rehabilitation program when compared to a standard exercise program.⁶³

Conclusion

Modulating hypermetabolism using anabolic and anti-catabolic therapies, in addition to the advances in surgical and intensive care management of burn patients, have led to tremendous improvements in outcomes following severe burns. Further dedicated research into the challenges presented by severe burns continues to accelerate our understanding of the physiological and cellular derangements that follow injury, with the ultimate aim of enhancing survival as well as the functional and rehabilitative outcomes for patients.