Mediators of the Hypermetabolic Response

Catecholamines and corticosteroids are the primary mediators of the hypermetabolic response following burns greater than 30% TBSA. There is up to a 50-fold surge of plasma catecholamine and corticosteroid levels that last up to months postburn. Burn patients have increased cardiac work, increased resting energy expenditures, increased myocardial oxygen consumption, marked tachycardia, severe lipolysis, hepatic dysfunction, full-body catabolism, increased protein degradation, insulin resistance, and growth retardation.

Genomic and Proteomic Changes to Burn Injury

After severe burn injury, considerable changes occur in every aspect of the human genome. These changes are immediate and persistent. The genetic response to this injury is so massive, there is no discrimination between desirable or undesirable effects of change. There is significant up-regulation of the innate immune response and down-regulation of the adaptive immune response.

Acute Phase Proteins (Cytokines and Hormonal Changes)

Proinflammatory cytokine levels peak immediately after burn, approaching normal levels only at 90 to 180 days postburn. Serum hormones, constitutive, and acute phase proteins are significantly deranged throughout acute hospital stay. Serum IGF-1, IGFBP-3, parathyroid hormone, and osteocalcin drop immediately after the injury and remain decreased compared with normal levels until 60 days postburn. Sex hormones and endogenous growth hormone levels decrease around 21 days postburn and remain low. Larger burn injuries are characterized by more pronounced and persistent inflammatory responses indicated by higher concentrations of proinflammatory cytokines that promote more severe catabolism.

Changes in Resting Energy Expenditures

Past studies showed metabolic rates of burn patients approaching 180% of that of predicted based on the Harris-Benedict equation. The resting metabolic rate of patients with large burns increases from normal predicted levels for TBSA less than 10% to twice that of normal predicted levels at 40% TBSA and higher. For severely burned patients, the resting metabolic rate at thermal neutral temperature (30°C) tops 140% of predicted basal rate on admission, reduces to 130% once the wounds are fully healed, then to 120% at 180 days after injury. Even 1 year postburn, the resting energy expenditures for burn patients are persistently elevated from predicted, based on the Harris-Benedict equation. The persistent muscle protein wasting from increases in catabolism result in decreased immune defenses, decreased wound healing, increased risk for pneumonia and other infections, and risk of death.

Multiorgan Dysfunction

Multiorgan dysfunction is a trademark of the acute phase response postburn. Immediately postburn, patients have low cardiac outputs, and low contractility, characteristic of early shock. However, 3 days postburn, cardiac outputs and heart rates are greater than 150% compared with nonburned patients. Postburn, patients have increased cardiac work that lasts well into the convalescence. Myocardial oxygen consumption values are significantly increased well after discharge. The liver increases significantly in size by 2 weeks postburn and remains increased twice normal.

Whole-Body Catabolism

Postburn, muscle protein is degraded much faster than it is synthesized. This leads to loss of lean body mass, and severe muscle wasting leading to decreased strength and failure to fully rehabilitate. Profound degradation of lean body mass secondary to chronic illness or hypermetabolism, hypercatabolic states, leads to immune dysfunction, decreased wound healing, pressure sores, pneumonia, and death. Severely burned, catabolic patients can lose up to 25% of total body mass after acute burn injury. The persistent and pervasive muscle wasting persists up to 9 months after burn injury resulting in significant negative whole-body catabolism, and is directly related to increases in metabolic rate. Severely burned patients have a daily nitrogen loss of 20 to 25 g/m ² of burned skin. At this rate, a fatal loss is reached in less than 30 days. This protein catabolism leads to significant growth retardation for up to 24 months postinjury.

Changes in Glucose Metabolism

Elevated circulating levels of catecholamines, glucagon, and cortisol in response to severe thermal injury perpetuate inefficient glucose production in the liver. This inefficiency is supported by stable isotope data demonstrating significant derangements in major ATP consumption pathways including urea production, increased protein turnover, and gluconeogenesis. Glycolytic-gluconeogenetic cycling is increased 2.5 times during the postburn hypermetabolic response coupled with an increase of 4.5 times in triglyceride–fatty acid cycling. All of these changes cumulate into impaired insulin sensitivity and severe hyperglycemia related to postreceptor insulin resistance. After injury, there are significantly elevated levels of fasting glucose, insulin, and significant reductions in glucose clearance. Despite having restricted glucose oxidation, glucose delivery to peripheral tissues is increased up to three-fold, leading to the elevated levels of fasting glucose. Increased glucose production is directed to support anaerobic metabolism of endothelial cells, fibroblasts, and inflammatory cells in the burn wound. Lactate, the end-product of the aforementioned anaerobic glucose oxidation pathway, is inefficient in providing glucose to the liver to produce more via the gluconeogenic pathway. Serum glucose and serum insulin remain significantly increased through the entire acute hospital stay. Insulin resistance appears during the first week postburn and persists for up to 3 years after injury.

Sepsis

Complications and/or physiologic derangements, such as sepsis, further increase resting energy expenditures and protein catabolism up to 40% compared with those with like-size burns that do not develop sepsis. The immediate and persistent changes in the innate and adaptive immune system postinjury make them more susceptible to sepsis, and thus at increased risk of further muscle and protein catabolism, propagating a vicious cycle. The emergence of multiresistant organisms has led to increases in sepsis-related infections and death overall. In combination, these responses lead to an increase in morbidity and mortality for victims of severe burn injury, compelling health care providers to secure therapeutic strategies to temper the often catastrophic response.

Mediators of the Hypermetabolic Response

Catecholamines and corticosteroids are the primary mediators of the hypermetabolic response following burns greater than 30% TBSA. There is up to a 50-fold surge of plasma catecholamine and corticosteroid levels that last up to months postburn. Burn patients have increased cardiac work, increased resting energy expenditures, increased myocardial oxygen consumption, marked tachycardia, severe lipolysis, hepatic dysfunction, full-body catabolism, increased protein degradation, insulin resistance, and growth retardation.

Genomic and Proteomic Changes to Burn Injury

After severe burn injury, considerable changes occur in every aspect of the human genome. These changes are immediate and persistent. The genetic response to this injury is so massive, there is no discrimination between desirable or undesirable effects of change. There is significant up-regulation of the innate immune response and down-regulation of the adaptive immune response.

Acute Phase Proteins (Cytokines and Hormonal Changes)

Proinflammatory cytokine levels peak immediately after burn, approaching normal levels only at 90 to 180 days postburn. Serum hormones, constitutive, and acute phase proteins are significantly deranged throughout acute hospital stay. Serum IGF-1, IGFBP-3, parathyroid hormone, and osteocalcin drop immediately after the injury and remain decreased compared with normal levels until 60 days postburn. Sex hormones and endogenous growth hormone levels decrease around 21 days postburn and remain low. Larger burn injuries are characterized by more pronounced and persistent inflammatory responses indicated by higher concentrations of proinflammatory cytokines that promote more severe catabolism.

Changes in Resting Energy Expenditures

Past studies showed metabolic rates of burn patients approaching 180% of that of predicted based on the Harris-Benedict equation. The resting metabolic rate of patients with large burns increases from normal predicted levels for TBSA less than 10% to twice that of normal predicted levels at 40% TBSA and higher. For severely burned patients, the resting metabolic rate at thermal neutral temperature (30°C) tops 140% of predicted basal rate on admission, reduces to 130% once the wounds are fully healed, then to 120% at 180 days after injury. Even 1 year postburn, the resting energy expenditures for burn patients are persistently elevated from predicted, based on the Harris-Benedict equation. The persistent muscle protein wasting from increases in catabolism result in decreased immune defenses, decreased wound healing, increased risk for pneumonia and other infections, and risk of death.

Multiorgan Dysfunction

Multiorgan dysfunction is a trademark of the acute phase response postburn. Immediately postburn, patients have low cardiac outputs, and low contractility, characteristic of early shock. However, 3 days postburn, cardiac outputs and heart rates are greater than 150% compared with nonburned patients. Postburn, patients have increased cardiac work that lasts well into the convalescence. Myocardial oxygen consumption values are significantly increased well after discharge. The liver increases significantly in size by 2 weeks postburn and remains increased twice normal.

Whole-Body Catabolism

Postburn, muscle protein is degraded much faster than it is synthesized. This leads to loss of lean body mass, and severe muscle wasting leading to decreased strength and failure to fully rehabilitate. Profound degradation of lean body mass secondary to chronic illness or hypermetabolism, hypercatabolic states, leads to immune dysfunction, decreased wound healing, pressure sores, pneumonia, and death. Severely burned, catabolic patients can lose up to 25% of total body mass after acute burn injury. The persistent and pervasive muscle wasting persists up to 9 months after burn injury resulting in significant negative whole-body catabolism, and is directly related to increases in metabolic rate. Severely burned patients have a daily nitrogen loss of 20 to 25 g/m ² of burned skin. At this rate, a fatal loss is reached in less than 30 days. This protein catabolism leads to significant growth retardation for up to 24 months postinjury.

Changes in Glucose Metabolism

Elevated circulating levels of catecholamines, glucagon, and cortisol in response to severe thermal injury perpetuate inefficient glucose production in the liver. This inefficiency is supported by stable isotope data demonstrating significant derangements in major ATP consumption pathways including urea production, increased protein turnover, and gluconeogenesis. Glycolytic-gluconeogenetic cycling is increased 2.5 times during the postburn hypermetabolic response coupled with an increase of 4.5 times in triglyceride–fatty acid cycling. All of these changes cumulate into impaired insulin sensitivity and severe hyperglycemia related to postreceptor insulin resistance. After injury, there are significantly elevated levels of fasting glucose, insulin, and significant reductions in glucose clearance. Despite having restricted glucose oxidation, glucose delivery to peripheral tissues is increased up to three-fold, leading to the elevated levels of fasting glucose. Increased glucose production is directed to support anaerobic metabolism of endothelial cells, fibroblasts, and inflammatory cells in the burn wound. Lactate, the end-product of the aforementioned anaerobic glucose oxidation pathway, is inefficient in providing glucose to the liver to produce more via the gluconeogenic pathway. Serum glucose and serum insulin remain significantly increased through the entire acute hospital stay. Insulin resistance appears during the first week postburn and persists for up to 3 years after injury.

Sepsis

Complications and/or physiologic derangements, such as sepsis, further increase resting energy expenditures and protein catabolism up to 40% compared with those with like-size burns that do not develop sepsis. The immediate and persistent changes in the innate and adaptive immune system postinjury make them more susceptible to sepsis, and thus at increased risk of further muscle and protein catabolism, propagating a vicious cycle. The emergence of multiresistant organisms has led to increases in sepsis-related infections and death overall. In combination, these responses lead to an increase in morbidity and mortality for victims of severe burn injury, compelling health care providers to secure therapeutic strategies to temper the often catastrophic response.

Early Excision and Grafting

The body’s response to severe burn injury is unlike any other disease state and far exceeds other catabolic, physiologic, and immunologic changes seen. One of the most innovative and constructive modifications of burn care was the institution of early excision and grafting of the burn eschar postburn injury. As a testament to the physiologic consequence of large burns, burns larger than 50% TBSA have a subsequent 40% decrease in metabolic rate if excised completely and grafted within 3 days of injury compared with those patients with like-size burns excised and grafted 7 days after injury. The process prevents further net muscle protein degradation and full-body catabolism. By waiting 3 weeks for full excision, patients had more than double the net muscle protein loss measured by stable isotope and 140% increase in log bacterial counts in quantitative tissue cultures. The incidence of sepsis in the “traditional” 3-week group was 2.5 times higher than the early excision and grafting group. The ramifications of this modification are enormous: it mitigates exorbitant resting energy expenditures and limits muscle protein catabolism improving morbidity and mortality.

Thermoregulation

Thermoregulation is the natural ability of the body to maintain core body temperature independent of environmental temperature and is mediated via metabolic activity and sweating. The ability to regulate core body temperatures is lost in severely burned patients. To complicate matters, there is an exhaustive loss of heat and fluid loss secondary to large burns. Metabolic rates are significantly increased in severe burns to compensate for this loss, nearly 4000 mL/m ² burn area per day. This response is propagated by increased ATP consumption and substrate oxidation. This action and response is analogous to cold acclimatization, and raises core and skin temperatures 2°C higher than normal compared with unburned patients. Patients that do not and cannot mount this response likely have sepsis and/or have exhausted physiologic capabilities to maintain needed body temperature. To mitigate fluid and heat losses and the metabolic response, by increasing ambient temperatures to 33°C (a thermal neutral temperature) the energy required for vaporization is derived from the environment rather than from the patient. This decreases resting energy expenditures, and muscle protein catabolism, and improves outcomes.

Nutrition

Another important modulator of the hypermetabolic response is early enteral feeding. If left with only oral alimentation, patients with severe burns lose 25% of their preadmission weight by 3 weeks postinjury. Nutritional replacement using 25 kcal/kg body weight in addition to 40 kcal per percent TBSA burn per day can maintain body weight in burned adults. In general, children require 1800 kcal/m ² plus 2200 kcal/m ² of burn area per day.

Enteral nutrition reduces bacterial translocation and sepsis. It maintains gut motility, and preserves first pass nutrient delivery to the liver. Parenteral nutrition alone or even in combination with enteral nutrition leads to liver failure, overfeeding, impaired immune response, and increased mortality. Parenteral nutrition should be reserved for those with prolonged ileus and or enteral feeding intolerance.

Analogous to resuscitative formulas, formulas used to predict total caloric requirements often provide about 40% more calories than actually needed. Actual caloric requirements are determined by measuring resting energy expenditures. Appropriate nutrient delivery is accomplished by feeding 1.4 times measured resting energy expenditures measured by indirect calorimetry using bedside carts. Feeding patients 1.2 times measured resting energy expenditures resulted in a loss of 10% of lean body mass, but maintained body weight. This increases risks for immune dysfunction. Feeding patients more than 1.4 times the resting energy expenditure there were gains in body weight but they were in fat deposition, not lean body mass. Specifically, by overfeeding carbohydrates in burn patients, there is increased fat synthesis, elevated respiratory quotients, and increased elimination of carbon dioxide. Management of ventilated patients becomes more arduous ; there is steatosis and hyperglycemia.

Burn patients have essential protein requirements 50% greater than healthy individuals in a fasting state : 1.5 to 2 g/kg body weight per day. The increased protein requirement is to maintain or even increase lean body mass. Higher supplementation of protein leads to increased urea production without improvements in lean body mass or muscle protein synthesis.

The nutritional needs of burn patients are extensive because of the insufficient glycogen stores, increased metabolic rates, and increased muscle protein catabolism. Research has led to dramatic improvements in net protein balance and metabolic rates. In general, diets high in fat demonstrated elevated protein degradation and poor lean body mass gains in comparison with high-carbohydrate diets, which did show the diet increased endogenous insulin production and improved lean body mass, and increased muscle protein synthesis. No studies have shown improvement in survival.

Exercise

The postburn hypermetabolic, hypercatabolic response persists long after the acute hospitalization. Early exicision and grafting, thermoregulation, and early enteral nutrition attenuate the response during the acute phase. Some patients have elevated metabolic rates and sustained muscle and protein catabolism up to 1 year after the original insult. Growth retardation lasts long into the rehabilitative phase. Burn survivors can often have significant functional limitations and deficits for years. Exercise training is an essential adjunct to any and all metabolic treatments. It increases endurance, strength, and lean body mass, and improves overall cardiopulmonary capacity. Resistance and aerobic exercise training programs profoundly improve power, muscle strength, and lean body mass.