madman
Super Moderator
Metabolic and Nutritional Support (2023)
Shahriar Shahrokhi, MD, FRCSC, Marc G. Jeschke, MD, PhD, FCCM, FRCS(C)
HYPERMETABOLIC RESPONSE
Hypermetabolism is a hallmark of larger burn injuries, that is, burns greater than 40% total body surface area (TBSA); but it can occur even in burns greater than 20% TBSA. The hypermetabolic response is characterized by marked and sustained increases in catecholamines, glucocorticoids, and glucagon.1 The hypermetabolic response postburn is mediated through a complex interaction of interleukins, tumor necrosis factor, platelet activation factor, reactive oxygen species, and nitric oxide along with other mediators.2
Initially after injury (during the first 48 hours), the patients experience an “ebb” phase that is characterized by:
*Decreased cardiac output
*Decreased oxygen consumption
*Decreased metabolic rate
*Impaired glucose tolerance
This is followed by a “flow” phase that is associated with a hyperdynamic circulation and hypermetabolism.3
The initial postburn period is marked by low cardiac output; however, in the ensuing 3 to 4 days, cardiac output increases to more than 1.5 times that of healthy volunteers
The heart rates of pediatric burn patients can increase further, approaching 1.6 times that of healthy volunteers.1 Postburn, patients have increased cardiac work, and myocardial oxygen consumption can surpass that of long-distance runners.
Hypermetabolism has been shown to profoundly alter and affect glucose, protein, and fat metabolism. Insulin release during this time period is doubled and plasma glucose levels are markedly elevated, indicating the development of hyperglycemic, hyperinsulinemic insulin resistance.4 These metabolic alterations are believed to resolve soon after complete wound closure. However, the hypermetabolic response to burn injury may last for more than 24 months after the initial event,5 and sustained hypermetabolic alterations postburn can persist for up to 3 to 5 years after the initial burn injury.5 For severely burned patients, the increases in catabolism result in loss of total body protein, which can in turn diminish immune defenses and decrease wound healing capacity.6
Postburn, the size of the liver can increase by 225% of normal by 2 weeks and remains enlarged by 200% of normal at the time of discharge.6
The elevation in catecholamines, cortisol, and glucagon postburn leads to increased production of free fatty acids, glucose, and amino acids. More significantly, the changes in the glycolysis and gluconeogenesis pathways result in hyperglycemia, and impaired insulin sensitivity. Even though the glucose delivery to peripheral tissue is increased, the inefficiency of anaerobic metabolism drives an increase in lactate production and a further increase in glucose production in the liver via the breakdown of lactate.1,5,6
Recently, adipose tissue was identified as a major contributor to hypermetabolism and catabolism. The adipose tissue undergoes a “browning response,” which is characterized by the release of energy, lipolysis, and massively increased beta-oxidation, all of which worsen the catabolic response.7
NUTRITIONAL SUPPORT
Postburn hypermetabolism, resulting in increased oxygen consumption, metabolic rate, urinary nitrogen excretion, lipolysis, and weight loss, directly correlates with increasing burn size. The increase can be 200% of normal. The energy requirements are met by mobilization of carbohydrate, fat, and protein stores leading to muscle mass loss and malnutrition. This malnutrition in burns is undone to some extent by the provision of nutritional support, to maintain and improve organ function. To determine the caloric requirements several formulas have been proposed:8
The Harris-Benedict formula:
*Men: 66.5 + 13.8(weight in kg) + 5(height in cm) - 6.76(age in years)
*Women: 655 + 9.6(weight in kg) + 1.85(height in cm) - 4.68(age in years)
*Can be adjusted for activity and stress factors.
*To meet the needs of a pediatric burn patient, will need 1.33 times the predicted basal energy expenditure for burns greater than 40% TBSA.
*To meet the needs of all the patients will need 1.4 times the measured resting energy expenditure.
The Curreri formula:
*Age 16 to 59: 25(weight in kg) + 40(TBSA)
*Age greater than 60: 20(weight in kg) + 65(TBSA)
*Often overestimates caloric needs. This formula provides for maintenance in addition to the caloric needs related to burn wounds.
*In pediatrics, formulas based on body surface area are more appropriate because of the greater body surface area per kilogram of weight.
The Toronto formula:
* - 4343 + 10.5(TBSA) + 0.23(calorie intake in last 24 h) +0.84(Harris-Benedict estimation without *adjustment) + 114(temperature) - 4.5(number of postburn days)
Must be adjusted with changes in monitoring but is useful in the acute phase.
OTHER NUTRIENTS
PHARMACOLOGIC MODALITIES TO ATTENUATE HYPERMETABOLISM
Adequate nutrition and other means, such as environmental temperature, early mobilization, and early excision can only attenuate hypermetabolism and catabolism but are by no means able to prevent or reverse lean body mass loss or profound protein loss. Therefore, in the search for improving outcomes in burn patients, various pharmacologic agents have been used to reduce the hypermetabolic response postburn.
Administration of recombinant human growth hormone (rhGH) (0.1–0.2 mg/kg/d intramuscularly) has been shown to have a host of beneficial effects:
*Increases donor site healing and quality of wound healing20
*Diminishes stress responses and inflammation27,28
*Elevates levels of insulin-like growth factor 1 (IGF-1)29
*Decreases basal energy expenditure and cardiac output30
*Augments muscle protein and preserves muscle growth31,32
However, a multicenter trial (in nonburn patients) revealed that morbidity and mortality of critically ill patients receiving rhGH were higher than in patients receiving a placebo.33 This was especially true for patients suffering from infections and sepsis because, in this patient group, GH profoundly increased multi-organ dysfunction syndrome (MODS) and mortality. Exogenous administration of growth hormone has also been linked to hyperglycemia and insulin resistance.34,35 In addition, rhGH was not found to benefit survival in pediatric patients with severe burns.36,37 The use of GH in burn patients is at this time not recommended.
Insulin-like Growth Factor
Given that IGF-1 is an effector of growth factor, administering IGF-1/binding protein-3 complex has been shown to ameliorate protein metabolism in burned children and adults with fewer episodes of hypoglycemia than rhGH.38
Some of the effects of IGF-1/binding protein-3 are38–41:
*Reduction in muscle protein breakdown
*Amelioration of gut mucosal integrity
*Improving immune function
*Attenuation of the acute-phase response
*Elevation of constitutive proteins in the serum and decrease in inflammatory response
However, other studies indicate that IGF-1 alone is ineffective in non burned critically ill patients. IGF-1 did show promise in terms of anabolism and reduction of the hypermetabolic response, but because of its side effects of hypoglycemia, electrolyte abnormalities, and neuro side effects the use of IGF-1 is currently not recommended.42,43
Oxandrolone
Oxandrolone is similar to testosterone but lacks its virilizing effects. Oxandrolone has been shown to stimulate muscle protein synthesis,44 reduce weight loss, and promote wound healing.45 Oxandrolone at a dose of 10 mg twice daily has also been shown to decrease hospital stay, morbidity, and mortality.46 When given at a dose of 0.1 mg/kg twice daily, oxandrolone decreases hospitalization, preserves lean body mass, and enhances protein synthesis in the liver.47 The dosing for older adults is 0.05 mg/kg twice a day. The long-term effects of oxandrolone are decreased hypermetabolism, and an increase in lean body mass and bone mineral content (increasing from 6 to 12 months postburn).48,49 Therefore, oxandrolone is recommended in burns to be given as an anabolic agent.
Testosterone
Testosterone has been shown to be anabolic in adult burn patients and older adults. The administration of testosterone should be considered when endogenous levels are profoundly depleted. The use in women should be restrictive and considered as a third-line/fourth-line treatment.
Propranolol
Propranolol, a b-adrenergic blocker, is an effective anticatabolic therapy postburn. Acutely, propranolol has an anti-inflammatory effect and can counter the loss of skeletal muscle, augment lean body mass, and decrease insulin resistance.50,51 If given at a dose to decrease heart rate by 15% to 20%, long-term propranolol treatment significantly reduces predicted resting energy expenditure, decreases the accumulation of central mass and central fat, prevents bone loss, and improves lean body mass accretion.50–52 Propranolol seems to be an effective agent to treat catecholamine-induced hypermetabolic stress response postburn. In pediatrics dosing is 1 to 4 mg/kg four times a day, and in adults 10 mg four times a day. Adverse events of propranolol are bradycardia, hypotension, and possibly hallucinations. Propranolol mainly acts as an anticatabolic agent and is considered in burn patients that suffer from a substantial inflammatory and hypermetabolic response.
Insulin
Thermally injured patients with hyperglycemia have a greater incidence of bacteremia/ fungemia, diminished wound healing capacity, more pronounced protein catabolism, and a lower likelihood of survival than burn patients with adequate glucose control.53,54 Insulin administration seems to promote muscle protein production, helps prevent lean body mass loss, diminishes the acute phase response, and enhances wound healing.55–61 Care must be taken to avoid hypoglycemia,62,63 because glucose variability and increased episodes of hypoglycemia tend to lead to greater morbidity and mortality. Hyperglycemia associated with insulin resistance is a clinically significant problem in burn patients and insulin administration while avoiding hypoglycemia improves morbidity and mortality.62–69
Metformin
Metformin, an oral hypoglycemic agent, has been suggested as a means to correct hyperglycemia in severely injured patients.70 Metformin inhibits gluconeogenesis and amplifies peripheral insulin sensitivity, thus countering the main metabolic processes, which leads to postburn hyperglycemia.70,71 Administration of metformin seems to increase muscle protein synthesis and improve net muscle protein balance.71 Additionally, metformin seems to have fewer associated hypoglycemic events, as compared with exogenous insulin administration.72–75 Metformin reduces plasma glucose concentration, decreases endogenous glucose production, and accelerates glucose clearance in the severely burned.72–75 Dosing should be 500 mg twice a day to 1000 mg three times a day. Metformin should only be given if the glomerular filtration rate is greater than 30 mL/kg.
SUMMARY
Nutrition and metabolic treatment and supplementation are essential for burn patients and have a direct effect on burn outcomes. Early and adequate nutrition is key. Other major interventions that affect metabolism include warm patient rooms and operating rooms, early mobilization and exercise, and early excision and grafting. In terms of adjunctive therapies, we recommend the use of oxandrolone, insulin, metformin, and propranolol, the latter under intensive care unit monitoring. If no adverse effects occur, anabolic agents should be administered, at minimum, for the duration of hospitalization. There is also good evidence for long-term treatment, up to 2 to 3 years postburn, for propranolol and oxandrolone.76
Shahriar Shahrokhi, MD, FRCSC, Marc G. Jeschke, MD, PhD, FCCM, FRCS(C)
HYPERMETABOLIC RESPONSE
Hypermetabolism is a hallmark of larger burn injuries, that is, burns greater than 40% total body surface area (TBSA); but it can occur even in burns greater than 20% TBSA. The hypermetabolic response is characterized by marked and sustained increases in catecholamines, glucocorticoids, and glucagon.1 The hypermetabolic response postburn is mediated through a complex interaction of interleukins, tumor necrosis factor, platelet activation factor, reactive oxygen species, and nitric oxide along with other mediators.2
Initially after injury (during the first 48 hours), the patients experience an “ebb” phase that is characterized by:
*Decreased cardiac output
*Decreased oxygen consumption
*Decreased metabolic rate
*Impaired glucose tolerance
This is followed by a “flow” phase that is associated with a hyperdynamic circulation and hypermetabolism.3
The initial postburn period is marked by low cardiac output; however, in the ensuing 3 to 4 days, cardiac output increases to more than 1.5 times that of healthy volunteers
The heart rates of pediatric burn patients can increase further, approaching 1.6 times that of healthy volunteers.1 Postburn, patients have increased cardiac work, and myocardial oxygen consumption can surpass that of long-distance runners.
Hypermetabolism has been shown to profoundly alter and affect glucose, protein, and fat metabolism. Insulin release during this time period is doubled and plasma glucose levels are markedly elevated, indicating the development of hyperglycemic, hyperinsulinemic insulin resistance.4 These metabolic alterations are believed to resolve soon after complete wound closure. However, the hypermetabolic response to burn injury may last for more than 24 months after the initial event,5 and sustained hypermetabolic alterations postburn can persist for up to 3 to 5 years after the initial burn injury.5 For severely burned patients, the increases in catabolism result in loss of total body protein, which can in turn diminish immune defenses and decrease wound healing capacity.6
Postburn, the size of the liver can increase by 225% of normal by 2 weeks and remains enlarged by 200% of normal at the time of discharge.6
The elevation in catecholamines, cortisol, and glucagon postburn leads to increased production of free fatty acids, glucose, and amino acids. More significantly, the changes in the glycolysis and gluconeogenesis pathways result in hyperglycemia, and impaired insulin sensitivity. Even though the glucose delivery to peripheral tissue is increased, the inefficiency of anaerobic metabolism drives an increase in lactate production and a further increase in glucose production in the liver via the breakdown of lactate.1,5,6
Recently, adipose tissue was identified as a major contributor to hypermetabolism and catabolism. The adipose tissue undergoes a “browning response,” which is characterized by the release of energy, lipolysis, and massively increased beta-oxidation, all of which worsen the catabolic response.7
NUTRITIONAL SUPPORT
Postburn hypermetabolism, resulting in increased oxygen consumption, metabolic rate, urinary nitrogen excretion, lipolysis, and weight loss, directly correlates with increasing burn size. The increase can be 200% of normal. The energy requirements are met by mobilization of carbohydrate, fat, and protein stores leading to muscle mass loss and malnutrition. This malnutrition in burns is undone to some extent by the provision of nutritional support, to maintain and improve organ function. To determine the caloric requirements several formulas have been proposed:8
The Harris-Benedict formula:
*Men: 66.5 + 13.8(weight in kg) + 5(height in cm) - 6.76(age in years)
*Women: 655 + 9.6(weight in kg) + 1.85(height in cm) - 4.68(age in years)
*Can be adjusted for activity and stress factors.
*To meet the needs of a pediatric burn patient, will need 1.33 times the predicted basal energy expenditure for burns greater than 40% TBSA.
*To meet the needs of all the patients will need 1.4 times the measured resting energy expenditure.
The Curreri formula:
*Age 16 to 59: 25(weight in kg) + 40(TBSA)
*Age greater than 60: 20(weight in kg) + 65(TBSA)
*Often overestimates caloric needs. This formula provides for maintenance in addition to the caloric needs related to burn wounds.
*In pediatrics, formulas based on body surface area are more appropriate because of the greater body surface area per kilogram of weight.
The Toronto formula:
* - 4343 + 10.5(TBSA) + 0.23(calorie intake in last 24 h) +0.84(Harris-Benedict estimation without *adjustment) + 114(temperature) - 4.5(number of postburn days)
Must be adjusted with changes in monitoring but is useful in the acute phase.
OTHER NUTRIENTS
PHARMACOLOGIC MODALITIES TO ATTENUATE HYPERMETABOLISM
Adequate nutrition and other means, such as environmental temperature, early mobilization, and early excision can only attenuate hypermetabolism and catabolism but are by no means able to prevent or reverse lean body mass loss or profound protein loss. Therefore, in the search for improving outcomes in burn patients, various pharmacologic agents have been used to reduce the hypermetabolic response postburn.
Administration of recombinant human growth hormone (rhGH) (0.1–0.2 mg/kg/d intramuscularly) has been shown to have a host of beneficial effects:
*Increases donor site healing and quality of wound healing20
*Diminishes stress responses and inflammation27,28
*Elevates levels of insulin-like growth factor 1 (IGF-1)29
*Decreases basal energy expenditure and cardiac output30
*Augments muscle protein and preserves muscle growth31,32
However, a multicenter trial (in nonburn patients) revealed that morbidity and mortality of critically ill patients receiving rhGH were higher than in patients receiving a placebo.33 This was especially true for patients suffering from infections and sepsis because, in this patient group, GH profoundly increased multi-organ dysfunction syndrome (MODS) and mortality. Exogenous administration of growth hormone has also been linked to hyperglycemia and insulin resistance.34,35 In addition, rhGH was not found to benefit survival in pediatric patients with severe burns.36,37 The use of GH in burn patients is at this time not recommended.
Insulin-like Growth Factor
Given that IGF-1 is an effector of growth factor, administering IGF-1/binding protein-3 complex has been shown to ameliorate protein metabolism in burned children and adults with fewer episodes of hypoglycemia than rhGH.38
Some of the effects of IGF-1/binding protein-3 are38–41:
*Reduction in muscle protein breakdown
*Amelioration of gut mucosal integrity
*Improving immune function
*Attenuation of the acute-phase response
*Elevation of constitutive proteins in the serum and decrease in inflammatory response
However, other studies indicate that IGF-1 alone is ineffective in non burned critically ill patients. IGF-1 did show promise in terms of anabolism and reduction of the hypermetabolic response, but because of its side effects of hypoglycemia, electrolyte abnormalities, and neuro side effects the use of IGF-1 is currently not recommended.42,43
Oxandrolone
Oxandrolone is similar to testosterone but lacks its virilizing effects. Oxandrolone has been shown to stimulate muscle protein synthesis,44 reduce weight loss, and promote wound healing.45 Oxandrolone at a dose of 10 mg twice daily has also been shown to decrease hospital stay, morbidity, and mortality.46 When given at a dose of 0.1 mg/kg twice daily, oxandrolone decreases hospitalization, preserves lean body mass, and enhances protein synthesis in the liver.47 The dosing for older adults is 0.05 mg/kg twice a day. The long-term effects of oxandrolone are decreased hypermetabolism, and an increase in lean body mass and bone mineral content (increasing from 6 to 12 months postburn).48,49 Therefore, oxandrolone is recommended in burns to be given as an anabolic agent.
Testosterone
Testosterone has been shown to be anabolic in adult burn patients and older adults. The administration of testosterone should be considered when endogenous levels are profoundly depleted. The use in women should be restrictive and considered as a third-line/fourth-line treatment.
Propranolol
Propranolol, a b-adrenergic blocker, is an effective anticatabolic therapy postburn. Acutely, propranolol has an anti-inflammatory effect and can counter the loss of skeletal muscle, augment lean body mass, and decrease insulin resistance.50,51 If given at a dose to decrease heart rate by 15% to 20%, long-term propranolol treatment significantly reduces predicted resting energy expenditure, decreases the accumulation of central mass and central fat, prevents bone loss, and improves lean body mass accretion.50–52 Propranolol seems to be an effective agent to treat catecholamine-induced hypermetabolic stress response postburn. In pediatrics dosing is 1 to 4 mg/kg four times a day, and in adults 10 mg four times a day. Adverse events of propranolol are bradycardia, hypotension, and possibly hallucinations. Propranolol mainly acts as an anticatabolic agent and is considered in burn patients that suffer from a substantial inflammatory and hypermetabolic response.
Insulin
Thermally injured patients with hyperglycemia have a greater incidence of bacteremia/ fungemia, diminished wound healing capacity, more pronounced protein catabolism, and a lower likelihood of survival than burn patients with adequate glucose control.53,54 Insulin administration seems to promote muscle protein production, helps prevent lean body mass loss, diminishes the acute phase response, and enhances wound healing.55–61 Care must be taken to avoid hypoglycemia,62,63 because glucose variability and increased episodes of hypoglycemia tend to lead to greater morbidity and mortality. Hyperglycemia associated with insulin resistance is a clinically significant problem in burn patients and insulin administration while avoiding hypoglycemia improves morbidity and mortality.62–69
Metformin
Metformin, an oral hypoglycemic agent, has been suggested as a means to correct hyperglycemia in severely injured patients.70 Metformin inhibits gluconeogenesis and amplifies peripheral insulin sensitivity, thus countering the main metabolic processes, which leads to postburn hyperglycemia.70,71 Administration of metformin seems to increase muscle protein synthesis and improve net muscle protein balance.71 Additionally, metformin seems to have fewer associated hypoglycemic events, as compared with exogenous insulin administration.72–75 Metformin reduces plasma glucose concentration, decreases endogenous glucose production, and accelerates glucose clearance in the severely burned.72–75 Dosing should be 500 mg twice a day to 1000 mg three times a day. Metformin should only be given if the glomerular filtration rate is greater than 30 mL/kg.
SUMMARY
Nutrition and metabolic treatment and supplementation are essential for burn patients and have a direct effect on burn outcomes. Early and adequate nutrition is key. Other major interventions that affect metabolism include warm patient rooms and operating rooms, early mobilization and exercise, and early excision and grafting. In terms of adjunctive therapies, we recommend the use of oxandrolone, insulin, metformin, and propranolol, the latter under intensive care unit monitoring. If no adverse effects occur, anabolic agents should be administered, at minimum, for the duration of hospitalization. There is also good evidence for long-term treatment, up to 2 to 3 years postburn, for propranolol and oxandrolone.76
