Update on Hypermetabolism in Pediatric Burn Patients

Abstract

Despite advancements in pediatric burn care, the profound hypermetabolic response associated with severe burns remains a multifaceted challenge throughout the continuum of care. Understanding the various physiologic disturbances that constitute hypermetabolism is crucial for a thorough evaluation and for implementing appropriate surgical and nonsurgical interventions. In this article, we describe the pathophysiology and treatment of hypermetabolism in pediatric burn patients with a focus on reducing resting energy requirements, minimizing infection, and optimizing nutrition for patients undergoing frequent surgical intervention.

Thermal injuries in children present unique challenges, from the initial burn evaluation to surgical reconstruction and medical management. Epidemiologic studies consistently reveal a high incidence of pediatric burns, with unintentional burn injury representing the third leading cause of death between 1995 and 2003 among U.S. children aged 5 to 9 years. ¹ More recent data from 2018 highlight the curiosity and vulnerability of 0- to 4-year-olds, an age group with the highest risk of burn injury and a significant mortality rate of 0.71 per 100,000 U.S. deaths. ²

While experienced high-volume burn centers have reduced patient mortality in developed countries, standardized management protocols addressing the complexities of burn hypermetabolism have yet to be established. ^{2 3} In short, thermal injuries induce systemic inflammation and a robust stress response as a means of normal wound healing. These resource-intensive mechanisms demand increased metabolism, protein breakdown, and cardiocirculatory dynamism, often at the expense of multi-organ dysfunction and immune system dysregulation. ^{4 5} Hypermetabolism can present as early as 12 hours from insult and persist for up to 1 to 2 years, contributing significantly to patient morbidity and health care utilization. ^{6 7 8 9} This article delves into the proposed mechanisms, observed consequences, and current interventions related to hypermetabolism in pediatric burn patients.

Mechanisms of Hypermetabolism

The mechanisms underlying hypermetabolism are complex and not yet fully understood; however, decades of research have yielded consistent laboratory findings to guide our understanding.

Metabolic changes following large burns are often characterized by “ebb” and “flow” phases in the days following the initial injury. The “ebb” phase typically occurs within the first 48 hours and is denoted by a hypometabolic response resulting in decreased cardiac output and lower oxygen consumption. ^{10 11} The subsequent 3 to 5 days mark the onset of the “flow phase,” during which the metabolic response gradually intensifies into a state of hypermetabolism. This phase is characterized by a rapid and sustained increase in inflammatory cytokines that stimulate the release of catecholamines and cortisol, leading to detrimental energy utilization patterns. ¹² Clinically, hypermetabolism can be observed through indicators such as elevated heart rate, cardiac output, and myocardial oxygen consumption following severe thermal injury. ¹⁰

The immune response that precipitates hypermetabolism begins immediately upon injury. ¹⁰ Burnt tissue releases histamine, free radicals, and inflammatory cytokines, promoting vasodilation and the recruitment of monocytes and macrophages. ¹³ Once these immune cells extravasate into the injured area, they phagocytose dead cells and release proinflammatory substances like tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), along with growth factors such as fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor. These substances promote the inflammatory and cell proliferation phases of wound healing. ²

Neutrophils are attracted to the site to combat infection, but they face impairments in their immune function due to the release of lipid–protein complexes from burned skin and the inflammatory environment. ^{2 14} Nonetheless, neutrophils continue to contribute to systemic inflammation by perpetuating the release of TNF-α, IL-1β, and IL-6. ²

Genetics

Immediately following a thermal injury, there is a sharp increase in proinflammatory cytokines; these elevated levels can persist for 3 to 6 months. ¹⁵ The extent of this cytokine response is directly related to the size and depth of the initial injury, affecting both the magnitude and duration of cytokine increases. ^{8 12 16 17}

Research using rat models suggests that genetic differences play a significant role in how individuals produce acute phase proteins, inflammatory cytokines, and signal-cascade mediators in response to thermal injury. ¹⁸ This genetic diversity may help explain why, when controlling for burn size, some children exhibit a much stronger immune response. Notably, there have been 10,000-fold differences observed in serum cytokine levels between surviving and non-surviving pediatric burn patients. ¹⁹

The continued circulation of such supraphysiologic proinflammatory cytokines contributes to the subsequent development of the stress response, which is the next step toward hypermetabolism.

Stress Response

It is well established that following thermal injury, the primary mediators of hypermetabolism are the significant increases in catecholamines (10–50-fold) and cortisol (5–8-fold), which can be detected in serum and urine for up to 9 months postburn. ^{12 20} This increase is particularly pronounced in boys and cases of severe thermal injuries, defined as burns covering more than 40% of total body surface area (TBSA). ²¹

Similar to cytokine levels, the concentrations of catecholamines were higher in patients who did not survive their burns, and there is a positive relationship between the extent of the initial burn injury and the quantity of measured catecholamines. ^{16 20 21} Clinically, the relationship between catecholamines and hypermetabolism is supported, as the use of propranolol in pediatric patients has been shown to decrease resting energy expenditure (REE), protein catabolism, supraphysiologic thermogenesis, and central mass accretion. ²²

Changes in energy mobilization are best understood in the context of elevated levels of circulating catecholamines and cortisol, both potent stimulators of glucagon and gluconeogenic hormone release. This phenomenon is also observed in hyper-catecholaminergic syndromes such as pheochromocytoma. ²³

This hormonal surge encourages glycogen breakdown and gluconeogenesis, primarily in the liver, leading to hyperglycemia and insulin resistance during the first week following a burn. ¹² These increased glucose levels support the energy needs of proliferating endothelial cells, fibroblasts, and inflammatory cells, which primarily rely on fast but inefficient anaerobic glucose oxidation.

Additionally, the liver converts the by-product lactate into glucose through gluconeogenesis. ¹² Despite the increased supply of glucose, there is a global breakdown of protein and adipose tissue to mobilize structural energy. This leads to an increase in the circulation of amino acids, fatty acids, and triglycerides (TGs), facilitating alternative gluconeogenic pathways. ¹² As a consequence, there is a decrease in lean body mass, as the rate of protein generation is greatly outweighed by its catabolism. ¹²

One significant contributor to protein losses may be the disruption in the hormonal environment, especially the role of growth hormone (GH) which primarily regulates protein synthesis during periods of stress and fasting. ²⁴ Following a burn injury, there is a complex interplay of hormones that leads to decreased serum levels of GH, insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), parathyroid hormone (PTH), and osteocalcin; these decreased levels can persist for up to 2 months following the injury, and the severity of hormonal disruption depends on the extent of the initial burn injury. ¹²

The importance of GH in protein loss has been demonstrated clinically with the supplementation of recombinant human GH (rhGH) in burn patients. This treatment reduces the hypermetabolic response, stimulates protein synthesis, and improves outcomes. ¹⁵ However, it is worth noting that rhGH has been associated with increased mortality rates in adult patients with prolonged critical illness after cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. ²⁵

Of equal or greater significance is the role of IGF-1, which is stimulated by GH, and may be a better medication to attenuate the postburn response. ¹⁵ The decrease in serum levels of IGF-1 and IGFBP-3 is more pronounced than the decrease in GH levels. Additionally, while IGF-1 and IGFBP-3 decrease immediately and remain low, GH levels only significantly decrease after 8 to 10 days of hospitalization and continue to decrease slowly throughout hospitalization. ¹⁵ The clinical importance of this hormonal interplay has been demonstrated by improvements in protein synthesis and immune function in animals and patients receiving IGF-1 and IGFB-3. ¹⁵

While not as severe as other physiologic changes, significant alterations can be observed in the serum levels of thyroxine (T4) and the free thyroxine index in children after major burn. ¹⁵ As mentioned earlier, PTH and osteocalcin experience an immediate decrease and maintain reduced levels over the long term. Interestingly, in children and adolescents, IL-1β and IL-6 reduce the sensitivity of the parathyroid glands to changes in serum calcium. ⁴ This leads to significant hypercalciuria, resulting in hypocalcemic hyperphosphatemic hypoparathyroidism, which leads to generalized bone resorption and decreases bone marrow concentration and mineral density in burned children. ^{4 26} The released calcium further prolongs and intensifies systemic inflammation. ⁴

Phosphate and magnesium can enhance immune function and increase the need for adenosine triphosphate (ATP) in skeletal muscle. ⁴ As bone resorption occurs, transforming growth factor-beta (TGF-β) is released, draining nearby skeletal muscle of calcium and worsening muscle protein loss. ⁴ As muscle breaks down, amino acids are consumed via gluconeogenesis, and nitrogenous by-products are excreted in the urine, leaving the body depleted of materials required to build new skeletal muscle. ⁴

Overall, these mechanisms create a systemic environment with significantly elevated serum glucose levels, which persist for 4 to 5 weeks after a burn and lead to increased circulating insulin in children. ⁴ Nevertheless, multiple studies suggest that, despite elevated insulin levels, glucose production in the liver and protein catabolism do not decrease, indicating acquired insulin resistance in the liver and skeletal muscle. ^{4 27}

As with several other physiologic disruptions, glucose levels may remain elevated for up to 6 months postburn. ²⁸ Increased insulin levels have been observed 3 years after the initial injury, despite normal pancreatic β-cell activity in pediatric burns. ²⁸ Therefore, the stress-induced changes in the hormonal and metabolic environment are thought to contribute to and sustain insulin resistance well beyond the acute phase of injury. ²⁸

Changes in Resting Energy Expenditure

Persistent sympathoadrenal activation alters the storage and utilization of energy, favoring systemic catabolism to fuel an inflammatory response. ⁵ Using the Harris–Benedict equation for basal metabolic rate, the percent predicted REE increases immediately following a burn. For severe burns involving TBSA ≥ 40%, this value can peak at 180 to 200% of normal. Metabolism remains increased at 110 to 120% up to 6 months after wound closure and up to 1 to 2 years following the initial injury. ^{9 15}

This hypermetabolic response to burns has been observed across many mammalian species and was initially thought to be an evolutionary advantage, facilitating wound healing and immune defenses. ²⁹

Consequences of Hypermetabolism

Over the past four decades, there have been notable improvements in burn patient outcomes. These advancements are primarily attributed to the establishment of dedicated burn centers and the development of more effective treatment algorithms, which include faster and more effective wound coverage, enhanced infection control, improved management of inhalation injuries, and more effective support for the body's hypermetabolic response. ^{30 31} Despite these improvements, severe burns are still associated with significant morbidity and mortality, often secondary to multiple organ dysfunction, septic shock, or hypermetabolic crisis. ^{31 32}

Systemic Effects

The hypermetabolic response to trauma, surgery, or critical illness is characterized by increased lipid and protein catabolism, peripheral insulin resistance, and an elevation in both blood pressure and heart rate. These changes result in higher REE, elevated body temperature, reduced lean body mass, and acute phase reactant synthesis. ^{9 33 34 35 36 37 38} The magnitude of this response varies according to age, comorbidity, and extent of trauma but is generally severe in burn patients.

One of the most profound systemic effects of the hypermetabolic response results from increased protein catabolism, in which amino acids from skeletal muscle provide a significant fuel source for the healing burn patient. Within days of injury, there is marked muscle wasting and subsequent loss of lean body mass, with minimal compensatory protein synthesis. ³⁹

This protein breakdown intensifies between 2 and 4 weeks postburn, resulting in a negative total-body nitrogen balance. ³⁹ If the rate of protein catabolism is too great or prolonged, clinical consequences can be severe. The proportion of weight loss while in a catabolic state strongly correlates with morbidity and mortality; a 10 to 15% reduction in lean body mass is associated with a significantly increased risk of infection, a 20 to 30% reduction can result in severe weakness and absent wound healing, and a 40% reduction carries a greater than 90% risk of mortality. ⁴⁰ These clinical consequences are particularly concerning in the pediatric population as severe burn patients can lose up to 25% of their total body mass. ⁴¹

Previous assumptions based on general surgical principles held that the protein metabolic response would dissipate with complete wound healing. ⁹ However, a prospective longitudinal study conducted by Hart et al demonstrated an exaggerated catabolic and hypermetabolic response in severely burned children lasting at least 9 months following injury. ⁹ Even beyond the period of acute hypermetabolism, linear growth delays have been observed in the pediatric population for up to 2 years after a burn injury. ⁴²

Multiple Organ Dysfunction

Prior to the introduction of early metabolic intervention, the leading cause of death in severe burn patients was anoxic brain injury. ³² Presently, the primary cause of death in such patients is sepsis, followed by respiratory failure, brain death, and shock. ³² Multi-organ dysfunction can present after a burn injury, often related to sepsis due to massive energy requirements and subsequent protein degradation. ⁴³ In the acute “ebb phase,” patients may also exhibit early signs of hypovolemic shock, such as decreased cardiac output and reduced contractility, due to compromised essential organs and cellular membrane transport. ^{15 44}

Effects on the Liver

The liver plays a central role in the hypermetabolic stress response following thermal injury, orchestrating a profound increase in endogenous glucose production through glycogenolysis, gluconeogenesis, lipolysis, and proteolysis. The initial period of stress is triggered by the proinflammatory response involving hormones, cytokines, and acute-phase proteins.

As acute-phase proteins such as C-reactive protein and haptoglobin are up-regulated to promote this response, there is an associated reduction in constitutive hepatic proteins, including albumin, prealbumin, transthyretin, transferrin, and retinol-binding protein. ^{15 45 46 47 48} Notably, albumin and transferrin levels can decrease by 50 to 70% compared to normal levels due to the shift in hepatic protein synthesis, as well as protein loss into the extravascular space through capillary leakage. ^{49 50 51 52} Similar to the persistence of muscle catabolism beyond complete wound healing as demonstrated by Hart et al, several studies have found that constitutive hepatic proteins remain low for up to 6 months after burn injury despite adequate nutrition. ^{9 15 46 47} This reduction may have adverse clinical consequences, as albumin and transferrin are essential transport proteins involved in regulating osmotic homeostasis and plasma pH. ^{49 50 51 52}

In addition to a shift in hepatic protein synthesis, the acute-phase response after thermal injury involves a dramatic increase in serum TG and free fatty acids. Consequently, there is an imbalance of TG compared to very low density lipoproteins, leading to massive fat mobilization into the liver and other major organs. ⁴⁵ These changes in fat distribution are further impacted by fatty liver changes due to protein–calorie imbalance, resulting from limited hepatic synthesis of lipoproteins. ^{45 53}

In severely burned pediatric patients, hepatic fat accumulation can lead to a greater than twofold increase in liver size. ^{47 54} This has profound clinical implications, as demonstrated in a 2001 study by Barret et al, in which autopsies of pediatric burn patients revealed hepatomegaly and fatty infiltration to be significantly associated with sepsis and death, noting increased hepatic failure, bacterial translocation, and endotoxemia. ⁵⁴

Liver damage from thermal injury also occurs due to edema, limited perfusion, proinflammatory cytokines, or other apoptotic signals. ⁴⁵ Serum levels of hepatic enzymes can increase by 50 to 200% compared to their baseline levels, with serum aspartate aminotransferase and alanine aminotransferase peaking on the first day after injury, and alkaline phosphatase on the second day postburn. ^{15 47} These enzymes ultimately return to their baseline during the acute hospitalization phase as the liver regenerates. It is important to note, however, that hepatic enzymes can be elevated for many reasons, especially in a growing child undergoing bone remodeling.

Effects on the Heart

Immediately following burn injury, there is an initial decrease in cardiac output due to impaired venous return and hypovolemia. ⁵⁵ This is soon followed by a postburn hypermetabolic response driven, in part, by elevated catecholamines, which induce protective stress to meet metabolic demands and support survival. ⁵⁶ During this phase, there is elevated myocardial oxygen consumption, myocardial hypoxia, and tachycardia, resulting in a hyperdynamic cardiovascular state. ^{57 58} Prolonged exposure to elevated catecholamine levels, which triggers sustained cardiac stress and increased REE, can lead to significant cardiac morbidity and mortality. ^{57 59 60}

In a 2011 retrospective review of burn survivors with over 40% TBSA affected, children experienced prolonged pathological elevations in average heart rate, cardiac output, and cardiac index for at least 2 years postburn. ⁵⁷ This was accompanied by an increase in rate pressure product, indicative of reduced cardiac efficiency over the same period. Although ejection fraction initially rose, it returned to baseline within 2 weeks after injury. ⁵⁹ Although the normalized ejection fraction indicates preserved cardiac function, it remains uncertain whether a prolonged elevation in cardiac workload leads to eventual cardiac failure in these patients.

A hyperdynamic cardiovascular state persists for over 2 years postburn. However, this response is less pronounced than the sympathetic response to significantly elevated catecholamine levels in healthy patients. ²⁰ Williams et al suggest that this could be due to dysregulation of beta-adrenergic receptors or physiologic autonomic nervous system changes resulting from trauma. ^{57 61} High catecholamine levels with reduced physiologic responses have been observed in patients with chronic cardiac failure and decreased cardiac reserve. ⁶² Despite the lack of evidence supporting chronic cardiac failure in pediatric burn patients, there is clear data to indicate persistent cardiac stress that may lead to future cardiovascular complications.

Effects on the Musculoskeletal System

As previously discussed, one of the most prominent effects of hypermetabolism in pediatric burn patients is the rapid loss of lean body mass. ³⁹ Due to the absence of appropriate protein synthesis, patients experience significant muscle atrophy, which often persists for several months despite complete wound healing. ⁹ This chronic loss of lean body mass ultimately impacts the musculoskeletal system by reducing strength and functional capacity.

In addition to muscle wasting, hypermetabolism also affects bone health in pediatric burn patients, as increased energy expenditure and metabolic demands strain the body's calcium homeostasis and skeletal integrity. ⁴ Severe burns generally affect the bone in two distinct phases: acute resorption in the first 2 weeks after injury, followed by an adynamic state with low bone turnover. ^{63 64} During the acute phase, bone resorption plays a dual role, liberating calcium to sustain the heightened inflammatory response and mobilizing phosphate and magnesium to meet the increased demands for ATP, especially in skeletal muscle. ^{4 64} This is further compounded by the release of muscle catabolic factors such as TGF-β from the bone matrix, which continues to promote muscle wasting. ^{4 65 66} These interactions produce a challenging scenario for pediatric burn patients, wherein the inflammatory response and muscle catabolism are intertwined with bone health ( Fig. 1 ). ⁴ As a result, patients have reduced bone mineral density, increasing the risk of fracture and long-term skeletal complications. This is of particular concern for pediatric patients who have not yet reached skeletal maturity.

Fig. 1.

A visual representation illustrating the complex interplay among muscle catabolism, bone resorption, and the heightened metabolic demands necessary to sustain the hypermetabolic response following a burn injury. Reproduced from Klein GL, The role of the musculoskeletal system in post-burn hypermetabolism. 2019 Metabolism;97:81–86, Copyright (2019), with permission from Elsevier . ⁴

A 1995 cross-sectional study was among the first to identify persistent osteopenia in children following burn injuries, suggesting a potential increase in the risk of early osteoporosis due to burn-induced bone loss. ⁶⁷ Subsequent studies have reinforced these findings, demonstrating reduced bone mineral content and bone mineral density for weeks after discharge. ^{68 69 70} This effect is even more pronounced for bone mineral content, which can remain significantly decreased for up to 3.5 years after injury compared to non-burned peers. ^{6 68 71}

The continuous loss of bone density in burn patients is a consequence of increased bone resorption and reduced bone formation, likely influenced by immobilization and the postburn inflammatory response. It is worth noting that even in nonburned pediatric patients, prolonged bed rest can lead to the loss of up to 10% of bone mass. ^{72 73} As such, it becomes challenging to precisely quantify the extent of bone loss directly attributable to the hypermetabolic response, given the requirement of immobilization after severe burn injuries.

Modulation of Hypermetabolism

Therapeutic strategies aim to mitigate the hypermetabolic response and its associated catabolic state by modifying the physiological and biochemical environment. Various strategies are utilized to achieve this goal, broadly categorized into nonpharmacologic and pharmacologic modalities. Nonpharmacologic therapies include early excision and grafting, nutritional support, optimizing the patient's environment, and promoting physical activity. Pharmacologic modalities used to temper the hypermetabolic response include analgesics, anabolic hormones, catecholamine antagonists, and rhGH. While the potential impact of antidiabetic agents on the regulation of postburn metabolism is currently under investigation, their definitive role remains uncertain. ³⁰

Environmental

Thermoregulation refers to the body's ability to maintain its core temperature regardless of environmental conditions. An intact thermoregulatory system relies on cutaneous vasodilation, sweating, and various metabolic processes to dissipate heat. ⁷⁴ Severely burned patients lose the capacity to regulate core body temperature, increasing their risk of complications. The hypermetabolic response following burn injury attempts to compensate for the significant water and heat loss experienced by these patients, with water loss reaching approximately 4,000 milliliters per square meter of burn area per day. ^{75 76 77 78} To address this heat loss, the body increases its metabolic rate through greater consumption of ATP and substrate oxidation, resulting in a 2°C increase in both core and surface temperatures compared to the normal range observed in nonburn patients. ⁷⁹

Optimizing the environment is a simple intervention that can counteract this response and have a profound impact on survival in pediatric patients with severe burn injuries. Maintaining the ambient temperature of operating rooms and patient rooms between 28°C and 33°C (82.4°F and 91.4°F, respectively) utilizes energy from the environment for vaporization rather than the patient's metabolic processes, reducing metabolic rates, lowering protein and muscle catabolism, and decreasing REEs.

Surgery

For severely burned patients, early escharectomy and skin grafting are arguably the most important interventions to attenuate hypermetabolism. In a 2000 retrospective review of 123 pediatric burn patients, time from initial injury to excision and grafting was strongly predictive of the metabolic response; those with burns encompassing greater than 50% TBSA had a 40% reduction in metabolic rate when excision and grafting were performed within 3 days, compared to patients with similarly sized burns who underwent excision and grafting 7 days after injury. ⁸⁰ A subsequent study by Hart et al revealed similar findings, with decreased net protein loss in pediatric patients who underwent debridement within 72 hours of injury compared to 10 to 21 days postburn. ⁸¹ Additionally, pediatric burn patients with early escharectomy had lower bacterial counts on tissue culture and a decreased incidence of sepsis compared to late excision and grafting. ⁸¹ Complete wound debridement should, therefore, occur as early as possible. It is important to note, however, that partial burn excision does not sufficiently reduce the postburn hypermetabolic state, even if performed early. ⁸²

Split-thickness skin grafts continue to be the gold standard for early and total wound coverage, with two types of autografts used for permanent closure: sheet skin grafts and meshed skin grafts. ⁸³ Sheet skin grafts are typically reserved for the most visible parts of the body (i.e., the face, neck, and hands) to minimize scarring. ⁸³ Disadvantages of sheet skin grafts include a large donor site and a higher incidence of hematoma.

For more extensive burns, with proportionately smaller available donor sites, split-thickness skin grafts can be meshed using various expansion ratios to provide adequate coverage. This technique offers additional advantages, such as improved wound drainage and reduced graft loss from hematoma. However, it is worth noting that using larger expansion ratios may lead to a higher incidence of hypertrophic scarring. ⁸³

If donor sites are insufficient for complete wound coverage, or if the patient's condition is unstable for autografting, biological dressings such as allografts, xenografts, or skin substitutes can be utilized. Allografts from cadaveric donors are the preferred material; however, various skin substitutes are also regularly used for wound coverage. ^{84 85} Skin substitutes provide better elasticity and texture than split-thickness skin grafts alone. Nevertheless, they are significantly more expensive and more susceptible to infection and still require skin grafting once the skin substitutes take.

Nutrition

Aggressive nutrition plays a critical role in reducing morbidity and mortality following severe burns. For pediatric patients, adequate nutritional support is especially crucial due to limited energy reserves and the substantial amount of energy devoted to growth at baseline. Furthermore, patients with severe burns typically require several procedures under anesthesia, which require standard perioperative fasting periods. As a result, these patients undergo numerous nutritional disruptions in the context of an already elevated metabolic demand. ⁸⁶

In addition to the required perioperative fasting periods that preclude consistent nutrition by mouth, oral alimentation may be inadequate in burn patients due to the prevalence of inhalation injuries, gastrointestinal dysfunction, feeding intolerance, and endotracheal intubation. ⁸⁷ Furthermore, the volume of oral feedings required to counter the effects of extreme hypermetabolism is often unsustainable. Even in the absence of significant complications, patients with severe burn injuries may lose up to a quarter of their preadmission weight within 3 weeks of hospitalization using an oral feeding route alone. ⁸⁷

Enteral nutrition is preferred over parenteral nutrition as it offers early, cost-effective intervention, stimulates blood flow, maintains gut function, and preserves first-pass nutrition to the liver. ⁸⁸ Furthermore, enteral nutrition reduces the incidence of infection, including translocation-bacteremia, sepsis, pneumonia, and central-line infections. ^{89 90}

Another vital factor to consider regarding nutritional support for severe burn patients is time to treatment. As discussed with burn excision and thermoregulation, a significant determinant of outcome is early intervention; the current recommendation for nutrition is the initiation of enteral feeds within 24 hours of injury. ⁸¹ In the context of acute gut mucosal damage and decreased nutrient absorption, this intervention is thought to provide optimal nutrition throughout the postburn period. ^{91 92} In fact, several studies have shown enteral feeding to reduce the hypermetabolic response, decrease serum catecholamines, cortisol, and glucagon, and deliver the required caloric requirements in the acute postburn period. ^{88 93}

In addition to early nutritional support, intraoperative enteral feeding has been proposed as a solution to perioperative nutritional disruptions. A 2022 systematic review and pooled analysis of critically ill pediatric burn patients assessed the safety and efficacy of continuous duodenal feeding during burn surgery, revealing adequate weight maintenance and reduced caloric deficits without aspiration events. ⁸⁶

Accurately calculating energy requirements is a critical and recurring task in ensuring nutritional support and guiding patient management. While some institutions perform bedside indirect calorimetry to measure REE, this approach is expensive to acquire and maintain. As a cost-effective alternative, most centers rely on equations designed to estimate caloric requirements. ⁸⁷ These formulas typically consider a patient's age, gender, temperature, weight, and burn size. Commonly adapted equations include Curreri, Harris–Benedict, Schofield height-weight (HW), and those from the World Health Organization ( Table 1 ). ^{87 94 95} However, as with all predictive models, there is a possibility of inconsistent or incorrect predictions, and using these equations may greatly overestimate caloric requirements. ^{94 96} Overfeeding can be particularly dangerous in pediatric patients, potentially resulting in hyperglycemia, fatty infiltration of liver, azotemia, and carbon dioxide retention. ⁹⁷

Table 1. Formulas used to calculate resting energy expenditure in pediatric burn patients.

Formula name	Equation
Galveston infant (0–1 y)	2,100 kcal/m 2  + 1,000 kcal/m 2 TBSA burned
Galveston revised (1–11 y)	1,800 kcal/m 2  + 1,300 kcal/m 2 TBSA burned
Galveston adolescent (12–16 y)	1,500 kcal/m 2  + 1,500 kcal/m 2 TBSA burned
Curreri Formula (16–59 y)	25 kcal/kg + 40 kcal/% TBSA burned
Harris–Benedict	F: REE = 655.10 + 9.56 W + 1.85 H − 4.68 A M: REE = 66.47 + 13.75 W + 5.0 H − 6.76 A
Schofield-height weight (HW) (0–18 y)	F: (< 3 y): REE = 16.252 W + 10.23 H – 413.5 M: (< 3 y): REE = 0.167 W + 15.174 H – 617.6 F: (3–10 y): REE = 16.969 W + 1.618 H + 371.2 M: (3–10 y): REE = 19.59 W + 1.303 H + 414.9 F: (10–18 y): REE = 8.365 W + 4.65 H + 200 M: (10–18) y): REE = 16.25 W + 1.372 H + 515.5
FAO/WHO/UNU (3–18 y)	F (3–10 y): REE = 22.5 W + 499 M (3–10 y): REE = 22.7 W + 495 F (10–18 y): REE = 17.5 W + 651 M (10–18 y): REE = 12.2 W + 746

Abbreviations: A: age (years); F: female; H: height (cm); M: male; REE: resting energy expenditure (kcal/day); TBSA: total body surface area; W: weight (kg); FAO/WHO/UNU: Food and Agriculture/World Health Organization/United Nations University equation.

Source: Adapted and modified from Suman et al, ⁹⁴ Rodriguez et al, ⁸⁷ and Schofield. ⁹⁵

Enteral formulas contain varying concentrations of proteins, fats, and carbohydrates and may include micronutrient supplementation. High-glucose, high-protein, and low-fat nutrition has been recommended, with carbohydrates and amino acids serving as the primary energy sources. ^{87 98 99 100} When determining dietary fat calories, it is essential to account for nondietary fat sources, such as propofol infusion, which can impact the daily total fat calorie requirements.

Protein is perhaps the most crucial substrate to consider in nutritional supplementation due to the significant impact of proteolysis during hypermetabolism. A widely used protein requirement for pediatric patients falls within the range of 2.5 to 4.0 k/kg/d. ¹⁰¹ Optimal protein replacement requires a delicate balance as the replacement rate may not always prove sufficient to prevent the loss of skeletal muscle protein in some patients, and excessive supplemental protein intake can lead to increased urea production rather than promoting lean body mass.

Individual amino acids may also play an essential role in nutrition, notably alanine, arginine, and glutamine. ⁸⁷ The clinical benefits of glutamine supplementation are still under investigation. Several small studies of adult burn patients have shown a reduced incidence of infections, decreased length of hospitalization, improved protein concentrations, and reduced mortality rates. ^{102 103} However, the latest study showed that supplemental glutamine did not reduce the time to discharge alive from the hospital in patients with severe burns. ¹⁰⁴

Exercise

As discussed in greater detail in a following paper, exercise is vital in modulating hypermetabolism in burn patients, mitigating both immediate and long-term consequences. The implementation of a comprehensive physical therapy and exercise program improves and maintains lean body mass, enhances the efficiency of amino acid utilization for muscle protein synthesis, and bolsters muscle strength and endurance. ¹⁰⁵

Pharmacological Agents

Pharmacological agents play a critical role in the management of pediatric burn patients, primarily due to the prolonged state of hypermetabolism and the relative insufficiency of nonpharmacological techniques. These interventions are designed to either block, reverse, or mediate critical mechanisms involved in the hypermetabolic response, with the overarching goal of reducing the profound catabolism that follows thermal injury.

Anabolic Agents

Oxandrolone, a testosterone analog, was initially approved as an adjunct treatment to promote weight gain in cases of substantial weight loss resulting from chronic infection, surgery, or severe trauma. In pediatric burn patients, oxandrolone has demonstrated its ability to counteract the hypermetabolic state by promoting muscle protein synthesis, improving muscle strength, and increasing bone mineral content. ^{106 107} These benefits have been associated with reduced hospital length of stay and improved outcomes. ¹⁰⁸ However, the use of oxandrolone is not without potential complications. In a 2004 clinical trial involving ventilator-dependent surgical patients, oxandrolone was found to prolong mechanical ventilation, possibly due to increased collagen deposition and fibrosis in cases of acute respiratory failure. ¹⁰⁹ Additionally, its usage has been associated with prolonged hepatic stress and persistently elevated liver enzymes. ¹¹⁰

On June 28, 2023, the Food and Drug Administration withdrew approval for oxandrolone due to serious concerns associated with the medication, prompting its removal from the market. Safety warnings included the risks of liver failure, intra-abdominal hemorrhage, hepatic neoplasms, and an increased likelihood of atherosclerosis. ¹¹¹

Recombinant Human Growth Hormone

When intramuscularly administered to pediatric patients with severe burns, rhGH has demonstrated substantial improvements in outcomes, including increased levels of endogenous IGF-1, reduced donor-site healing times, shorter hospital length of stays, and decreased overall care costs. ^{112 113 114} Furthermore, patients who received rhGH exhibited substantially improved scarring 2 years following burn injury compared to those who received a placebo. ¹¹⁵

Despite evidence of both safety and efficacy in severely burned pediatric patients, rhGH is associated with significant side effects, notably hyperglycemia and insulin resistance. ^{116 117} While some physicians advocate for rhGH use in pediatric burn patients with close monitoring, concerns for possible complications have led to limited widespread utilization. ^{12 30}

Insulin-Like Growth Factor-1

IGF-1 plays a central role in mediating the effects of rhGH. Administration of IGF-1 alone yields significant improvements in protein metabolism, albeit often accompanied by hypoglycemia in burn patients. ¹¹⁸ However, when combined with equimolar doses of IGFBP-3, patients experience fewer hypoglycemic episodes and an increase in muscle protein synthesis. ^{119 120} This combination therapy offers additional advantages, such as enhanced gut mucosal integrity, improved immune function, and reduced protein catabolism. ^{119 121} Importantly, the IGF-1 and IGFBP-3 combination exhibits fewer side effects than IGF-1 alone, making it a potentially important mediator of hypermetabolism in pediatric burn patients.

Antidiabetic Agents

It is well documented that the postburn hypermetabolic response includes a hyperinsulinemic hyperglycemic state similar to the underlying mechanism of type II diabetes. ¹²² The primary distinctions lie in the abrupt onset and severity of this condition compared to the more chronic course of diabetes. Sudden onset stress-induced hyperglycemia in burn patients is linked to unfavorable outcomes, notably bacteremia, fungemia, enhanced protein catabolism, and an increased mortality rate compared to nonburn patients and burn patients with adequate glucose control. ^{123 124}

The first prospective randomized control trial to evaluate the effectiveness of insulin therapy for burn patients was published in 2010 and involved nearly 240 pediatric burn patients. Compared to the control group, pediatric burn patients who received insulin therapy showed a reduced incidence of infections and sepsis, improved organ function, and decreased insulin resistance. ¹²⁵

Achieving strict glycemic control in burn patients through intensive insulin therapy presents unique challenges. These patients receive continuous high-calorie enteral feeds; however, the need for frequent surgical procedures and daily dressing changes may disrupt nutrition, affecting gastrointestinal motility and increasing the risk of hypoglycemia. A 2014 study of 760 pediatric burn patients found that those who experienced ≥ 1 hypoglycemic episode had a significantly higher risk of postburn mortality. ¹²⁶ To minimize this risk, the ideal glycemic target is around 130 mg/dL, with critical care literature recommending a range of 90 to 140 mg/dL for burn patients. ¹²⁷

In recent years, metformin has emerged as a promising solution for managing hyperglycemia in postburn patients without inducing hypoglycemic episodes. ^{128 129} A recent clinical trial by Jeschke et al demonstrated that metformin is as effective as insulin in reducing hyperglycemia in severely burned patients, with significantly fewer hypoglycemic episodes. ¹³⁰ The authors also reported the potential benefits of metformin in fat metabolism and the modulation of inflammatory responses following burn injuries. ¹³⁰

Metformin has recently been studied in severely burned mice models to assess its impact on postburn muscle catabolism. ¹³¹ The authors examined the gastrocnemius muscle at 1 and 2 weeks postburn, finding preserved myofiber cross-sectional area in metformin-treated mice. ¹³¹ Additionally, the burned mice treated with metformin demonstrated increased expression of Pax7, a transcription factor responsible for regulating muscle progenitor cells, supporting metformin's potential in treating burn-induced skeletal muscle wasting. ¹³¹

Propranolol

Propranolol is a nonselective β1/β2 receptor antagonist that has emerged as a highly effective treatment for hypermetabolism in severe burns by counteracting the actions of catecholamines, the primary drivers of hypermetabolism. ³⁰ When administered acutely, propranolol exhibits anti-inflammatory and antistress effects, resulting in reduced muscle wasting, improved lean body mass, and enhanced glucose metabolism by reducing insulin resistance. ^{132 133 134 135} These benefits are closely linked to improved organelle function, as propranolol restores mitochondrial function and mitigates endoplasmic reticulum stress. ¹³³ Furthermore, long-term propranolol treatment offers several advantages, including a decrease in heart rate, REE, central mass and central fat accumulation, prevention of bone loss, and improvement of lean body mass. ¹³⁶

Compared to many other pharmacological interventions for managing postburn hypermetabolism, propranolol stands out for its minimal adverse effects. Research strongly suggests that propranolol can effectively mitigate the hyperdynamic, hypermetabolic, hypercatabolic, and osteopenic responses observed in pediatric burn patients. ^{103 136} As such, propranolol is currently the primary medication administered to address hypermetabolism following severe burn injuries. ^{136 137} Nevertheless, it is worth noting that the literature on whether propranolol significantly reduces postburn mortality or length of hospitalization remains limited. More extensive studies with larger sample sizes and long-term follow-up may be necessary to assess its efficacy fully.

Conclusion

In recent decades, advancements in burn care have undeniably led to improved outcomes. Nevertheless, the profound and intricate hypermetabolic response associated with severe burn injuries remains a multifaceted challenge. This response encompasses various physiological disturbances, including insulin resistance, immune dysfunction, protein catabolism, and a hyperdynamic cardiovascular state. Hypermetabolism can be especially pronounced in the pediatric population, underscoring the importance of tailored interventions with minimal long-term adverse effects. Key interventions, such as early excision and grafting of burn wounds, are crucial in reducing resting energy requirements, minimizing infection risk, and ultimately enhancing patient outcomes. Additional interventions include propranolol to combat muscle catabolism, insulin or metformin to maintain glycemic control, and early enteral feeding to support nutrition. While each of these measures has significantly contributed to the modulation of hypermetabolism and the reduction of mortality rates, it is their combination that continues to drive treatment forward, further improving outcomes for severely burned patients.