Hypermetabolic response to moderate-to-severe burn injury and management

INTRODUCTION — Profound metabolic alterations affect patients suffering from moderate-to-severe burns. The hypermetabolic response in burn patients is characterized by hyperdynamic circulatory, physiologic, catabolic, and immune system responses. Early recognition and treatment improves clinical outcomes [1-4].

Attenuation of the hypermetabolic response is accomplished by altering the physical, physiologic, and biochemical environment of the burn patient with early burn wound excision, grafting, optimizing nutrition, adjusting ambient temperatures, increasing lean body mass, and pharmacologic treatments. Nonpharmacologic therapies, such as providing specific nutrients and growth factors as well as activities and exercise, are also emerging as essential components of the management of burn patients [5,6].

The metabolic changes that occur following moderate-to-severe burns and the attenuation of the hypermetabolic response are reviewed here. The general care of the burn patient, including burn wound care and nutritional support, is reviewed separately. (See "Overview of the management of the severely burned patient" and "Overview of nutrition support in burn patients".)

HYPERMETABOLIC RESPONSE — The hypermetabolic response to injury is characterized by increased blood pressure and heart rate, peripheral insulin resistance, and increased protein and lipid catabolism, which lead to increased resting energy expenditure, increased body temperature, total body protein loss, muscle wasting, and stimulated synthesis of acute-phase proteins [1-3,5-9]. These responses occur in all trauma, surgical, or critically ill patients, but the magnitude with which they occur and their duration are particularly severe and sustained for burn patients [2,10,11].

The cause of this complex response is not well understood. A marked and sustained increase in the secretion of catecholamines, glucocorticoids, glucagon, and dopamine initiates the cascade of events leading to an acute hypermetabolic response with its ensuing catabolic state [7,12-19]. Interleukins 1 and 6, platelet-activating factor, tumor necrosis factor (TNF), endotoxin, neutrophil-adherence complexes, reactive oxygen species, nitric oxide, and coagulation and complement cascades have been implicated in regulating this response to burn injury [20]. Once these cascades are initiated, their mediators and byproducts appear to perpetuate the persistent and increased metabolic rate associated with altered glucose metabolism [21]. Perturbations in the innate immune response to the burn injury are caused by the release of damage-associated molecular patterns (DAMPs). DAMPs bind to toll-like receptors to initiate an immunosuppressive state. Collectively, burns lead to an increased risk of systemic inflammatory response syndrome, acute respiratory distress syndrome, and multiorgan dysfunction [22-24].

Time course

Phases — Two distinct phases of metabolic regulation are described following injury [25]:

●Ebb phase – The changes associated with the "ebb phase" occur within the first 48 hours of a burn injury [25,26]. This phase is characterized by decreased cardiac output, oxygen consumption, and metabolic rate as well as impaired glucose tolerance and hyperglycemia.

●Flow phase – The flow phase represents a gradual increase in metabolism to reach a plateau within the first five days postinjury. This phase is associated with hyperdynamic circulation and the development of insulin resistance. In response to glucose load, insulin release is twice that of controls during this time period [27,28], and plasma glucose levels are markedly elevated [28,29]. (See "Insulin action".)

Duration — The hypermetabolic response (flow phase) may last for more than 12 months after the initial event and does not resolve completely after wound closure [7,12,19,30-32]. Sustained hypermetabolic alterations include persistent elevations of the stress mediators (24 hour urine cortisol levels, serum cytokines, catecholamines, and basal energy requirements). Impaired glucose metabolism and insulin sensitivity can persist for up to three years after severe burn injury [33].

Magnitude — The metabolic rate increases proportionally with burn size [31,32]. A 15 to 20 percent total body surface area (TBSA) burn injury initiates a catabolic response, including impaired immunity and accentuating fluid shifts [34]. Adults with a 20 percent TBSA burn injury develop a metabolic rate between 118 to 210 percent of that predicted by Harris-Benedict equations for basal metabolic rate [35]. Patients with burns greater than 40 percent TBSA almost always experience hypermetabolism [30]. A further increase in hypermetabolism occurs in patients with burns of 50 to 60 percent TBSA, after which there is minimal further increase in hypermetabolic rate [36].

In a prospective longitudinal study in which resting energy expenditure was measured by indirect calorimetry, stable isotope study, and body composition, children with burns greater than 40 percent TBSA developed a metabolic rate of 180 percent of the basal metabolic rate (BMR) during the acute admission, which persisted at an elevated rate of 150 percent of BMR following complete wound closure and was maintained at 110 percent of BMR at one year [2,7]. (See "Clinical assessment and monitoring of nutrition support in adult surgical patients".)

Altered hemodynamics — Depending upon the size of the burn for both children and adults, patients will initially have a low cardiac index and will be extremely vasodilated. Both populations will go into a hyperdynamic state of tachycardia with increased cardiac output.

Depending upon the comorbidities of the adults, the patient may experience atrial fibrillation or any other rhythm that they are prone to experiencing. However, compared with children, the magnitude of hemodynamic changes in adults may not be as profound due to coexisting comorbidities [37-39]. For children, heart rates can exceed 180 percent of predicted values for age-matched children, and cardiac outputs can exceed 150 percent; both can remain elevated for up to two years after injury [37].

Altered glucose metabolism — Under normal circumstances, a postprandial increase in blood glucose concentration stimulates the release of insulin from pancreatic beta cells. Insulin mediates peripheral glucose uptake into skeletal muscle and adipose tissue and suppresses hepatic gluconeogenesis, thereby maintaining blood glucose homeostasis. Glucose metabolism in healthy subjects and in patients with diabetes is discussed in detail elsewhere. (See "Insulin action".)

In critical illness, metabolic alterations can significantly change energy substrate metabolism. In order to provide glucose, release of stress mediators opposes the anabolic actions of insulin. By enhancing adipose tissue lipolysis and skeletal muscle proteolysis, stress mediators (ie, counterregulatory hormones) increase gluconeogenic substrates, including glycerol, alanine, and lactate (figure 1), thus augmenting hepatic glucose production in burned patients [40-43].

Hyperglycemia fails to suppress hepatic glucose release during this time, and the suppressive effect of insulin on hepatic glucose release is attenuated, significantly contributing to persistent hyperglycemia [33,44,45]. Catecholamine-mediated enhancement of hepatic glycogenolysis as well as direct sympathetic stimulation of glycogen breakdown further aggravate the hyperglycemia in response to stress [41]. Catecholamines also impair glucose disposal via alterations of the insulin-signaling pathway and GLUT4 translocation in muscle and adipose tissue, resulting in peripheral insulin resistance [40,46].

Insulin resistance in severely burned patients begins as early as three days postinjury, predominantly in the liver [47], and lasts up three years postinjury [33]. It is primarily mediated by the persistent elevation in catecholamines and cortisol levels, which lead to increased endogenous glucose production, in conjunction with the impaired insulin-mediated glucose uptake.

Altered protein and lipid metabolism — Alterations in metabolic pathways and proinflammatory cytokines, such as tumor necrosis factor (TNF), contribute to lean-muscle protein breakdown, both during the acute and convalescent phases in response to burn injury [48,49]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

In contrast to starvation, in which lipolysis and ketosis provide energy and protect muscle reserves, a moderate-to-severe burn considerably reduces the ability of the body to use lipids as an energy source. Skeletal muscle becomes the major source of substrate for glucose production, which leads to marked wasting of lean body mass (LBM) within days after burn injury [2,50] and which persists for at least nine months post-burn [7,51]. Since skeletal muscle is responsible for 70 to 80 percent of whole-body insulin-stimulated glucose uptake, decreases in muscle mass may significantly contribute to this persistent insulin resistance post-burn injury [52]. (See "Insulin resistance: Definition and clinical spectrum".)

Interestingly, the observed white adipose tissue (WAT) browning after burn injury appears to be a culprit, if not the main facilitator, of cachexia [53]. The sustained catecholamine surge in burns initiates WAT browning and the cascade of events leading to the hypermetabolic response [54,55], indicating that WAT browning may be detrimental for burn patients. Despite these findings, it remains to be determined if the attenuation of WAT browning is sufficient to overcome the impaired muscle and liver metabolic processes that have already occurred in the hypermetabolic response to the injury.

A 10 to 15 percent loss in LBM is associated with a significant increase in infection rates and marked delays in wound healing [56]. The resultant muscle weakness further prolongs mechanical ventilatory utilization, inhibits sufficient cough reflexes, and delays mobilization in protein-malnourished patients, thus contributing to mortality [57]. Persistent protein catabolism may also account for growth and developmental delay frequently observed in pediatric patients with burns greater than 40 percent TBSA [58].

The profound wasting of lean body mass is further exacerbated by immobility. The classic teaching for critically ill burn patients was prolonged bed rest and immobility; however, this increases the risk for hypertrophic ossification, contractures, muscle wasting and weakness, neuropathies, pressure necrosis and pressure ulcers, deep vein thrombosis, prolonged psychological disturbances, longer lengths of stay, and increased ventilator days. Current evidence demonstrates the safety and efficacy of early mobility protocols to shift this paradigm [59,60]. (See 'Exercise and adjunctive measures' below.)

ATTENUATION OF THE HYPERMETABOLIC RESPONSE — Therapeutic approaches focus on attenuating or blunting the hypermetabolic response and its ensuing catabolic state. A number of different strategies are used to alter the physiologic and biochemical environment. For adults and children, we recommend early burn excision and grafting, aggressive pain control using opioids acutely, insulin, and/or metformin to maintain blood glucose levels between 110 and 150. For children, we also recommend recombinant human growth hormone (rhGH) during the chronic phase of burn care.

The hypermetabolic response can be attenuated using nonpharmacologic and pharmacologic modalities. Nonpharmacologic modalities include early wound excision and closure, nutrition support, environmental support, exercise, and other adjunctive measures. Specific pharmacotherapies that can attenuate the hypermetabolic response include pain relievers, anabolic hormones, anabolic steroids, catecholamine antagonists, and recombinant human growth hormone, if needed, for children [1]. Some pharmacotherapies are more effective in the acute rather than chronic phase of the burn injury. The acute phase is defined as the period immediately following the resuscitation phase, when the patient is hemodynamically stable, capillary permeability is restored, and diuresis has begun. It generally starts 48 to 72 hours post-burn injury. The chronic or rehabilitation phase begins when wounds are healed.

Oxandrolone, which is a testosterone analog with a low level of virilizing androgenic effects, improves muscle protein catabolism, reduces weight loss and growth arrest, and increases donor-site wound healing in burn patients. It was recommended for its beneficial effects attenuating the hypermetabolic response to burn injury for adults and children in both the acute and chronic phases of burn injury [61]. However, at the manufacturer's request and because of safety concerns, approval for use was removed by the United States FDA as of June 28, 2023, and the drug will no longer be manufactured [62].

Early excision and grafting — Early excision of necrotic tissue and wound closure has been an important advancement in the treatment of patients with severe burn injuries and a mainstay of therapy [2,7,63-66]. Early burn excision and grafting is associated with a reduction in metabolic parameters [30,67,68]. Wound closure alone, however, does not eliminate the hypermetabolic response [7].

A meta-analysis of six randomized trials showed a significant reduction in mortality with early excision and grafting in burn patients without inhalation injury (risk ratio [RR] 0.36, 95 percent CI 0.20-0.65) compared with conservative treatment of dressing changes and delayed skin grafts following eschar separation [63]. The mean length of hospital stay was significantly shorter for the early excision group (standardized mean difference [SMD] 8.89), but the requirement for blood transfusions was significantly higher (SMD 1.65). There was no difference in duration of sepsis, wound healing time, and skin graft take between the two groups.

While burn wound closure within the first five days is optimal, it is not always possible. A retrospective study of 143 burn patients showed that a delayed primary wound closure (days 6 to 12) had a similar advantage of early wound closure in reducing risk of septicemia, mortality, morbidity, hospital stay, and cost of treatment in comparison with 449 patients treated with delayed closure, a practice that allowed wounds to granulate prior to skin grafting [69]. Early excision and skin grafting is also associated with decreased severity of hypertrophic scarring, joint contractures, and stiffness and promotes faster rehabilitation [70,71]. (See "Overview of surgical procedures used in the management of burn injuries".)

Propranolol — Beta blockade attenuates the hypermetabolism in pediatric burn patients and may also be beneficial in adult burn patients [72-76]. (See "Beta blockers in the treatment of hyperthyroidism" and "Major side effects of beta blockers".)

Beta blockers blunt the effects of elevated catecholamines, resulting in decreased cardiac oxygen demand and decreased resting metabolism. Stable isotope and serial body composition studies showed that administration of propranolol reduces skeletal muscle wasting and increases LBM post-burn [77]. The underlying mechanism of action is unclear, but it may cause an increase in protein synthesis in response to persistent protein breakdown and reduced peripheral lipolysis [78]. Propranolol reduces fatty infiltration of the liver, which typically occurs as the result of enhanced peripheral lipolysis and altered substrate handling [79,80].

In a randomized trial of propranolol versus placebo in 25 severely burned children, propranolol significantly decreased heart rate and resting energy expenditure [74]. The net muscle protein balance, which is the difference between protein synthesis and breakdown, was increased by 82 percent over baseline in the propranolol group compared with no significant change in the untreated control group. Another randomized trial that included 179 pediatric patients with more than 30 percent TBSA burn found that administration of propranolol attenuated the hypermetabolic responses for one year post-burn [81].

Beta blockers may also improve burn outcomes [75,81-83]. A small retrospective cohort study of adult burn patients found an association between preinjury treatment with beta blockers and improved wound healing and reduced burn-related mortality [75]. There was no evidence that post-burn injury treatment with beta blockers reduced the mortality rate in adult burn patients. A separate trial found that treatment with propranolol in adults (10 to 20 mg three times a day) and children (4 mg/kg/24 hours) significantly reduced the rates of infection and sepsis compared with placebo (21 versus 30 percent and 7 versus 10 percent, respectively) [82].

Reduce pain and anxiety — The metabolic rate of the burn patient is adversely affected by pain, anxiety, and activity [1]. Background, procedurally related pain, and anxiety greatly increase metabolic rates.

Burn injuries cause one of the most intense and prolonged types of pain, and judicious management of pain with intravenous analgesics, appropriate sedation, and supportive psychotherapy is important to attenuate the hypermetabolic response [84]. Intravenous opioids (continuous or bolused) are most often used to relieve pain. Supportive psychotherapy is helpful in reducing patient anxiety [85]. (See "Management of burn wound pain and itching" and "Paradigm-based treatment approaches for management of burn pain".)

Nutrition support — Adequate nutritional support is imperative for the treatment of severely burned patients to reduce the catabolic effects [86]. An enteral route is preferred [67], but the timing of initiation may vary (algorithm 1). (See "Overview of nutrition support in burn patients".)

Various formulations and equations have been developed to address the increased energy requirements of adult and pediatric burn patients [87-91]. The most widely used formula is the Curreri formula, though this may overestimate nutritional needs [91]. (See "Nutritional demands and enteral formulas for adult surgical patients", section on 'Calculating energy requirements'.)

Increased lipid administration to reduce fatty acid deficiency is commonplace in nutritional supplementation of nonburn critically ill patients but in burn patients may increase complications, including hyperlipidemia, hypoxemia, fatty liver infiltration, higher incidence of infection, and higher postoperative mortality [50,79,92,93]. The livers of burn patients secrete less very low-density lipoprotein (VLDL), and this contributes significantly to triglyceride accumulation in the liver [94]. Hence, the extent to which exogenous lipids can be used as an energy source after burn injury is considerably limited [36,42,95].

Whether supplemental administration of glutamine provides a clinical benefit is not known for certain. In animal models, glutamine administration reduces the hypermetabolic response through a variety of mechanisms [96-98]. In a small multicenter trial, resting energy expenditure, serum catecholamines, glucagon, lactate, and homeostasis model assessment were significantly lower among 27 severely burned patients (TBSA 30 to 70 percent) who received intravenous glutamine compared with 28 patients who did not [99]. While intravenous glutamine at doses of 0.3 to 0.5 grams per kilogram per day attenuated the post-burn hypermetabolic response and reduced organ damage, the length of hospitalization and mortality rates were similar between the groups.

Glycemic control — Nutritional management includes avoidance of hyperglycemia, which is associated with higher morbidity and mortality in moderate-to-severe burn patients. (See "Glycemic control in critically ill adult and pediatric patients".)

The ideal target glucose range is uncertain. In general, target glucose levels for moderately to severely burned patients include:

●Morning glucose level of 130 mg/dL (7.2 mmol/L)

●Daily average glucose level of 140 mg/dL (7.8 mmol/L) for at least 70 percent of the hospital admission

However, additional clinical trials are needed to define the ideal glucose levels for the treatment of critically ill, trauma, and severely burned adult patients.

●Insulin – In severely burned patients, insulin administered during acute hospitalization improves muscle protein synthesis, accelerates donor-site healing time, attenuates LBM loss and the acute phase response, and reduces infection and mortality rates [100-108]. In addition to its anabolic actions, insulin exerts anti-inflammatory effects, potentially neutralizing the proinflammatory actions of glucose [105]. These results suggest a dual benefit of insulin administration: reduction of proinflammatory effects of glucose by restoration of euglycemia and a proposed additional insulin-mediated anti-inflammatory effect [109]. Maintaining a continuous insulin infusion in burn patients can be challenging since these patients require a large caloric load. In addition, burn patients require frequent operations and dressing changes, which intermittently halts enteral nutrition, leading to variations in glucose levels [2]. Insulin resistance can also develop during the acute phase and persist for three years in pediatric burn patients [33]. (See "Management of diabetes mellitus in hospitalized patients", section on 'Patients receiving enteral or parenteral feedings'.)

●Metformin – Metformin, a biguanide, counters the two main metabolic processes that underlie burn injury-induced hyperglycemia by inhibiting gluconeogenesis and augmenting peripheral insulin sensitivity [110-114]. A trial that randomly assigned 44 severely burned patients to metformin or insulin found that metformin controlled blood equally as well as insulin but with less hypoglycemia (15 versus 6 percent), and it also improved insulin sensitivity (as measured by oral glucose tolerance test at discharge) [115]. (See "Metformin in the treatment of adults with type 2 diabetes mellitus".)

●Incretin-based therapies – Another approach to treating hyperglycemia in burn patients without increasing the risk of hypoglycemia is incretin-based therapies. The incretins include glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Exogenous GLP-1 reduces glucose concentration in patients with type 2 diabetes after major surgery [116] and in those who are critically ill without diabetes and receiving enteral nutrition [117]. In a trial that included 24 severely burned patients, exenatide, a synthetic peptide that possesses incretin-mimetic actions including suppression of glucagon secretion and activation of GLP-1, significantly decreased the amount of exogenous insulin required to maintain glucose levels between 80 and 140 mg/dL (4.4 to 7.8 mmol/L) [118]. The GLP-1 analogue tested in this trial appears to be safe and reliably modulated glucose in these patients. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

Exercise and adjunctive measures — A balanced physical therapy program is essential to restore metabolic variables and prevent burn wound contractures. In a randomized trial of progressive resistance and aerobic exercises versus traditional outpatient home therapy in 21 children, both groups had a significant increase in muscle strength compared with baseline [119]. However, the study group had significantly greater improvements in muscle strength (80 versus 38 percent in the home group). The study group also improved the distance walked (40 versus 12 percent).

Recombinant human growth hormone — Delays in growth are frequently observed in children who suffer severe burns. It is hypothesized that the delay in vertical growth is related to a low serum level of growth hormone. In a two-year observational study in children with moderate-to-severe burns, there was a significant difference in height velocity in 38 children treated with rhGH compared with 41 children who did not receive rhGH (47^th versus 32^nd percentile) [120]. However, rhGH did not attenuate the hypermetabolic response.

Neither short- nor long-term administration of rhGH was associated with an increase in mortality in severely burned children [121,122]. However, rhGH is associated with an increase in mortality in adult burn patients and is not recommended in this population [123]. For children, rhGH use is recommended during the chronic phase of burn management, and rhGH should not be used concurrently with an infection or sepsis. Administration during the acute phase is associated with an increased risk of septic events [65,120,123-126].

In a systematic review that included 13 randomized trials (six in children, seven in adults), treatment with rhGH shortened donor site healing time (by 3.15 days; 95% CI 1.54-4.75) and burn wound healing time (by 9.07 days; 95% CI 4.39-13.76) in adults compared with placebo [127]. In children, treatment with rhGH also shortened donor site healing time (by 1.70 days; 95% CI 0.87-2.53); data were not sufficient to assess burn wound healing time. Growth hormone increased the incidence of hyperglycemia in adults compared with placebo (risk ratio 2.43; 95% CI 1.54-3.85) but not in children. Treatment did not alter mortality or observed scarring.

Environmental support — Burn patients can lose as much as 4000 mL/m² burned/day of body water through evaporative loss from extensive burn wounds that have not healed or are not covered by grafts [128]. The altered physiologic state partly generates sufficient energy to offset heat losses associated with inevitable water loss. The body attempts to raise skin and core temperatures to 2ºC greater than normal. One prospective study found that raising the ambient temperature from 25ºC to 33ºC diminished the magnitude of this obligatory response from 2.0 to 1.4 times resting energy expenditure [129].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Care of the patient with burn injury".)

SUMMARY AND RECOMMENDATIONS

●The hypermetabolic response to injury is characterized by a hyperdynamic circulatory response, increased protein and lipid catabolism, and peripheral insulin resistance, which increase resting energy expenditure and body temperature and decrease total body protein, leading to muscle wasting. These responses occur in all trauma, surgical, or critically ill patients, but the magnitude to which they occur and duration are particularly severe and sustained for burn patients. (See 'Hypermetabolic response' above.)

●Early excision and grafting of the burn wound is the most important intervention for treating patients with moderate-to-severe burn injuries, substantially reducing resting energy requirements. It also reduces the risk of burn wound infection and sepsis, length of hospital stay, and burn-related mortality. (See 'Early excision and grafting' above and "Burn wound infection and sepsis".)

●For children with moderate-to-severe burns, we suggest treatment with propranolol for one year (Grade 2B). Propranolol attenuates the hypermetabolism and reverses muscle-protein catabolism. There is no evidence to support the routine use of propranolol in adult burn patients. (See 'Propranolol' above.)

●Because burn injuries cause one of the most intense and prolonged types of pain, pain management is important to attenuate the hypermetabolic response. Intravenous opioids, continuous or bolused, are most often used to relieve pain. (See 'Reduce pain and anxiety' above.)

●For stress-related hyperglycemia in burn patients without a past history of diabetes, we recommend treatment with insulin (intravenous or injectable) (Grade 1B). Insulin significantly lowers the incidence of sepsis and mortality in those patients with good glucose control compared with those who had poor control. (See 'Glycemic control' above and "Overview of nutrition support in burn patients", section on 'Glycemic control'.)

●For patients with moderate-to-severe burns, a balanced physical therapy program to restore metabolic variables, prevent burn wound contracture, improve body mass, and increase muscle strength should be included in the treatment plan. In addition, increasing the ambient temperature from 25 to 33ºC diminishes resting energy expenditure. (See 'Exercise and adjunctive measures' above and 'Environmental support' above.)