Burn Hypermetabolism, Nutrition, and Endocrine Response

Overview

Severe burn injury produces metabolic and endocrine derangements that have no parallel in the rest of critical care. The 2011 SEMICYUC-SENPE consensus guideline characterizes the response to severe burns as "the most hypermetabolic existing model of aggression," combining sustained hypermetabolism with hypercatabolism and a high degree of skeletal-muscle destruction ^[1]. The clinical work, in turn, is built around three interlocking jobs: feed the patient adequately without overfeeding, blunt the catabolic drivers with pharmacology where evidence supports it, and protect lean body mass through wound closure, thermal management, and exercise [1, 5, 15, 16].

The hypermetabolic state is driven by an enormous and sustained catecholamine surge, elevated cortisol in proportion to burn size, and a chronic inflammatory state that does not fully resolve when the wound closes [2, 11]. Energy expenditure remains elevated past 184 percent of baseline through 42 days even when early excision and aggressive enteral feeding are provided ^[10]. Gene-expression changes in nonburned skeletal muscle persist up to 18 months after injury ^[11], and post-burn hypermetabolism lasts at least 9 to 12 months on the consensus estimate ^[5]. Modern burn-center practice has converged on a small set of evidence-supported interventions that modify the trajectory: early enteral nutrition, beta-blockade with propranolol, the anabolic steroid oxandrolone, recombinant human growth hormone, insulin for glycemic control, and structured resistance exercise during convalescence [5, 15, 16]. None of these reverses the response; each shifts a measurable component.

Epidemiology

The hypermetabolic response is burn-size dependent. A 2007 prospective pediatric burn study found that morbidity and mortality were burn-size dependent and began to escalate at 60 percent TBSA, with the percentage-predicted resting energy expenditure (REE) highest in the >80 percent TBSA group, followed by the 60 to 79 percent TBSA group ^[13]. Patients with burns less than 40 percent TBSA do not enter a catabolic state unless sepsis develops, while patients with burns greater than 40 percent TBSA always experience catabolism that produces metabolic derangements lasting at least 1 year in most body tissues ^[15]. A 2000 study of determinants of skeletal-muscle catabolism after severe burn found that increasing age, weight, and delay in definitive surgical treatment all predict increased catabolism (P < 0.05) ^[14].

The literature base on nutrition in burn care is substantial and continues to grow. A 2023 bibliometric analysis identified 260 publications on nutritional support for burns, with the United States contributing the highest number (n = 119) and highest citation count (n = 4,424) ^[70]. Despite this volume, the SEMICYUC-SENPE guideline cautions that exact calculation of calorie-protein requirements remains difficult even when indirect calorimetry is used, due to high loss of proteins and CO2 through the burn wound itself ^[1].

Pathophysiology

Ebb and flow phases

The classical bi-phasic framing dates to Wolfe's 1981 review: the acute "ebb" or shock phase is a hypodynamic state with depressed cardiac output and metabolic rate, while the chronic "flow" phase is a hyperdynamic state lasting many weeks with elevated cardiac output and metabolic rate ^[4]. Without adequate nutritional therapy, severe protein wasting occurs during the flow phase through an accelerated rate of protein catabolism, and the increase in protein catabolism is itself associated with an increase in the rate of glucose production ^[4]. Hyperglycemia in the early phase is driven both by increased rates of glucose production and by peripheral insulin resistance ^[4].

Catecholamines as the central driver

Wilmore's foundational 1974 work demonstrated that hypermetabolism after thermal injury is positively related to the rate of urinary catecholamine excretion, and that combined alpha and beta adrenergic blockade decreased metabolism from 69.6 to 57.4 kcal/m²/hr (P < 0.01) ^[6]. The Wilmore group concluded that burned patients are internally warm rather than externally cold, with catecholamines mediating the increased heat production, likely through alterations in hypothalamic function ^[6]. Subsequent work confirmed that lipolysis in burned patients is stimulated specifically by the beta-2 adrenergic receptor; selective beta-1 blockade does not reduce lipolysis, while combined beta-1 and beta-2 blockade does ^[9].

The catecholamine surge interacts reciprocally with thyroid hormones. In severely burned patients, plasma norepinephrine and epinephrine concentrations correlate inversely with serum T3 ^[7]. Cortisol is also elevated in proportion to burn size, while plasma corticotrophin (ACTH) is not, suggesting that factors other than ACTH contribute to the elevated cortisol ^[8]. Cortisol appears less prominent than catecholamines as a mediator of the elevated thermogenesis, though it correlates with metabolic rate through a common relationship with burn size ^[8].

Persistence beyond wound closure

A central, surprising finding of the modern era is that hypermetabolism does not resolve with wound healing. Gene-expression studies in nonburned human skeletal muscle show that severe burn induces rapid skeletal-muscle proteolysis that persists for up to 1 year and results in muscle atrophy despite dietary and rehabilitative interventions ^[12]. Atrogin-1 and MuRF-1 expression are more than 4-fold and 3-fold higher in burn patients than controls; IL-6 receptor is over 13-fold higher ^[12]. In severely burned children, gene-expression changes in skeletal muscle remain detectable at 18 months after injury, with normalization only by 24 months ^[11]. A 2000 continuous-metabolic-monitoring study found that even with early excision (mean 6.5 days post-burn) and aggressive enteral nutrition meeting 99.4 percent of measured caloric needs, mean daily energy expenditure remained 184.9 percent of Harris-Benedict baseline through 42 days ^[10].

Hormonal milieu

The endocrine status is markedly altered with an initial and then sustained increase in proinflammatory stress hormones such as cortisol and other glucocorticoids and catecholamines including epinephrine and norepinephrine ^[5]. These hormones exert catabolic effects leading to muscle wasting, the intensity of which depends on the percentage of total body surface area involved as well as the time elapsed since initial injury ^[5]. Serum IGF-1 concentrations are persistently low in burn patients; the proteolysis of IGFBP-3 may be an important cause of the decreased serum IGF-1 values ^[65]. Severe burn injury is also associated with vitamin D deficiency, low bone turnover, and abnormalities in calcium homeostasis ^[17]; the conversion of 7-dehydrocholesterol to previtamin D3 is reduced in children a mean of 14 months after the burn ^[17].

Protein and substrate kinetics

Adults are more catabolic than children during the acute phase after burn. A 2011 retrospective analysis of muscle protein kinetics found that muscle net protein balance was -43 ± 61 nmol Phe/min/100 ml leg volume in adults versus 8 ± 68 in children (P < 0.05), and muscle protein fractional synthesis rate was 0.11 versus 0.16 percent per hour (P < 0.05) ^[3]. Muscle protein breakdown did not differ between groups, suggesting that synthesis has age-related specificities that account for the better, though still negative, net balance in children ^[3]. Skeletal muscle is the primary fuel source supporting wound healing in the burn-induced hypermetabolic state, and muscle catabolism is sustained long after the wound has healed, indicating that additional mechanisms beyond wound healing are involved ^[2].

Assessment

Energy expenditure measurement

Indirect calorimetry is the reference method for setting caloric targets. A 2019 narrative review concluded that indirect calorimetry should be utilized to determine caloric requirements, with trophic feeding strategies preferred in the initial resuscitative phase to prevent overfeeding while maintaining enteric and immune function ^[21]. Predictive equations consistently overestimate measured REE. A 1987 comparison study reported that the Curreri equation overestimated measured energy expenditure by 25 percent on admission and 36 percent on discharge, and the modified Harris-Benedict equation overestimated by 32 and 39 percent respectively, indicating excessive overfeeding from both standard formulas across the hospital course ^[24]. In pediatric burn patients, measured REE × 1.3 differed significantly from Harris-Benedict × 2 and from the Mayes-Galant equation, which over-predicted by 29 and 19 percent respectively ^[22].

A 2019 Bland-Altman analysis in major burns identified 1.2 × Harris-Benedict, the Thumb 25 equation, and the Ireton-Jones equation as having the highest accuracy and reliability among predictive equations; the Hangang equation showed the highest concordance correlation coefficient (0.67) and lowest RMSE in the validation set, and the Thumb 25 was the most accurate predictor with predicted REE within ±10 percent of measured REE in 52.5 percent of patients ^[20]. Among extremely severe burn patients undergoing sedation and mechanical ventilation, the Thumb formula was the most accurate of four tested equations (accuracy 25.9 percent), but all formulas had limited accuracy; sedation itself causes a significant decrease in REE ^[23].

A 1999 long-term study found that in clinical settings without indirect calorimetry, REE can be stated to be 50 to 60 percent above Harris-Benedict in patients with TBSA over 20 percent for at least 20 days ^[19]. Declining REE during the hospital course correlates with mortality (P < 0.05), and declining energy expenditure appears to be a harbinger of mortality in severely burned patients ^[18]. REE/predicted basal metabolic rate correlates directly with burn size, sepsis, ventilator dependence, and muscle protein catabolism (P < 0.05) ^[18].

Muscle mass assessment

Skeletal-muscle ultrasound has emerged as a feasible point-of-care tool for tracking muscle architecture in burns. A 2023 reliability study of 20 burned adults found intraclass correlation coefficients above 0.97 for quadriceps muscle layer thickness and above 0.95 for rectus femoris cross-sectional area using average measurements ^[63]. Measurement was feasible in 94 to 96 percent of attempted assessments using no-compression technique, with smaller relative minimal detectable changes (6.5 versus 15 percent) than maximum-compression technique ^[63]. The authors concluded that ultrasound provides feasible and reliable values of quadriceps muscle architecture that can be adapted to clinical scenarios commonly encountered in acute burn settings ^[63].

Glycemic monitoring

Glucose monitoring system accuracy varies in burn patients and is degraded by anemia and high-dose ascorbic acid therapy ^[40]. In a 2014 pilot study of intensive insulin therapy, ascorbic acid produced significant GMS2 performance bias (29.2 ± 27.2; P < 0.001) ^[40]. Use of an accurate sensor was associated with lower mean bias, glycemic variability, mean insulin rate, and frequency of hypoglycemia (all P < 0.001 or better) compared with a less-accurate sensor ^[40]. The authors concluded that anemia and high-dose ascorbic acid therapy negatively impact glucose-monitoring-system accuracy and tight glycemic control, and that automatic correction of confounding factors improves glycemic control ^[40].

Management

Nutrition support

Enteral nutrition first

The strongest signal in the modern nutrition literature is in favor of early enteral nutrition. A 2024 systematic review of 19 studies (1,066 participants) found that early enteral nutrition (EEN) compared with non-EEN was associated with significantly lower mortality (OR 0.39, 95 percent CI 0.20 to 0.74, P = 0.004), faster wound healing (mean difference -10.77 days, P < 0.00001), fewer gastrointestinal complications (OR 0.18, P < 0.00001), lower gastrointestinal hemorrhage rates (OR 0.12, P = 0.0001), lower sepsis rates (OR 0.40, P = 0.0005), shorter hospital stay (MD -12.08 days, P < 0.00001), and higher prealbumin levels (MD 29.04, P < 0.00001) ^[43]. The reviewers concluded that EEN is beneficial to reduce complications and the length of hospital stay, maintain organ function, optimize nutritional status, promote wound healing, and improve the survival rate of patients ^[43].

A 2007 head-to-head comparison of total enteral nutrition (TEN) versus total parenteral nutrition (TPN) in severe burn patients found that on postburn day 4 and 8, serum gastrin, plasma motilin, and superoxide dismutase were significantly higher and plasma malondialdehyde, endotoxin, and TNF were significantly lower in the TEN group than the TPN group ^[44]. The authors concluded that enteral nutrition was a more effective route to preserve gastrin secretion and motility, lower intestinal ischemia-reperfusion injury, reduce intestinal permeability, decrease plasma endotoxin and inflammatory mediators, and maintain mucosal barrier function; whenever gastrointestinal function permits, enteral nutrition was superior to parenteral nutrition early after burn ^[44]. The 2011 SEMICYUC-SENPE guideline likewise recommends starting nutritional-metabolic support early, preferentially through the enteral route, with parenteral nutrition as complementary support ^[1]. A 2002 review of total parenteral nutrition notes that the enteral route is indicated when gastrointestinal function is normal but the parenteral route is beneficial in several clinical conditions and is associated with few procedure-related complications ^[50].

The 2004 EAST practice management guideline for nutritional support of the trauma patient emphasizes that nutritional support is an integral, though often neglected, component of the care of the critically injured patient, with recommendations based when possible on studies using trauma or burn patients ^[49].

Pediatric considerations and intraoperative feeding

A 2022 systematic review of intraoperative enteral nutrition in critically ill pediatric burn patients pooled 4 studies of 496 patients (median TBSA 43.8 percent, 30 percent with inhalation injury) and reported no aspiration events; pooled analysis found no differences in aspiration, pneumonia, or wound infection rates between intraoperatively-fed and non-fed patients (P > 0.05) ^[45]. Intraoperatively-fed patients had an average gain of 144.4 kcal/kg and 1.7 days of exclusive enteral nutrition, versus a loss of -119.1 kcal/kg and -1.4 days in the interrupted-feeding cohort, with a cumulative positive caloric balance of +2,673 kcal in fed patients versus a deficit of -7,899 kcal in those with interrupted feeding ^[45]. The authors concluded that continuous intraoperative duodenal feeding during burn surgery appears to be safe in the pediatric burn population, with no reported episodes of aspiration ^[45].

A 2019 pediatric review of EN timing pooled studies of early versus late EN and found no significant difference in mortality between early and late groups (OR 0.72, P = 0.17), but a 3.69-day reduction in length of stay with early EN (P < 0.00001), along with higher serum insulin concentration and lower caloric deficit and weight loss ^[46]. Early EN was associated with a higher incidence of diarrhea and vomiting and decreased intestinal permeability ^[46].

Post-operative re-initiation

A 2014 pilot review of gradual versus goal re-initiation of enteral nutrition after burn surgery in hemodynamically stable patients found that the goal-rate group met 99 ± 12 percent of caloric goals during the 36 hours after surgery versus 58 ± 21 percent in the slow re-initiation group (P = 0.003), with no incidence of emesis, aspiration, or ischemic bowel in either group ^[47]. The authors concluded that enteral nutrition could be re-initiated at goal rate after the first excision and grafting in patients who previously tolerated gastric enteral nutrition and who returned from surgery hemodynamically stable ^[47].

Tube securement

A 2013 controlled study of nasal bridling to secure enteral tubes in burn patients reported significantly fewer tube insertions and abdominal radiographs per tube day in the bridle group than the control group, with clinical advantages over securement with traditional adhesive tape ^[48]. Complications were generally less common in the bridle group, though the differences did not reach statistical significance ^[48].

Caloric targets and overfeeding

A landmark 2002 Hart and Wolfe analysis of energy expenditure and caloric balance in severely burned patients found that erosion of lean body mass was not attenuated by increased caloric balance, while fat mass increased with caloric supply (P < 0.05); in surviving burn patients, caloric delivery beyond 1.2 × REE results in increased fat mass without changes in lean body mass ^[18]. This framing of "more is not better" caloric provision sits behind the modern preference for measured rather than predicted energy targets [18, 21]. A 2023 bibliometric synthesis notes that a diet of ≥60 percent carbohydrates and 12 to 15 percent fat is suitable for burn patients but that the optimal ratios have not been fully determined, and individualized nutritional support programs are the trend in the field ^[70]. The 2019 Wise review emphasizes that exogenous protein and caloric provision performed in isolation is insufficient to optimize outcomes and should be incorporated within a multidisciplinary approach including muscle loading and pharmaceutical adjuncts ^[21]; controversy persists regarding optimal protein targets, and weight-based estimates remain the norm ^[21].

Glycemic control

Hyperglycemia as a prognostic signal

A 2017 study of 1,438 burn patients found that hyperglycemia was the only independent predictor of bacteremia (AUC 0.736) and also a predictor of pneumonia (AUC 0.766) and urinary tract infection (AUC 0.802), and that acute glucose dysregulation may be more important than diabetes in predicting infectious outcomes after burns; admission glucose may therefore have prognostic value ^[41]. A 2013 study of acute versus chronic hyperglycemia and outcomes in burn injury found that chronic hyperglycemia before burn injury was associated with altered glycemic response after burn injury, longer length of stay (13 versus 9 days; P = 0.038), and higher rate of unplanned readmission (18.8 versus 3.6 percent; P = 0.001), though survival rates were similar ^[42].

Insulin

A 2014 pilot study confirmed that severely burned patients benefit from intensive insulin therapy for tight glycemic control ^[40]. Hyperglycemic episodes and exogenous insulin requirements are higher among recombinant human growth hormone recipients, and beta-blockade with propranolol improves insulin resistance, providing two examples of how the pharmacologic interventions interact in the management of glycemic control [27, 71]. Submaximal insulin can promote muscle anabolism without eliciting a hypoglycemic response when paired with adequate amino-acid availability ^[72]; accurate point-of-care glucose monitoring is essential because anemia and high-dose ascorbic acid degrade glucose-monitoring-system accuracy ^[40].

Metformin and exenatide

A 2016 phase II RCT compared metformin with insulin for glucose control in severely burned patients and found that metformin controlled blood glucose equally well to insulin with no difference between groups; the metformin group had only one mild hypoglycemic episode (6 percent) versus 15 percent incidence of hypoglycemia in the insulin group (P < 0.05) ^[39]. Oral glucose tolerance testing at discharge showed that metformin significantly improved insulin sensitivity (P < 0.05), and metformin had a strong antilipolytic effect compared with insulin and was associated with significantly reduced inflammation (P < 0.05) ^[39]. The authors concluded that metformin decreases glucose as effectively as insulin without causing hypoglycemia, with additional benefits including improved insulin resistance and decreased endogenous insulin synthesis ^[39].

A 2010 RCT in severely burned pediatric patients found that exenatide produced similar daily-average glucose values to standard intensive insulin therapy (130 ± 28 versus 138 ± 25 mg/dl, P = 0.31) while requiring significantly less exogenous insulin (22 ± 14 versus 76 ± 11 IU per patient per day, P = 0.01), with similar hypoglycemia incidence between groups; exenatide was well tolerated and potentially represents a novel agent to attenuate hyperglycemia in the critical care setting ^[38].

Pharmacologic modulators of hypermetabolism

Propranolol (beta-blockade)

The longest-standing evidence-supported pharmacologic modulator of burn hypermetabolism is propranolol. A 2016 systematic review and meta-analysis of nine RCTs and one non-randomized controlled trial of adrenergic blockade after burn injury found a positive effect favoring propranolol that significantly decreased resting energy expenditure (Hedges' g = -0.64, 95 percent CI -0.8 to -0.5, P < 0.001) and trunk fat (g = -0.3, P < 0.001), while improving peripheral lean mass (g = 0.45, P < 0.001) and insulin resistance (g = -1.35, P < 0.001); occurrence of adverse events did not differ significantly between treated and control groups ^[27]. A 2007 study in severely burned children confirmed that propranolol does not increase inflammation, sepsis, or infectious episodes; mortality was 6 percent in controls and 5 percent in the propranolol group, infections occurred in 30 percent of controls and 21 percent on propranolol, and sepsis incidence was 10 versus 7 percent ^[28]. Propranolol significantly decreased REE and predicted REE during acute hospital stay and decreased serum TNF and IL-1beta (P < 0.05) ^[28].

A 2023 RCT examining the metabolomic mechanism of propranolol found that propranolol substantially alters several essential metabolic pathways involved in energy and nucleotide metabolism and catecholamine degradation (P < 0.05), with lipidomic shifts toward an anti-inflammatory phenotype, mediated by decreased activation of hormone-sensitive lipase at serine 660 and reduced endoplasmic reticulum stress through decreased phospho-JNK (P < 0.05) ^[25]. The investigators concluded that propranolol's ability to mitigate pathophysiological changes to essential metabolic pathways results in significantly improved stress responses ^[25].

A 2015 RCT of propranolol in severely burned adults found that daily average heart rate over the first 30 days was significantly lower in the propranolol group (P < 0.05); the average number of days between skin grafting procedures was 10 ± 5 days versus 17 ± 12 days in controls (P = 0.02), and propranolol was associated with a 5 to 7 percent improvement in perioperative hematocrit during grafting procedures of 4,000 to 16,000 cm² (P = 0.002) ^[26]. The authors concluded that propranolol during acute hospitalization diminishes blood loss during skin grafting procedures and markedly improves wound healing in severely burned adults ^[26]. A 2009 study of propranolol in hospitalized burn patients reported faster healing of superficial burns (16.13 ± 7.40 versus 21.52 ± 7.94 days, P = 0.004) and shorter time to skin graft for deep burns (28.23 ± 8.43 versus 33.46 ± 9.17 days, P = 0.007) ^[29].

Oxandrolone (anabolic steroid)

Oxandrolone is a synthetic testosterone analogue used in burn care ^[30]. A 2016 systematic review and meta-analysis of oxandrolone in severe burns found that oxandrolone did not affect mortality (RR 0.85, 95 percent CI 0.38 to 1.89, P = 0.69) or infection (RR 0.87, P = 0.26), and the groups showed no significant difference in liver dysfunction (RR 1.15, P = 0.41) ^[30]. Treatment with oxandrolone shortened length of stay by 3.02 days, donor-site healing time by 4.41 days, time between surgical procedures by 0.63 days, and reduced weight loss by 5 kg and nitrogen loss by 8.19 g per day ^[30]. Oxandrolone treatment also led to an additional gain in lean body mass of 3.99 percent at 6 months and 10.78 percent at 12 months in patients with severe burns ^[30].

A 2003 Ann Surg study found that oxandrolone improved protein net balance, lean mass, and gene expression in severely burned patients; body weights and fat-free mass decreased significantly in the placebo group while remaining stable in the oxandrolone group ^[31]. A 2003 study by Demling and DeSanti showed that patients receiving oxandrolone in the rehabilitation unit regained weight and lean mass two to three times faster than with nutrition alone (P < 0.05), and the restored body weight and lean mass were maintained 6 months after discontinuation of oxandrolone, while lean mass was not yet restored in the nutrition-alone group ^[32]. A 2004 study of long-term oxandrolone in severely burned children found that lean body mass was significantly greater with oxandrolone at 6, 9, and 12 months after burn (P < 0.001), bone mineral content was significantly greater at 12 months (P < 0.016), and age- and gender-matched bone mineral density z-scores were significantly better (P < 0.039); liver transaminases were unaffected ^[33]. A 2005 Ann Surg study of metabolic and hormonal changes during long-term oxandrolone treatment in burned children reported improved lean body mass, bone mineral content, and muscle strength compared with controls during treatment (P < 0.05), with significant increases in height and weight observed after the end of treatment ^[34].

Recombinant human growth hormone

A 2009 RCT of long-term growth hormone treatment in severely burned children found that rhGH administration markedly improved growth and lean body mass while significantly attenuating hypermetabolism; serum growth hormone, IGF-1, and IGFBP-3 were significantly increased and percent body fat decreased significantly compared with placebo (P < 0.05) ^[35]. Resting energy expenditure improved with rhGH administration, most markedly at the 0.1 mg/kg/day dose (P < 0.05), and long-term administration of 0.1 and 0.2 mg/kg/day rhGH significantly improved scarring at 12 months postburn (P < 0.05) ^[35]. An unexpected decrease in bone mineral content occurred in the 0.2 mg/kg/day group along with a decrease in PTH and increase in osteocalcin (P < 0.05) ^[35].

A 2004 RCT of growth hormone in burned children found that recombinant human growth hormone therapy did not adversely affect scar formation; types I and III collagens were increased in the reticular layer of scars from both groups compared with paired normal skin, IGF-1 was significantly increased in the rhGH group, and no between-group differences were seen using scar scales, planimetry, or immunohistochemistry ^[36]. A 2016 study of sustained-release growth hormone during rehabilitation of adult burn survivors found that oxygen consumption at the lactate threshold, maximum oxygen consumption, lean body mass, knee extensor peak torque, and IGF-1 and adiponectin levels were significantly higher in the SR-hGH group than controls at 3 months ^[37]. There were no differences in body weight, blood pressure, bone mineral content, percent body fat, or burn scar characteristics between groups ^[37].

A 2000 study of decreased serum IGF-1 in burn patients found that fish oil and low-fat nutrition solutions correlated with higher serum IGF-1 concentrations; the presence of fish oil allowed for more rapid recovery of serum IGF-1 levels ^[65]. A 2004 study of IGF-1/IGFBP-3 in severe burn found that exogenous IGF-1/IGFBP-3 treatment partially reverses the post-burn shift toward a predominant Th2 phenotype, increasing IL-2 and IFN-gamma production while decreasing IL-4 (P < 0.05) ^[64].

Drug interactions and combination therapy

A 1996 mechanism study of beta-blockade combined with growth hormone in burned children found that exogenous rhGH increased the rate of appearance of free fatty acids, while propranolol decreased the rate of FFA appearance but maintained the rate of secretion of fatty acids in the form of VLDL-TG from the liver ^[16]. The authors concluded that propranolol administration to burned children receiving rhGH is safe, with salutary cardiovascular effects, decreased release of free fatty acids from adipose tissue, and increased efficiency of the liver in secreting fatty acids as VLDL triglycerides ^[16].

Pharmaconutrients

Glutamine

Glutamine is the most-studied pharmaconutrient in burns, with conflicting evidence. A 2022 multicenter RCT of intravenous glutamine versus standard care in severe burn patients found that the glutamine group had significantly lower levels of diamine oxidase, lactulose/mannitol ratio, β2-microglobulin, lactate dehydrogenase, hydroxybutyrate dehydrogenase, and cardiac troponin I (P < 0.05 or 0.01), along with significantly lower resting energy expenditure, serum catecholamines, glucagon, lactate, and HOMA (P < 0.05 or 0.01) ^[52]. No significant difference was found in length of hospitalization or mortality between groups ^[52]. The investigators concluded that glutamine moderately alleviates the hypermetabolic response and reduces organ damage after severe burns ^[52].

A 2024 systematic review and meta-analysis of glutamine in burn patients pooled 16 trials and reported a length-of-hospital-stay reduction of 7.95 days (95 percent CI -10.53 to -5.36), improved wound healing rates and times, and reduced wound infection (RR 0.38, 95 percent CI 0.21 to 0.69) but no reduction in nonwound infection or in-hospital mortality ^[51]. The reviewers explicitly cautioned that positive effects were either influenced by or based on small-scale, single-center studies, and concluded that based on the current available data, they do not recommend the routine use of glutamine supplement for burn patients in hospital ^[51]. An earlier 2004 stable-isotope study of short-term enteral glutamine in burned children found that during the glutamine feeding period, leucine flux and leucine oxidation rate were significantly lower than during conventional feeding, but no significant difference in net leucine accretion into proteins was demonstrated; the authors suggested that several days of glutamine supplementation may be required to restore plasma glutamine levels and stimulate protein synthesis ^[53]. A 2005 study of glutamine granules supplementing enteral nutrition in severely burned patients found significantly higher plasma glutamine, prealbumin, and transferrin in the glutamine group, along with lower urine nitrogen and 3-methylhistidine excretion and shorter hospital stay (46.59 ± 12.98 versus 55.68 ± 17.36 days, P < 0.05) ^[54].

Micronutrients

Trace elements

A 1998 double-blind placebo-controlled trial of trace element supplementation in major burns found that plasma selenium remained normal in the trace-element group but decreased in controls (P < 0.05 on days 1 and 5); the number of infections per patient was significantly lower in the trace-element group (1.9 ± 0.9 versus 3.1 ± 1.1, P < 0.05), driven by fewer pulmonary infections, and early trace element supplementation was associated with shorter hospital stay when data were normalized for burn size ^[56]. A 2007 study by Berger et al. of trace element supplementation after major burns demonstrated that plasma TE concentrations were significantly higher in the TE group, skin contents of selenium (P = 0.05) and zinc (P = 0.04) increased significantly by day 20 in burned areas, and plasma and tissue antioxidant status was improved by supplementation ^[55]. The number of infections in the first 30 days was significantly lower in the TE group (median 2 versus 4 infections per patient, P = 0.015), and wound healing was improved with lower requirements for regrafting (P = 0.02) ^[55]. The SEMICYUC-SENPE guideline likewise indicates a role for high-dose micronutrient supplementation in critically ill burn patients ^[1].

Vitamin D

Vitamin D deficiency is common after severe burns and is associated with worse outcomes. A 2017 study of 318 burn patients on admission found that 14.5 percent had vitamin D deficiency, 65.1 percent had insufficiency, and only 20.4 percent had normal vitamin D levels; patients with deficiency or insufficiency experienced higher rates of complications and longer ICU and hospital length of stay compared with those with normal vitamin D levels ^[59]. A 2004 Lancet study by Klein et al. demonstrated that severe burn injury is associated with vitamin D deficiency, low bone turnover, and abnormalities in calcium homeostasis, with reduced conversion of 7-dehydrocholesterol to previtamin D3 in children a mean of 14 months after the burn ^[17]. A 2009 study by the same group found that supplementation of burned children with a standard multivitamin tablet stated to contain 400 IU of vitamin D2 failed to correct the vitamin D insufficiency; serum 25(OH)D was 21 ± 11 ng/ml in the supplemented group (sufficient range 30 to 100), with only one of eight children having a sufficient value, and bone mineral content of the total body and lumbar spine failed to increase as expected ^[58].

Thiamine

A 2010 study of thiamine supplementation in burn patients found that serum thiamine levels increased significantly with supplementation (P < 0.001) and were closely associated with decreases in pyruvate and lactate levels ^[57]. The authors noted that further study of changes in metabolic flux and a randomized controlled trial of thiamine supplementation are required to establish whether thiamine supplementation is beneficial to burn patients ^[57].

Non-pharmacologic strategies and exercise

Early excision, thermal neutrality, and wound closure

The non-pharmacologic strategies for blunting hypermetabolism include early excision and wound closure of the burn wound, aggressive treatment of sepsis, elevation of environmental temperature to thermal neutrality (31.5 ± 0.7 °C), high-carbohydrate high-protein continuous enteral feeding, and early institution of resistive exercise programs ^[5]. The 2005 Pereira and Herndon review of pharmacologic modulation of the hypermetabolic response argued that early burn-wound excision and complete wound closure, prevention of sepsis, maintenance of thermal neutrality by elevation of ambient temperature, and graded resistance exercises during convalescence are simple, highly effective primary treatment goals ^[15]. Even with these measures, hypermetabolism cannot be completely reversed, but it may be manipulated by nonpharmacologic and pharmacologic means ^[15]. The 2000 Noordenbos continuous-metabolic-monitoring study makes this concrete: even with all full-thickness burns completely excised by a mean of 6.5 days postburn and enteral feedings meeting 99.4 percent of measured caloric needs, mean daily energy expenditure remained 184.9 percent of Harris-Benedict baseline through 42 days ^[10].

Exercise

A 2023 RCT of exercise training in adults with acute burn injury (n = 57, burns 10 to 70 percent TBSA) allocated patients to standard of care or to additional resistance and aerobic training commenced as early as possible according to safety criteria ^[60]. Exercise training induced significant improvements in quadriceps muscle layer thickness, rectus femoris cross-sectional area, muscle strength, and the BSHS-B subscale hand function, and the authors concluded that exercise during the acute phase reduced muscle wasting and improved muscle strength throughout burn-center stay ^[60]. A 2018 systematic review and meta-analysis of exercise training post-burn found no significant differences post-exercise in VO2peak, REE, or muscle strength between groups, but evidence suggested exercise had a beneficial effect on body composition (g = 0.59, P = 0.03), need for surgical release of contractures (RR = 0.34, P = 0.004), and health-related quality of life ^[61]. The reviewers cautioned that a lack of evidence existed regarding the safety of exercise training post-burns ^[61]. A 2001 RCT of a 12-week resistance exercise program in children with burn injuries found that participation in a resistance exercise program resulted in significant improvement in muscle strength, power, and lean body mass relative to a standard rehabilitation program without exercise ^[62].

Complications

Multiorgan dysfunction

A 2014 study of multiorgan dysfunction in pediatric burn patients found that respiratory failure has the highest incidence in the early phase of postburn injury and decreases starting 5 days postburn; cardiac failure has the highest incidence throughout hospital stay; hepatic failure increases with hospital length of stay and is associated with high mortality during the late phase of acute hospital stay; renal failure has an unexpectedly low incidence but is associated with high mortality during the first 3 weeks postburn; and three or more organ failures are associated with very high mortality ^[69].

Bone loss

Severe burns cause exaggerated catabolism of muscle protein and inhibit bone deposition ^[33]. Children with vitamin D deficiency after severe burn fail to increase bone mineral content of the total body and lumbar spine, as well as lumbar spine bone density, with standard multivitamin supplementation ^[58]. Long-term oxandrolone administration in severely burned children safely improves lean body mass, bone mineral content, and bone mineral density ^[33], but rhGH at higher doses (0.2 mg/kg/day) produced an unexpected decrease in bone mineral content along with a decrease in PTH and an increase in osteocalcin ^[35].

Hyperglycemia-associated infectious risk

Admission hyperglycemia and acute glucose dysregulation independently predict bacteremia, pneumonia, and urinary tract infection after burn injury, with hyperglycemia in some analyses outperforming a diabetes diagnosis as an infectious-outcome predictor ^[41]. Chronic pre-burn hyperglycemia is associated with longer length of stay and higher unplanned readmission after burn injury ^[42].

Special Considerations

Pediatric patients

Children mount a less catabolic muscle protein response than adults during the acute phase after burn. Muscle net protein balance is significantly less negative in children (8 ± 68 versus -43 ± 61 nmol Phe/min/100 ml in adults; P < 0.05), and muscle protein fractional synthesis rate is higher in children (0.16 versus 0.11 percent per hour; P < 0.05) ^[3]. The hypermetabolic response in children with the largest burns (>80 percent TBSA) is the most severe, with the highest percentage predicted REE, greatest loss of body weight, lean body mass, muscle protein, and bone mineral content (P < 0.05) ^[13]. Children with greater than 80 percent burns also have the highest urine cortisol concentrations, with significant myocardial depression and increased change in liver size ^[13]. Long-term oxandrolone in severely burned children safely improves lean body mass, bone mineral content, and bone mineral density at 6, 9, and 12 months ^[33], and rhGH at 0.1 mg/kg/day significantly attenuates hypermetabolism and improves scarring at 12 months ^[35]. A 2010 RCT of exenatide in severely burned pediatric patients was well tolerated and significantly reduced exogenous insulin requirements without increasing hypoglycemia ^[38].

Elderly patients

A 2015 prospective study of the pathophysiologic response to burns in the elderly compared with adults found that elderly patients had a profoundly increased mortality, more premorbid conditions, and longer hospital stay (P < 0.05); the incidence of infection and sepsis was not higher (P > 0.05), but a significantly increased incidence of multi-organ failure was found (P < 0.05) ^[67]. These clinical outcomes were associated with a delayed hypermetabolic response, increased hyperglycemic and hyperlipidemic responses, an inverted inflammatory response, immune compromise, and substantial delay in wound healing ^[67]. The Lethal Dose 50 burn size in the elderly has remained unchanged over the past three decades, despite the increased demand for elderly burn care ^[67]. A 2024 multicenter retrospective analysis of elderly severe burn patients identified age, total burn area, full-thickness burn area, serum creatinine within the first 24 hours, and activated partial thromboplastin time within the first 24 hours as independent risk factors for 28-day mortality; elderly patients with severe burns had injuries mainly from flame burns, often with moderate to severe inhalation injury, enhanced inflammatory response, elevated blood glucose, and impaired organ function in the early stage ^[68].

Sex differences

A 2007 study of sex differences in long-term outcome after severe thermal injury found that predicted REE was significantly decreased in girls at discharge and at 6, 12, and 18 months postburn (P < 0.05) ^[66]. Girls had improved change in bone mineral content and percent fat compared with boys (P < 0.05), and significantly higher levels of IGF-1, IGFBP-3, free thyroxine index, T4, and insulin (P < 0.05); no differences were found for T3 uptake, osteocalcin, cortisol, growth hormone, and PTH between groups ^[66]. The authors concluded that girls have a reduced REE associated with changes in bone content and endogenous anabolic hormones ^[66].

Outcomes

Resting energy expenditure and its trajectory are themselves prognostic. Declining REE during the hospital course correlates with mortality (P < 0.05), and declining energy expenditure appears to be a harbinger of mortality in severely burned patients ^[18]. Early enteral nutrition in severe burn patients was associated with significantly lower mortality in a 2024 systematic review (OR 0.39, 95 percent CI 0.20 to 0.74) ^[43]. Long-term oxandrolone administration produces sustained gains in lean body mass that persist after the drug is discontinued [32, 33]. Long-term rhGH administration improves growth, lean body mass, and scarring while attenuating hypermetabolism ^[35]. Propranolol decreases REE, improves insulin resistance and lean mass, and reduces blood loss during grafting without increasing infection or sepsis rates [27, 28, 26]. The combined picture is that no single intervention reverses the burn-induced hypermetabolic response, but a multimodal approach moderates the catabolic trajectory toward better lean-mass preservation, fewer infections, and shorter hospital stay [5, 15, 21].

Controversies and Evidence Gaps

Caloric targets remain a contested question. The 2002 Hart and Wolfe analysis showing that caloric delivery beyond 1.2 × REE produces fat rather than lean mass ^[18] sits uneasily next to older formulas (Curreri, Harris-Benedict) that systematically overestimate measured REE by 25 to 40 percent ^[24]. The 2011 SEMICYUC-SENPE guideline acknowledges that exact calculation of calorie-protein requirements in these patients is difficult even when indirect calorimetry is used, due to high loss of proteins and CO2 through the skin ^[1]. The optimal macronutrient ratio (carbohydrate, protein, fat) has not been fully determined ^[70], and weight-based protein estimates remain the norm despite acknowledgement that they are imprecise ^[21].

The glutamine literature illustrates how evidence direction can change with study scale. Earlier single-center studies suggested benefit on length of stay and wound healing, and a 2022 multicenter RCT showed reductions in REE, serum catecholamines, glucagon, lactate, HOMA, and organ-damage markers ^[52]. A 2024 meta-analysis confirmed benefits in length of stay, wound healing, and wound infection but found no mortality reduction, and noted that the positive effects were either influenced by or based on small-scale, single-center studies; the meta-analysis investigators concluded that they do not recommend routine use of glutamine in hospital based on currently available data ^[51]. The same tension exists for thiamine, where supplementation increases serum thiamine and reduces pyruvate and lactate but a definitive RCT is not yet available ^[57].

The use of standard multivitamin supplementation to correct vitamin D insufficiency after severe burn does not work; specific high-dose vitamin D supplementation appears necessary, though the dosing has not been established by RCT [17, 58]. The 2009 Klein study found that 400 IU vitamin D2 in a standard multivitamin failed to correct vitamin D insufficiency in burned children ^[58].

The role of rhGH continues to evolve. Long-term rhGH administration in severely burned children significantly attenuates hypermetabolism and improves lean body mass and scarring ^[35], but at the higher 0.2 mg/kg/day dose produces unexpected decreases in bone mineral content along with decreases in PTH and increases in osteocalcin ^[35]. Hyperglycemic episodes and exogenous insulin requirements are higher in rhGH recipients ^[71]. These adverse effects, plus the unblunted muscle wasting seen on prior burned subsets in stable-isotope work, leave the optimal patient selection and dosing for rhGH unsettled.

Adrenergic-blockade evidence is positive on metabolic and wound-healing outcomes, but the 2016 meta-analysis investigators noted that further trials on adult populations with a broader range of outcome measures are warranted ^[27]. Whether propranolol changes mortality in burn patients has not been definitively established at meta-analytic scale.

Metformin is an emerging alternative to insulin for glucose control in severely burned patients, with a 2016 phase II RCT showing equal glycemic control with significantly less hypoglycemia and improvements in insulin sensitivity and antilipolytic effect ^[39]. A larger phase III trial confirming these signals across multiple centers is not yet published.

Exercise training during the acute phase reduces muscle wasting and improves muscle strength in a 2023 RCT ^[60], but a 2018 systematic review found inconsistent effects on VO2peak, REE, and muscle strength and explicitly cautioned that the safety of exercise training post-burns has not been adequately characterized ^[61].

Finally, the persistence of hypermetabolism past wound healing remains incompletely explained. Gene-expression and protein-balance studies show that mechanisms beyond wound healing are involved in the sustained muscle catabolism [2, 12], but the molecular drivers of the post-discharge phase are not fully mapped, and no intervention has been shown to completely reverse the response [5, 15].

References

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