Burns in Children
W.B. Norbury, M.G. Jeschke, and D.N. Herndon
Introduction
Burns account for around 700,000 emergency department visits every year resulting in around 50,000 admissions to hospital in the United States [1]. Around 50 % of these admissions have burns of less than 10 % total body surface area (TBSA) and, as such, have near normal metabolic rates. For the remainder, the rise in metabolic rate is linked to burn size and for those with severe thermal injuries (8 40 % TBSA) the change in patient metabolism is, if left unchecked, set to last for more than 12 months. The change contributes, at least in part, to long term deleterious effects on the individual. It has been previously shown that the ensuing period of hypermetab- olism and catabolism following a severe burn leads to impaired immune function, decreased wound healing, erosion of lean body mass, and hinders rehabilitative efforts delaying reintegration into normal society. However, the magnitude and lon- gevity of these changes has yet to be fully elucidated. Strategies for attenuating these maladaptive responses may be divided into pharmacological and non-pharmacolog- ical. Non-pharmacological approaches include prompt, early excision and closure of wounds, pertinacious surveillance for and treatment of sepsis, early commencement of high protein high carbohydrate enteral feeding, elevation of the immediate envi- ronmental temperature to 31.5 °C ( „ 0.7°C), and early institution of an aerobic resis- tive exercise program. Several pharmacotherapeutic options are also available to fur- ther reduce metabolic rate and as such attenuate the erosion of lean body mass;
these include anabolic agents such as recombinant human growth hormone, insulin, and oxandrolone and also beta blockade using propranolol. This chapter will men- tion what has been shown in the past concerning these metabolic changes during the acute admission, but will concentrate on the long term sequelae of these changes and how they can be attenuated by early institution of different pharmacological interventions.
Acute Metabolic Alterations Following Burn Injury
The Hypermetabolic ResponseSevere burns lead to a hypermetabolic response far in excess of that seen in any other disease state [2] and although patients admitted with multiple traumatic wounds have an increase in metabolic rate that rises further when placed on a venti- lator to between 30 and 75 % that of normal, those admitted with burns involving more than 40 % of the TBSA have increases in metabolic rate of between 80 to 200 % of normal. The subsequent wound and metabolic response result in a nitrogen defi-
cit of up to 30 g/day. This hypermetabolic response is characterized by a hyperdy- namic circulation, hyperthermia, increased oxygen and glucose consumption, car- bon dioxide production, glycogenolysis, lipolysis, proteolysis, and futile substrate cycling [3]. The magnitude of the response is dependent on body weight at admis- sion, time from burn to removal of eschar and the percentage of TBSA that is burned [4] (Fig. 1, 2). Recently gender has been shown, in pediatric patients, to have a direct effect on resting energy expenditure with female children having a reduced resting energy expenditure (REE) at all time points during acute hospitalization up to 9 months post-burn [5]. The rise in metabolic rate has a large net catabolic effect on the individual, the magnitude of which is dependent both on the severity of hypermetabolism and the development of sepsis during admission [4]. REE rises in a curvilinear manner from around normal levels for small burns of less than 10 % TBSA to double the predicted level for individuals with burns in excess of 40 % TBSA. For those patients maintained at thermal neutrality (33 °C) the REE increase is attenuated at 1.8 times predicted during acute admission, this then reduces to 150 % when fully healed, 140 % at 6 months post burn, 130 % at 9 months and 110 % at 12 months [6] (Fig. 3).
Fig. 1. a Association between admission weight and negative protein balance; b Association between time to primary wound excision and negative protein net balance. Data presented as mean „ SEM. From [4]
with permission
Fig. 2. Influence of burn size area (‹ or & 40%
total body surface area [TBSA]) on catabolism.
Data presented as mean „ SEM. *p ‹0.0001 by Student t test. From [4] with permission
Fig.3. Resting energy expenditure.
Indirect calorimetry was used to measure energy expenditure in a resting state at admission, full heal- ing, and 6, 9, and 12 months after burn. At all time points, the energy expenditure was higher than the basal metabolic rate predicted for age-, sex-, weight-, and height- matched individuals by the Harris- Benedict equation. Error bars repre- sent 95 % confidence intervals.
From [6] with permission
Mediators of Hypermetabolism
The cause of the hypermetabolic response is unclear; however, endotoxin, platelet- activating factor (PAF), tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6, arachidonic acid metabolites using the cyclooxygenase and lipoxygenase pathways, neutrophil-adherence complexes, reactive oxygen species (ROS), nitric oxide (NO), and the coagulation and complement cascades have all been implicated in regulating this response [7].
Cytokines
IL-1 and TNF have been linked in the past to the rise in metabolic rate seen in chronic inflammatory conditions such as rheumatoid arthritis [8]. Together with IL-6 these cytokines play an important role in the initial development of the acute phase metabolic response [9]. A recent study [10] has highlighted the changes in cytokine expression seen following severe burn injuries in children: The results showed significant increases in both pro- and anti-inflammatory cytokine expres- sion immediately following the initiating event. During the first week following injury, significant increases were seen in IL-1q , IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 p70, and IL-13 as well as interferon * (IFN * ), monocyte chemoattrac- tant protein 1 (MCP-1), macrophage inflammatory protein 1q , and granulocyte col- ony-stimulating factor (G-CSF). However within 5 weeks the serum concentrations of most cytokines had reduced again but remained above those for non-burned patients.
Catecholamines
The increase in circulating levels of catecholamines has long been attributed to a compensatory mechanism countering the internal cooling of the patient caused by fluid evaporation from the wound. This increase in catecholamine consequently leads to an increase in metabolic rate. However, the entire increase in REE cannot be attributed to this effect as when [ and q -adrenoceptor blockade is initiated the resulting reduction in REE amounts to only about 15 % [4].
Cortisol
Cortisol has been implicated in both the initiation and maintenance of the hyper- metabolic response albeit via different receptors.
It is well established that a combination of these factors is responsible for the ini- tial response to severe burn injury. However, little is known about the factors that maintain the hypermetabolic response once these have reduced to near normal lev- els. Cytokine levels are close to normal 5 weeks from initial injury, cortisol levels are almost normal at around 100 days, and catecholamine levels are back to near normal at around 100 days following initial injury. So how can we explain the sustained increase in REE that is seen following severe injury? Typically the acute response to stressful stimuli commences in the hypothalamus with the release of corticotropin releasing factor (CRF) which in turn binds to CRF-1 receptors in the anterior pitui- tary. Although almost certainly linked to the initiation of hypermetabolism, recently the CRF type-2 receptor ligand has been proposed as integral to maintenance of the hypermetabolism associated with burns [11]. The receptor ligand most likely to be involved is one of the urocortin (UCN) peptides. Localization studies have proposed UCN2 or UCN3 to be the peptides affecting the CRF-2 receptors in the hypothala- mus [12]. Once levels of CRF have fallen to near normal levels it is the UCNs that have been implicated in maintaining this deleterious effect [11].
Consequences of Acute Metabolic Changes
Alterations in Metabolism of Carbohydrate, Protein, and Fat
The increase in energy expenditure is mirrored by substrate oxidation resulting from increases in ATP consumption. Increases in catecholamine, glucagon and glu- cocorticoid production lead to enhanced glycogenolysis and protein breakdown in both the liver and skeletal muscle. This in turn leads to increases in triglyceride, urea, and glucose production (gluconeogenesis), which consequently leads to hyper- glycemia. The process of substrate cycling leads to increased thermogenesis, which raises core and skin temperature to 2 °C above that of normal, unburned patients.
Raised catecholamine levels also increase peripheral lipolysis and subsequent tri- glyceride-fatty acid cycling lead to fatty infiltration of the liver such that the liver weight increases by 120 % [13] (Table 1); this, has been associated with an increased incidence of sepsis; however, no causative effect has been found.
A large proportion of the glucose produced by the liver is directed towards the burn wound where it is consumed by the anaerobic metabolism of inflammatory cells, fibroblasts, and endothelial cells; this in turn produces lactate which is recycled back to the liver and into gluconeogenic pathways. The catabolism of protein in skel- etal muscle produces three carbon amino acids, such as alanine, that are also recy- cled to the liver to contribute to gluconeogenic pathways. The release of catechol- amines increases glucagon secretion, which in turn promotes gluconeogenesis. The relative insulin resistance seen following a major burn combined with increased hepatic gluconeogenesis lead to hyperglycemia; patients in this situation have been
Table 1. Liver weight per body weight (BW) for normal vs burned patients (2 months to 15 years of age) [13]
Full-Thickness Burn ( %) Liver wgt/BW (g/kg) Weight Increase ( %)
Normal (n = 14) 0 34.3 „ 1.1 –
Burn (n = 14) 76 „ 5 75.6 „ 6.0* 120
burn size and liver weight ratios are means „ se, *p‹ 0.001
shown to have an increased rate of muscle protein breakdown [14]. A study measur- ing whole body protein flux in normal individuals showed a three fold increase in the rate of protein catabolism with no accompanying alteration in protein synthesis during a period of hyperglycemia [15]. Endogenous anabolic hormone levels change, with both insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 significantly lower immediately after burn, and neither reaching normal levels after 40 days post-burn. Serum insulin levels are significantly increased during the same time period with female patients producing up to 3 times normal levels;
however, in the presence of insulin resistance hyperglycemia remains a problem.
Endogenous growth hormone levels also fall 4 to 5 fold initially and remain below half the normal level during the first 40 days. The result of these levels combined with relative insulin resistance in the burns patient leads to a marked reduction in protein synthetic ability which can only be reversed by restoration of more normal levels from an exogenous source.
Erosion of Lean Body Mass
The change in regulation of skeletal muscle during the stress response following major trauma is due to the activation of pathways of protein breakdown. Recent studies have shown one of the chief protagonists to be the ubiquitin-proteasome pathway [16]. Ubiquitin is a common 8 kDa peptide found throughout all eukaryotic cells (hence the name). During skeletal muscle degradation it is activated in a step- wise process to covalently attach to other proteins, reducing their ability to disasso- ciate from proteosomes and subsequently leading to degradation of the protein it has attached to. Ubiquitin has seven lysine residues, the use of which confers differ- ent functions. Chains of ubiquitin peptides linked via lysine 48 lead to degradation of the target protein by the proteasome. However, those linked by lysine 63 appear to confer signaling functions in the nuclear factor-kappa B (NF-κB) pathway, and act as mediators in DNA repair and the stress response. The role of ubiquitin peptides linked by other lysine residues is still unclear. The ubiquitin pathway is stimulated by TNF and the rise in glucocorticoids seen following severe thermal injury. The other main reason for the net loss of skeletal muscle is due to an imbalance in the rate of amino acid production secondary to protein breakdown and the ability of the cell to retain and re-use these amino acids. A study comparing the protein turnover in patients suffering from massive burns with that in normal individuals reported an increase in both muscle protein degradation and muscle protein synthesis in the burns group [17]. However, there was an 83 % increase in muscle protein degrada- tion compared with a 50 % increase in muscle protein synthesis. In the same study absolute values of inward transport of phenylalanine, leucine, and lysine were not significantly different in the two groups. However, the ability of transport systems to take up amino acids from the bloodstream, as assessed by dividing inward transport by amino acid delivery to leg muscle, was 50 – 63 % lower in the patients. In contrast, outward phenylalanine and lysine transport were 40 % and 67 % greater in the patients than in the controls, respectively [17]. These results suggest that the increased protein synthesis seen is secondary to the rise in amino acid concentra- tion; however this synthetic rate is unable to keep up with the acceleration in protein breakdown. The increased net efflux of amino acids from the cell is facilitated by accelerated outward transmembrane transport and impaired influx due to the hyperdynamic circulation caused by the rise in catecholamine release [17].
Wound Healing Delays
This rise in metabolic rate and resulting loss of total body protein results in decreased immune defenses, decreased wound healing, and exhaustion which hin- ders rehabilitation [6].
Effects of Cortisol
The 8-fold increase in urinary cortisol that is seen in the acute stages following burn injury has been linked to a marked decrease in bone formation and mineral apposi- tion, a lack of detectable surface osteoblasts, a reduction in type-I collagen expres- sion in bone, and a reduction in biochemical markers of osteoblast differentiation, all consistent with an effect of excessive glucocorticoids [18]. Increases in glucocor- ticoids, together with Fas ligand have been shown to induce lymphocyte apoptosis following burn injury. Hypercortisolemia has been shown to increase REE and glu- tamine flux in a dose-dependent manner through an increase in de novo synthesis.
The increase in REE was not accompanied by any significant change in respiratory quotient, therefore, it has been surmised that this increase is due to raised oxidation of fat. Typically, following a severe thermal injury a protracted amount of time is spent in intensive care undergoing multiple operations in order to speed the recov- ery of the patient. Much of this time is spent in bed with much less time spent exer- cising than for normal individuals. The combination of hypercortisolemia and pro- longed inactivity substantially increases muscle protein catabolism via a reduction in muscle protein synthesis [19].
Effects of Catecholamines on Infection and Inflammation
The increase in catecholamines following burn injury has been implicated in several deleterious outcomes. Stimulation of the [ 1-adrenergic receptor population acts as an upstream activator of p38 mitogen activated protein kinase (MAPK), JNK, and NF-κB in burn trauma [20]. Since these molecules are important in the signal trans- duction pathway that induces inflammatory cytokine biosynthesis, the alpha-recep- tor may be an important mediator of burn-induced inflammatory cytokine secre- tion. The increase in norepinephrine has been linked to increased CCL2 production and the generation of the type 2 T cell phenotype [21]. Norepinephrine has also been linked to reduced production of burn associated CCL3 [22], an important q - chemokine that regulates migration of monocytes, T cells, neutrophils, eosinophils, basophils, and natural killer (NK) cells.
CXC Chemokines and Burns
The levels of CXCL8 (IL-8), an important factor in chemoattraction and activation of polymorphonuclear neutrophils (PMN) are raised far in excess of normal range in burns patients in the first 5 days after injury. When burns patients become septic there is another large rise in CXCL8 that correlates closely with patient mortality;
this may be in part due to the reduced surface expression of CXCR2 (one of the receptors for CXCL8) on PMN.
CC Chemokines and Burns
As stated earlier there is an increase in CCL2 (MCP-1) production that is 80 fold higher than normal in those patients with large burns; this in turn stimulates type 2 T cell generation and subsequent IL-4 production by the activated T cells. IL-4 and IL-3 produced by activated Th2 cells stimulate production of ineffective macro- phages via increases in CCL17 (thymus and activation regulated chemokine, TARC).
Therefore, both CCL2 and CCL17 are seen as deleterious to the outcome of the burns patient, leading to increased incidence of infection. CCL3 and CCL5 have all been shown to be decreased in burns patients. CCL3 is an important modulator of host defense against bacterial infection.
Delayed Metabolic Changes
As has been explained earlier, the expression of cortisol in the acute and delayed stages of burn recovery appears to be governed by two different pathways. Whatever the mechanism leading to the protracted course of hypercortisolemia, the effects are the same. Acutely, osteoblasts increase the production of receptor activator of NF-kB ligand (RANKL) in response to rises in glucocorticoid, which in turn increases oste- oclastogenesis and bone resorption. By 2 weeks following burn, the derangement has shifted from boney resorption to reduction of bone formation, with reduction of osteoblasts on the bone surface and reduced marrow stromal cell differentiation into osteoblasts [18]. Therefore, bone mass is lost due acutely to the pro-resorptive com- bination of cortisol together with cytokines (IL-1q and Il-6) and their subsequent cessation of bone formation. This, together with reduced bone loading secondary to reduced patient function, leads to inexorable bone loss. The bone loss found in those children that have suffered a severe thermal injury is associated with an increase in extrapolated fracture incidence of two-fold in male and one third in female children [23]. Also, as previously alluded to, insulin resistance remains a problem long after the burn wound has been closed. The mechanisms for this are as yet unclear, however, a picture of hyperinsulinemia together with hyperglycemia is typical following severe thermal injury.
Consequences of Delayed Metabolic Changes
Up to 12 months, there is severe retardation in weight, height, lean body mass, and bone mineral content; however a recent study has shown that at around 18 months following injury the repair mechanisms of the injured individual are restored such that there are significant increases in all four parameters (Fig. 4) [24].
These effects may have been elicited by increases in both IGFBP-3 and parathy- roid hormone levels that were seen to be significantly increased when compared to serum levels at discharge. Improvements in muscle strength, power, the muscle’s capacity for work, and aerobic capacity can all be increased with resistive training in a supervised program [25].
Fig. 4. Percentage change in weight (a), height (b), lean body mass (c), and bone mineral content (d) at 6, 12, 18, and 24 months after discharge in 25 pediatric patients who had suffered 8 40 %TBSA burns, compared with discharge values. Values are means „ SEM. There was a significant difference between the first year and second year after injury for all values, * 18 months, # 24 months. From [24] with permission
Treatment Options for Attenuation of Deleterious Effects of Hypermetabolism
Propranolol
Propranolol has been used successfully to block the effects of endogenous catechol- amines that have been implicated as primary mediators of the hypermetabolic response. In the initial stages after burn, levels of catecholamines show a 10-fold increase. The resulting hyperdynamic circulation, increased basal energy expendi- ture, and catabolism of skeletal muscle proteins are all deleterious for the patient. As described at the beginning of the chapter, catecholamines stimulate lipolysis via the q 2-adrenoceptor. The effects of propranolol in the burn patient include reduced thermogenesis, tachycardia, cardiac work, and REE. The dose used is different for each patient; however, a reduction in heart rate by 20 % is seen to produce reduced cardiac work load and fatty infiltration (secondary to reducing peripheral lipolysis and hepatic blood flow) [26]. Propranolol has been shown to enhance intracellular recycling of free amino acids leading to reduced skeletal muscle wasting and increased lean body mass [27]. The exact mechanisms for the beneficial changes seen in the burns patient following administration of this mixed q 1/ q 2 adrenocep- tor antagonist remain to be identified.
Oxandrolone
Oxandrolone is a synthetic testosterone analog; it can be taken orally, is inexpensive, and has only 5 % of the virilizing action seen in testosterone. Use of oxandrolone in
the burns setting at a dose of 0.1 mg/kg twice daily increases protein synthetic effi- ciency [28] and anabolic gene expression in muscle, and improves lean body mass by increasing net muscle protein synthesis, thereby attenuating muscle wasting. In severely burned children treated during acute hospitalization, oxandrolone signifi- cantly improved net protein synthesis, lean body mass, bone mineral content, syn- thesis of the hepatic constitutive proteins such as albumin and pre-albumin, and attenuated the acute phase reactive protein levels [29]. Oxandrolone improved body composition and strength in severely burned children during the 12 months of treat- ment. Its effect on height and weight continued after treatment was discontinued [29]. The ability of this treatment option to increase lean body mass in an outpatient setting together with the enteral route of administration makes it an ideal medica- tion in the post-burn rehabilitation of children. Bone mineral content was also shown to be improved following long term treatment with oxandrolone versus unburned controls. A recent multicenter trial also showed that there was a signifi- cant decrease in acute hospital stay [30].
Growth Hormone
Recombinant human growth hormone (rhGH) administered via injection at a dose of 0.2 mg/kg during the acute admission resulted in reduced donor site healing time by 25 %, reduced length of stay in hospital from 0.80 days/ %TBSA to 0.54days/
%TBSA [31] and improved quality of wound healing with no increase in scarring [32]. The growth retardation also typically seen following severe burns in pediatric patients was prevented during administration of rhGH during hospital admission [33]. A favorable attenuation of the hepatic acute phase response was also seen, with increased concentrations of IGF-I (the secondary mediator of rhGH) and increased albumin production. When given at a dose of 0.05 mg/kg/day for the first year fol- lowing burn injury, improvements in height, lean body mass, and bone mineral con- tent were seen. These improvements remained after the treatment had been stopped.
Additionally, rhGH has a positive effect on immune function by reducing Th2 and enhancing Th1 cytokine production [34]. The benefits of rhGH are not without some side effects, most notably hyperglycemia during the acute admission. An increased mortality rate seen in non-burned critical care patients [35] is not present in burned pediatric patients [36]. Improved wound healing, reduced tissue wastage and length of stay in hospital are all major benefits that will improve both the physi- ological and psychological rehabilitation of the patient. Currently the drawbacks for rhGH are the side effects and mode of delivery; ongoing investigations are address- ing these points along with trials incorporating beta-blocking agents.
Ketoconazole
Ketoconazole is an imidazole antifungal agent. As with other imidazoles, it has a five-membered ring structure containing two nitrogen atoms. Ketoconazole is avail- able as oral tablets, a cream, and a dandruff shampoo formulations. The oral formu- lation has been available in the USA since 1981. Like all azole antifungal agents, ketoconazole works principally by inhibition of cytochrome P450 14a-demethylase (P45014DM) an enzyme in the sterol biosynthesis pathway that leads from lanosterol to ergosterol [37]. Ketoconazole inhibits the 11q -hydroxylation and 18-hydroxylation reactions in the final steps during the synthesis of adrenocorticosteroids [38] and may even function as a glucocorticoid receptor antagonist [39].
Insulin
Recently it has been restated that severe hyperglycemia in patients suffering from massive burns is associated with an increase in muscle protein catabolism [14], reduced graft take, and an increase in mortality [40]. Euglycemia maintained using insulin for non-burned, surgical critical care patients significantly reduced the inci- dence of infection and mortality [41]. The use of insulin has been shown to signifi- cantly reduce donor site healing time from 6.51 ( „ 0.95) days to 4.71 ( „ 2.3) days [42]. A continuous infusion used in burn patients prevented muscle catabolism and conserved lean body mass in the absence of increased hepatic triglyceride produc- tion [43]. Submaximal doses (3 mU/kg/min) of insulin administered via infusion to burns patients resulted in net protein muscle anabolism without the need for large doses of carbohydrate [44]. Insulin has been shown to attenuate the inflammatory response by decreasing the pro-inflammatory and increasing the anti-inflammatory cascade, thus restoring systemic homeostasis and reducing the drive of the hyper- metabolic response. Continuous intravenous insulin infusions at doses that will maintain euglycemia (glucose between 100 and 140 mg/ml) after severe burns down- regulates acute phase protein levels and attenuates muscle catabolism, preserving lean muscle mass [45]. Recently, insulin administered to burned children was shown to blunt the increase in C-reactive protein (CRP), IL-1q , and TNF levels after injury, in the absence of normoglycemia. In another recent study involving pediatric patients in whom the glucose levels were maintained at between 90 and 120 mg/ml, intensive insulin therapy was shown to be safe and effective, reducing infection rates and improving survival [46]. The mechanism are unclear for this response; however, it is likely to be caused by inhibition of NF-kB with stimulation of IkB in monocytes [47]. This would result in reduced length and severity of infections and attenuate multiorgan dysfunction associated with burn shock. Although pharmacological doses of insulin have been shown to increase glucose uptake into tissue and this uptake is accompanied by increased amino acid uptake and increase lactate release, the exact mechanisms are still unclear. Proposed pathways include activation of sodium-dependent transport systems, initiation of protein translation and direct regulation of proteolytic activities. Metformin may also be used to attenuate hyper- glycemia in patients with severe burns, thereby increasing muscle protein synthesis.
Other anti-hyperglycemic agents such as dichloroacetate may also have beneficial results in reduction of post-burn hyperglycemia [48].
Insulin-like Growth factor-1
The beneficial effects of rhGH are derived through IGF-I and IGFBP-3 the levels of which are raised by 100 % during treatment, relative to healthy individuals. There- fore, an infusion of equimolar doses of IGF-I and IGFBP-3 has been shown to improve protein metabolism in both adult and pediatric burn patients with signifi- cantly less hyperglycemia than rhGH alone [49]. Interestingly, there was no addi- tional benefit seen with higher doses of the infusion; using 1 mg/kg/day was suffi- cient to achieve the desired effect. Attenuation of the type I and II acute phase response was seen following infusion leading to reduced acute phase protein pro- duction and increased constitutive protein production by the liver. Another poten- tially beneficial effect of an infusion of IGF-I/IGFBP-3 has been shown in a human model where there was a partial reversal of the detrimental change in the Th1/Th2 cytokine profile [50]. Typically, following massive thermal injury, there is a shift to
a predominant Th2 cytokine response resulting in increases in lymphocyte produc- tion of IL-4 and IL-10, together with decreased production of IL-2 and IFN* . How- ever, this combination drug has yet to become commercially available and further studies are required.
Conclusion
As well as the exercise programs outlined above, several pharmacological options for attenuation of the hypermetabolic response are available. Propranolol has now been shown to have a prolonged effect on heart rate and REE, and to improve weight gain, lean body mass, and bone mineral content. Recent developments have shown a link between propranolol and attenuation of infection rates. The mecha- nisms underlying the changes seen are most likely due to the interaction of catechol- amines and chemokine expression, particularly the reduction in the normally pro- tective CCL3 (MIP-1[ ) and the increase in both CCL2 (MCP-1) and CCL17 (TARC), which act together for a combined systemic inflammatory response. The testoster- one analog, oxandrolone, at a dose of 0.1 mg/kg given twice daily for 12 months fol- lowing injury raised serum levels of IGF-1, T3 uptake, and free thyroxin index, lead- ing to improved lean body mass and bone mineral content [29]. When looking at the effects of recombinant rhGH given over a 12 month period we find that there are significant improvements in height, weight, lean body mass, bone mineral content, cardiac function, and muscle strength. The long term effects of extended treatment with insulin are currently being examined.
The hypermetabolic response that follows a severe burn cannot be halted or reversed; however, its effects can be limited by prompt surgical removal of the burn eschar, aggressive treatment of developing sepsis, early enteral feeding with a high carbohydrate high protein diet, and a program of resistance exercises. The addition of anabolic and anticatabolic agents is increasing the improvements seen during burn recovery. The aims of ongoing research in this field are to further delineate the mechanisms involved in these processes allowing us to prevent the hypermetabolic response from gaining momentum.
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