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Nutrition and Anabolic Pharmacotherapies in the Care of Burn Patients

Abdikarim Abdullahi and Marc G. Jeschke
Nutr Clin Pract published online 14 May 2014
DOI: 10.1177/0884533614533129

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533129
research-article2014
NCPXXX10.1177/0884533614533129Nutrition in Clinical PracticeAbdullahi and Jeschke

Invited Review
Nutrition in Clinical Practice
Volume XX Number X
Nutrition and Anabolic Pharmacotherapies in the Month 201X 110
2014 American Society
Care of Burn Patients for Parenteral and Enteral Nutrition
DOI: 10.1177/0884533614533129
ncp.sagepub.com
hosted at
online.sagepub.com
Abdikarim Abdullahi, MSc1; and Marc G. Jeschke, MD, PhD1,2,3,4

Abstract
Thermal injury is a devastating injury that results in a number of pathological alterations in almost every system in the body.
Hypermetabolism, muscle wasting, depressed immunity, and impaired wound healing are all clinical features of burns. Failure to address
each of these specific pathological alterations can lead to increased mortality. Nutrition supplementation has been recommended as a
therapeutic tool to help attenuate the hypermetabolism and devastating catabolism evident following burn. Despite the wide consensus on
the need of nutrition supplementation in burn patients, controversy exists with regard to the type and amount of nutrition recommended.
Nutrition alone is also not enough in these patients to halt and reverse some of the damage done by the catabolic pathways activated
following severe burn injury. This has led to the use of anabolic pharmacologic agents in conjunction with nutrition to help improve
patient outcome following burn injury. In this review, we examine the relevant literature on nutrition after burn injury and its contribution
to the attenuation of the postburn hypermetabolic response, impaired wound healing, and suppressed immunological responses. We also
review the commonly used anabolic agents clinically in the care of burn patients. Finally, we provide nutrition and pharmacological
recommendations gained from prospective trials, retrospective analyses, and expert opinions based on our practice at the Ross Tilley Burn
Center in Toronto, Canada. (Nutr Clin Pract. XXXX;xx:xx-xx)

Keywords
nutritional support; wound healing; micronutrients; burns

In the United States, the incidence of burns is estimated to be
more than 2 million cases per year and is responsible for 3400
deaths annually.1 An important consequence of thermal injury
is the debilitating alterations in metabolism and immunity that
lead to adverse outcomes in these patients. Is this high mortal-
ity in burns inevitable, or can the care and treatment that these
patients receive be improved? If there is potential for improve-
ments, what therapeutic strategies should be adapted? This
review addresses these areas by providing an overview of the
postburn pathological alterations that occur; we then address
the nutrition and anabolic agents used in the clinical care of
burn patients. Finally, based on our current clinical practice,
we recommend guidelines for optimal nutrition supplementa-
tion required to effectively manage the postburn response.
Pathological Alterations in the Human
Body After Thermal Injury
Burn injury results in devastating pathological perturbations in
a number of organs and tissues.2 These responses are not unique
to thermal injury but are present in various other traumas.
However, the severity, duration, and magnitude are unique to
burns. Postburn perturbations consist of hypermetabolism,3
inappropriately hyperactive immune response,4 and inadequate
wound healing.5 These perturbations, discussed in more detail
below, have been suggested to be major contributors to poor
outcome following burn injury and that treatment or alleviation
of these responses is beneficial for patient outcomes.
Hypermetabolism
The metabolic response to burn injury differs significantly from
that seen in other traumas. Unlike other forms of trauma, burn
injury results in a more heightened hypermetabolic response,6,7
with debilitating consequences distinct only to burn patients.8
The changes in metabolism seen after burns are not uniformly
distributed among tissues. In fact, the liver, skeletal muscle, and
adipose tissues have been regarded as bearing most of the burn-
induced pathological changes in the body (Figure 1). Taking
into consideration the compromised skin barrier, a hallmark of
burns, heat loss coupled with ineffective thermoregulation
From 1Sunnybrook Research Institute, Toronto, Ontario, Canada;
2
University of Toronto, Toronto, Ontario, Canada; 3Ross Tilley Burn
Centre, Toronto, Ontario, Canda; and 4Sunnybrook Health Sciences
Centre, Toronto, Ontario, Canada.
Financial disclosure: None declared.
Corresponding Author:
Abdikarim Abdullahi, Sunnybrook Health Sciences Centre, Ross Tilley
Burn Centre, Rm D7-04B, 2075 Bayview Avenue, Toronto, ON, M4N
3M5, Canada.
Email: abdikarim.abdullahi@sunnybrook.ca

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2 Nutrition in Clinical Practice XX(X)
Figure 1. Schematic overview of the postburn catabolic alterations in adipose, liver, skeletal muscle, and skin tissues. FFA, free fatty
acid.
manifests as an increased hypermetabolic response.9 This
hypermetabolic state is characterized by significant alterations
in both energy production and expenditure.10 Initially, with the
rise in catecholamines11 and the activation of the -adrenergic
receptor,11 glycogen and fat stores become rapidly depleted.12,13
These catabolic hormones facilitate the activation of key molec-
ular pathways involved in energy production such as gluconeo-
genesis10,13 and lipolysis.12,14 Glycogen is continually broken
down to liberate glucose and the triglycerides metabolized to
free fatty acids, resulting in high levels of circulating glucose
and free fatty acid in the blood. In addition, skeletal muscle pro-
teins are broken down to release amino acids, which are trans-
ported to other hyperactive tissues following burn injury.15
These amino acids are then used as substrates by the liver for
gluconeogenesis. Indeed, burn patients can oxidize amino acids
at rates 50% higher than those seen in healthy fasting individu-
als.16 Such high breakdown rates frequently translate into sig-
nificant loss of lean body mass, decreased wound healing, and
immune incompetence, all of which increase mortality.17,18 At
first glance, this postburn response of increased lipolysis and
gluconeogenesis appears as a meaningful systemic response to
cope with the trauma. The overprovision of glucose not only
helps the body to meet the heightened energy demands follow-
ing burn injury but also helps to spare lean body mass by limit-
ing protein catabolism and amino acid oxidation.19 However,
prolonged elevated circulating levels of glucose can have dev-
astating effects such as hyperglycemia,20 wound infections,21,22
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fatty liver infiltration,14,23 and suppressed immunity24 that con-
tribute to increased risk of mortality. Thus, this hypermetabolic
response, which initially began as a compensatory adaptive
response to the burn injury, quickly manifests as a series of
counterproductive events that further complicate patient
recovery.
Immunosuppression
Burn injury induces massive impairments in both innate and
cell-mediated immunity, facilitating an environment condu-
cive to pathogen growth, which can elicit serious infections.
Initially, following burn, the immune system responds rapidly
by activating cells and mediators of the innate and adaptive
immune systems. Immune responses are regulated by antigen-
presenting cells (APCs) such as monocytes/macrophages and
dendritic cells, which are components of the innate immune
system,25 and T helper (TH) and cytotoxic T lymphocytes,
which are components of acquired (adaptive) immunity.26
APCs are the first to react to the injury by inducing the produc-
tion of proinflammatory cytokines such as tumor necrosis
factor (TNF-) and interleukin (IL-1, IL-6, and IL-8).26,27
However, a lot like the hypermetabolic process, this attempt of
our body to react accordingly to this trauma quickly becomes
counterproductive as inappropriate hyperactive inflammatory
response occurs, leading to a profound depression in cell-
mediated immunity. This hyperactive immune system
Abdullahi and Jeschke 3
phenomenon that characterizes many trauma patients has been
coined the two-hit response phenotype.28,29 The burn (first
hit) initially activates and primes the immune system ,as dis-
cussed earlier. In trauma patients, infections (second hit), usu-
ally involving an opportunistic pathogen, can elicit severe
septic shock, leading to multiorgan failure.29 Studies have
shown that the 2-hit response is a consequence of the cells
from our innate immune system, primarily macrophages,
becoming hyperactive following the second hit (infection).28
Upon activation, the macrophages induce the production and
secretion of heightened levels of inflammatory cytokines,
which result in systemic inflammation and organ failure.30 The
deleterious effects of the second hit involve not only multior-
gan failure in the patient but also the manifestation of immuno-
suppression. In fact, studies have shown defective macrophage
activity,30 impaired antigen processing,4 and reductions in
helper T cells (CD4)4,27 in posttrauma patients. Thus, any
immune-targeted interventions in postburn patients should not
only encompass a restoration of depressed immune responses
but also aim to decrease, as opposed to completely abrogate,
the hyperactive immune response.
Impaired Wound Healing
Following thermal injury to the skin, the human body reacts by
activating the wound-healing process to reestablish skin integ-
rity. The wound-healing process encompasses 4 highly regu-
lated distinct phases: homeostasis, inflammation, proliferation,
and reepithelialization/remodeling.31 For optimal wound heal-
ing to occur, these phases and their physiologic functions must
occur in the proper sequence, at a specific time, and continue
for a specific duration at an optimal intensity.31 Multiple fac-
tors can initiate and lead to impaired wound healing. In gen-
eral, the factors that influence the repair process in burn
patients can be categorized into local and systemic factors.32
Local factors usually affect the immediate environment of the
wound, whereas systemic factors are those secreted mediators
affecting more than just the immediate environment. For
instance, oxygen is an important local factor critical for opti-
mal wound healing, since it enhances angiogenesis, keratino-
cyte differentiation, and collagen synthesis.33,34 Due to
overconsumption of oxygen during the hypermetabolism phase
following burn injury, the microenvironment of the early
wound is significantly depleted of oxygen and is hypoxic.
Prolonged hypoxia can have detrimental effects on wound
healing since it can amplify the levels of free radicals that pro-
mote tissue destruction.33,34 Systemic factors such as the
inflammatory cytokines released following burn injury can
also have devastating effects on wound repair. As discussed
earlier, following thermal injury, the body reacts by overpro-
duction of inflammatory cytokines such as IL-1, IL-2, IL-3,
and TNF-.27 These inflammatory cytokines initially are ben-
eficial to prevent infection of the wound, but overproduction of
these cytokines transcends the initial beneficial effect and
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quickly causes tissue destruction and deregulation in cells cru-
cial to wound repair.35,36 For example, these inflammatory
cytokines result in defective macrophage activity, impaired
leukocyte chemotaxis, and dysfunctions in both fibroblasts and
epidermal cells.35 The decreased activity of these critical cells
not only impairs wound healing but also results in adequate
clearance and defense against pathogens such as bacteria,
which can result in sepsis, an issue far more dangerous than
proper wound closure.
Thus, the changes described in the metabolic and immuno-
logical pattern following burn are primarily protective.
However, when these metabolic and immunological patterns
endure and become heightened, they become harmful.
Prolonged catabolism and multiorgan failure is a risk factor
and can be lethal, especially for those populations with preex-
isting comorbidities.
Nutrition Support in Alleviating the
Postburn Pathological Alterations
Adequate nutrition support is vital in the care of trauma patients
but becomes more critical in burn patients. The initial goal of
nutrition support is to provide an adequate energy supply to
meet heightened energy demands and prevent malnutrition.
Following this primary goal, nutrition support is used to allevi-
ate and modulate the postburn catabolic and pathological
responses of hypermetabolism, immunosuppression, and dis-
turbed wound healing. Despite the obvious need for nutrition
support in these patients, the supply of excess nutrition in the
form of carbohydrates and fat can result in hyperglycemia and
fat infiltration of organs.37-39 Currently, no standardized nutri-
tion support guidelines exist for burn patients. There are only
recommendations,40-42 and we at the Ross Tilley Burn Center
recommend the use of high carbohydrate/high glucose, high
protein/amino acid intake, and a low-fat diet with emphasis on
unsaturated fatty acids to attenuate the catabolic and pathologi-
cal mechanisms following burn (Table 1).19
Attenuation of Hypermetabolism
Carbohydrates
Carbohydrate supplementation to burn patients is critical since
it not only provides a fuel source for wound healing but also
prevents deficits in lean body mass by sparing protein from
oxidation for energy. It is imperative that before supplying
burn patients with carbohydrates, one should assess the mini-
mum baseline adult carbohydrate requirement (2 g/kg/d),19 and
the maximum rate at which glucose can be absorbed in severely
burned patients is 7 g/kg/d.19 These are important values to
keep in mind since burn patients have caloric requirements that
far exceed the bodys maximum ability to assimilate glucose.
Therefore, in burns, consensus recommendations are to deliver
55%60% of energy as carbohydrates without exceeding 5 mg/
4 Nutrition in Clinical Practice XX(X)
Table 1. Nutrition Guidelines for Burn Patients.
Nutrient Recommendation Agreement
Carbohydrate 57 mg/kg/min Strong
Protein 1.52 g/kg/d Strong
2.54.0 g/kg/da
Lipids <20% of nonprotein calories Strong
Recommendations are based on consensus among the American Burns
Association and American Society for Parenteral and Enteral Nutrition as
well as our institution at the Ross Tilley Burn Center. Recommendations
are also based on randomized and placebo-controlled trials investigating
major burns. Each recommendation was thus allocated a grade (strong to
weak) based on the level of consensus among the 3 organizations above
as well as evidence from randomized and placebo-controlled studies.
a
Denotes recommendations only for pediatric burn patients; otherwise,
recommendations listed are either for both or adults only.
kg/min in adults and children, which corresponds to 7 g/kg/d in
adult patients.41 Therefore, suboptimal carbohydrate delivery
following burn injury can lead to uncontrolled protein catabo-
lism, whereas excess supplementation can elicit hyperglyce-
mia in the burn patient.
Proteins
As previously mentioned, protein catabolism is a hallmark of
burns, resulting in significant losses in lean body mass. It has
been estimated that postburn catabolism can exceed 150 g/d or
almost one-half pound of skeletal muscle.19,43 Sustained loss of
lean body mass can result in adverse outcomes for these patients,
hampering their ability to recover. Clinically, protein recommen-
dations for healthy individuals are estimated at 0.81 g/kg/d.10,19
However, studies have shown burn patients oxidize amino acids
at a rate that is 50% higher than in healthy individuals. As such,
the required protein intake is higher for burn patients (1.52 g/
kg/d in burned adults and 2.54.0 g/kg/d in burned children).19,40,41
Providing adult burn patients with protein in excess of the recom-
mended 1.52 g/kg/d has shown no added benefit.44
Fats
While burn patients during the hypermetabolic response do
experience increased lipolysis, the extent of lipid catabolism is
not nearly as significant as proteolysis. In fact, while burn
patients do experience increased rates of lipolysis and
-oxidation of fat, only about 30% of the liberated free fatty
acids are degraded while the remaining undergoes reesterifica-
tion into triglycerides. Only few studies are available regarding
lipid recommendations in burns. Therefore, in our institution,
we believe fat should only comprise less than 25% of nonpro-
tein calories in burn patients,19,42 since a number of studies
have suggested that excessive fat intake can cause immunosup-
pression.45 More important, the composition of fat supplemen-
tation is more important, with an emphasis on unsaturated fatty
acids such as -3 fatty acids, which are metabolized without
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eliciting proinflammatory compounds.43 The role of -3 fatty
acids in enhancing immunity and acting as a substrate for the
synthesis of prostanoids and leukotrienes is currently being
elucidated. Although there are insufficient data to clinically
recommend -3 fatty acids, a recent study has shown some
promise with regard to beneficial effects such as reductions in
hyperglycemic episodes and intensive care unit stay.42,46
Immunonutrition
Many immunological alterations occur after a thermal injury,
as discussed earlier. A wide array of functional deficits in
immunity occurs, from significant atrophy of lymphoid organs
to impaired immune cells. Although a wide variety of nutrition
agents exist that claim to improve immunity, we focus primar-
ily only on those nutrition agents that have significant evidence
in helping to correct postburn immunosuppression. Studies
have shown certain specific nutrients exert immune-enhancing
effects, particularly in critically ill patients. These include
amino acids such as glutamine and arginine.
Glutamine
Glutamine is a nonessential amino acid that serves as an oxida-
tive fuel source for rapidly proliferating cells such as entero-
cytes, lymphocytes, and macrophages.47 By serving as an
important energy source for enterocytes and lymphocytes,48 it
helps to maintain small bowel integrity and preserves gut-asso-
ciated immune function.49,50 During traumatic states such as
burn injury, the body requires an exogenous source of gluta-
mine to replenish the stores lost due to the catabolic muscle
response. In fact, it has been shown that glutamine is quickly
depleted in the serum and muscle tissue of postburn patients.48,51
The biggest evidence in support of glutamine supplementation
in burn patients has come from studies that have shown gluta-
mine supplementation decreased the incidence of infection,
length of hospital stay, and mortality.48,51,52,53,54 Although a
number of studies have looked at glutamine supplementation in
burn patients, many of these studies are flawed, with problems
such as inconsistent findings, high variability among dosage
used, small sample size, and diverse outcome measures.42,47
Presently, it is therefore difficult to recommend a precise dose
of glutamine supplementation in burn patients, since more evi-
dence-based studies with consistent dosage usage are needed.
Arginine
Arginine is a semi-essential amino acid, and like glutamine, it
is an important fuel source for cells involved in immunity.55 As
with a number of other amino acids, burn injury with its cata-
bolic state significantly promotes arginine oxidation. This
results in arginine becoming conditionally essential in burn
patients. Arginine has been shown to promote T-cell function
and increase helper T-cell levels.55 In addition, it has been
Abdullahi and Jeschke 5
shown to stimulate macrophages and natural killer cell func-
tion.55 In burn patients, it is imperative that the gastrointestinal
mucosal integrity is maintained since deficits in integrity can
result in bacterial translocation and multiorgan failure by way
of sepsis. Arginine has been shown to be important in gut
immunity following severe burns, suggesting its beneficial
effects.56,57 Moreover, several studies have demonstrated
decreased length of hospital stay, reduced acquired infections,
and improved immunity among trauma patients supplemented
with various combinations of arginine, fish, and canola oil.58,59
Micronutrients in Wound Healing
Another hallmark of burns is disrupted wound healing. The
increased reactive oxygen species, elevated levels of inflam-
matory cytokines, and inactive phagocytic cells to clear away
debris and pathogens have all been implicated in creating an
environment not conducive to wound healing. Although micro-
nutrient supplementation in burn patients has been quite con-
troversial, several micronutrients have been recommended in
these patients. We focus our attention on a few select micronu-
trients that have received attention in burn care and treatment.
Vitamins
The notion of vitamin supplementation in burn patients devel-
oped from findings that have shown depleted levels of some key
vitamins such as vitamin A, C, and D following burn injury.60-63
So why should burn patients be supplemented with these vita-
mins following burn injury? Well the idea is that these vitamins
can mediate deficiencies in wound healing and immune function
following burn injury.40,60,62 For instance, vitamin A plays an
important role in wound healing through its actions in promoting
epithelial growth. Vitamin C is also another critical nutrient vital
for optimal healing since it promotes the synthesis and cross-
linkage of collagen as well as neutralizing free radicals follow-
ing burn injury.64 In fact, burn patients require up to 20 times the
recommended daily allowance of vitamin C.43 The specific pop-
ulation affected by burn injury also affects which group stands to
benefit from the supplementation of specific vitamins. For
example, vitamin D is highly recommended for burned children
to attenuate the significant depletion of bone minerals seen in
this subpopulation following burn injury.61,62
Trace Elements (Zinc, Selenium, and
Copper)
There has been a growing interest in trace element supplemen-
tation in burn patients because of its role as an endogenous
antioxidant defense system. Critically ill burn patients are
characterized by increased free radical production and a subse-
quent depletion of trace element balance, resulting in a reduced
capacity to deal with these deleterious molecules. Among
trauma patients, trace element deficiencies are most prominent
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Table 2. Anabolic Guidelines for Burn Patients.
Pharmaceutical
Agent Recommendation Agreement
Insulin Glucose control at 130 mg/dL Strong
Oxandrolone 0.1 mg/kg Strong
10 mg/kg/12 ha
Propranolol 10 tid Strong
4 mg/kg/da
Recommendations are based on consensus among the American Burns
Association and American Society for Parenteral and Enteral Nutrition as
well as our institution at the Ross Tilley Burn Center. Recommendations
are also based on randomized and placebo-controlled trials investigating
major burns. Each recommendation was thus allocated a grade (strong to
weak) based on the level of consensus among the 3 organizations above
as well as evidence from randomized and placebo-controlled studies.
a
Denotes recommendations only for pediatric burn patients; otherwise,
recommendations listed are either for both or adults only.
in burns and have been associated with delayed wound healing
and infections.64,65 One consideration for burn patients has
been zinc supplementation, which aids in wound healing, lym-
phocyte function, and protein synthesis.64-67 Among the trace
elements, burn patients have a specific copper deficiency.68
Copper is a vital element in collagen synthesis and optimal
wound healing.68 Evidence has indicated that by restoring
these micronutrients, patient outcome is greatly improved.64-67
Currently, there are no evidence-based practice guidelines
available for the assessment and provision of trace elements in
burn patients.42 Thus, complete multivitamin and mineral sup-
plementation should be considered in the care of these patients.
Pharmacologic Modalities in Alleviating
the Postburn Pathological Alterations
Strategies to attenuate the net protein loss and hypercatabolic
state in severely burned patients through nutrition supplemen-
tation are not enough and most often require supplementation
with pharmacological agents. A number of anabolic hormones
have been used clinically to offset the postburn muscle catabo-
lism and hyperglycemia (Table 2). Each anabolic agent has a
specific mode of action, but there are considerable interrela-
tionships and overlap in terms of effects among them (Table 3).
Insulin
Since its discovery in 1921, insulin has become one of the most
widely used metabolically active agents in the care of critically
ill trauma patients. This is because insulin, unlike any other
hormone, has multifactorial effects in a number of tissues. In
addition to its effects on glucose metabolism, insulin has ana-
bolic effects on fat and muscle metabolism.69,70 A number of
clinical trials in burn patients have demonstrated that insulin
decreases protein degradation and improves insulin resis-
tance.69-71 During the early phase of postthermal injury, patients
6 Nutrition in Clinical Practice XX(X)

Table 3. Anabolic Agents Used in the Care of Burn Patients.

Anabolic Agent Target Tissues Effect

Insulin Liver Decreases proteolysis
Skeletal muscle Improves lean body mass
Fat tissue Decreases fat oxidation
Promotes glucose homeostasis
Metformin Liver Promotes glucose homeostasis
Oxandrolone Skeletal muscle Improves lean body mass
Decreases proteolysis
Propranolol Fat tissue Decreases fat oxidation
Promotes glucose homeostasis
Glucagon-like peptide 1a Liver Promotes glucose homeostasis
Decreases proteolysis
Insulin-like growth factor 1a Skeletal muscle Improves lean body mass
Decreases proteolysis
a
Glucagon-like peptide 1 and insulin-like growth factor 1 are currently in the investigative stages, and clinical trials are under way to assess their
suitability in burn care; as such, no established recommendations exist for these 2 therapies currently.

experience hyperglycemia as a result of the catabolic state and
hormonal environment that favors glucose appearance along
with impaired glucose extraction by tissues.72,73 This hypergly-
cemic state following burn injury can be detrimental and can
lead to adverse outcomes in these patients if not controlled and
resolved swiftly.38,74,75 Studies have shown that burn patients
with poor glucose control experience a significantly higher
incidence of infections and mortality compared with burn
patients with good glucose control.39,74,75 This early postburn
pathological state of hyperglycemia and insulin resistance can
be addressed through exogenous insulin administration, which
not only works to normalize glucose levels but also improves
muscle protein synthesis, thereby attenuating the loss in lean
body mass.71,76-78 Although insulin administration in burn
patients is associated with beneficial clinical outcomes, inci-
dences have been reported in burn patients experiencing epi-
sodes of hypoglycemia, which is just as detrimental as
hyperglycemia.79 In fact, there has been great controversy as to
the range of euglycemic control at which burn patients should
be kept. Recently, a multicenter clinical trial was conducted in
Europe to investigate the effect of insulin administration on
morbidity and mortality in postseptic patients. While the
results showed insulin administration had no effects on mortal-
ity, the findings did show the rate of severe hypoglycemia was
4-fold higher in the intensive therapy group compared with the
conventional therapy group.80 We have recently reviewed the
practice of glucose control in burns, and the findings were
summarized in our recently published study.81
Due to the uniqueness of burn patients in terms of the
weekly operations, daily dressing changes, and the continuous
enteral feeding of large caloric loads, maintaining a hyperinsu-
linemic euglycemic state is challenging. Since literature is
scarce with regard to the optimal glucose target levels in burns,
we recently conducted a study to investigate the ideal glucose
target in severely burned children.82 Our clinical trial study
assessed the optimal glucose range in thermally injured
patients, and our data demonstrate a U-shaped glucose curve,
in which poor outcome is associated with both low and high
glucose levels. In particular, our findings have shown that a
range of 130140 mg/dL is the best glucose target for this pop-
ulation.82 This target is below 150160 mg/dL, the range at
which hyperglycemia starts to become apparent, and it is not
too low, thereby avoiding the detrimental effects of hypoglyce-
mia. Thus, currently we recommend that glucose control be
implemented at a target of 130 mg/dL using insulin.
Insulin-Like Growth Factor 1
Insulin-like growth factor 1 (IGF-1) is a peptide that shows
close resemblance to proinsulin. It also has metabolic and ana-
bolic properties very similar to those of insulin.83 The IGF
receptor is ubiquitously expressed in a number of tissues, and
the active form of the peptide is bound in plasma by IGF-
binding proteins.84,85 The attenuation of stress-induced hyper-
metabolism and increased protein synthesis makes IGF-1 a
favorable agent in the clinical treatment of trauma patients.79,85
Because the actions of IGF-1 depend on other circulating pro-
teins and androgens such as IGF-1BP and growth hormone
(GH), clinical trials have used the infusion of equimolar doses
of recombinant human IGF-1 and IGFBP-3 as a complex in
burn patients and noticed reductions in protein catabolism, as
well as reductions in hypoglycemia compared with when
recombinant GH was used solely.86 Studies have also shown
that the IGF-1/BP-3 complex improves gut mucosal integrity,
heightens immune function, and attenuates the heightened
inflammatory response observed following burn injury.43 The

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Abdullahi and Jeschke 7
use of this peptide clinically is currently on hold, since unpub-
lished data have indicated that it increases neuropathies and
cautioned against the further use of IGF-1/BP-3 in severely
burned patients.
Glucagon-Like Peptide 1
Glucagon-like peptide 1 (GLP-1) is an incretin peptide that is
secreted by the L cells of the intestinal epithelium in response to
nutrient uptake.87,88 It is classified as a potent insulinotropic hor-
mone because of its stimulatory actions on pancreatic cells.89,90
In fact, GLP-1 has been shown to enhance glucose-stimulated
insulin secretion and improve glucose uptake in skeletal muscle,
hepatic tissue, and adipose tissue.89-91 In severely diabetic
patients, GLP-1 administration normalized blood glucose lev-
els.90,92 In addition, GLP-1 has been demonstrated to decrease
blood glucose in severely burned patients in conjunction with
insulin therapy.93 Most insulinotropic agents such as sulfonyl-
ureas and benzoic acid pose the risk of hypoglycemia when
administered in excess amount. However, GLP-1 is distinct in
that it does not elicit a hypoglycemic state even in instances of
overdose.87 Therefore, compared with other insulinotropic
agents, GLP-1 is a safer therapeutic agent in controlling blood
glucose without the adverse risk of hypoglycemia.
Metformin
Metformin, a biguanide pharmacological agent, has recently
been added clinically as an alternative to insulin in correcting the
postburn hyperglycemic state.94 By reducing hepatic gluconeo-
genesis and augmenting peripheral insulin sensitivity, metfor-
min acts to counter the 2 main prominent metabolic perturbations
that underlie thermal injury.95,96 Studies have also linked metfor-
min to improving lean body mass by reducing muscle catabo-
lism, which leads to amino acid oxidation, primary precursors
fueling endogenous glucose production.13,97,98 Aside from its
beneficial dual-action properties on muscle catabolism and glu-
cose homeostasis, metformin is also appealing in that the risk of
hypoglycemia is significantly reduced.97,99 Gore et al100 found
reduced plasma glucose concentration, decreased endogenous
glucose production, and enhanced glucose clearance following
metformin treatment in severely burned patients. In a follow-up
study by Gore et al97 in severely burned patients, metformin
treatment resulted in an increased fractional synthetic rate of
myofibrillar proteins and improved net muscle protein balance.
Regardless of the desired therapeutic effects of metformin, it is
far from being a significant agent in the treatment arsenal of the
burn populace due to its association with fatal lactic acidosis.101
Such undesired effects can be avoided by contraindicating this
drug in patients who have or are suspected of having septic
shock, hypovolemia, and heart failure, which are commonly
seen in burn patients. While we do recognize that more evi-
dence-based clinical trials must be conducted about the benefits
of metformin, on the basis of our experience, we believe
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metformin use should be considered in patients who have been
assessed not to have any impairments in lactate elimination.
Oxandrolone
Anabolic steroid analogues such as oxandrolone were devel-
oped to maximize the clinical advantage of testosterone while
decreasing the androgenic side effects of this naturally occur-
ring hormone. Oxandralone improves muscle protein catabo-
lism via a decrease in efflux of amino acids and influx into the
cell.102,103 In addition, oxandrolone has been used clinically in
burn patients to reduce weight loss and improve lean body mass
during the acute phase of injury.3,102,104-106 In a double-blinded
randomized study, it was shown that the administration of 10
mg bid of oxandrolone decreased hospital stay and improved
mortality.107 Another randomized double-blinded study also
found similar findings, in that administration of 0.1 mg/kg bid
decreased length of hospital stay, preserved lean body mass,
and promoted hepatic protein synthesis.108 Although patients
treated clinically with oxandrolone have minimal complica-
tions, it should be cautioned that oxandrolone can elevate
hepatic enzymes in the plasma, indicating liver damage. Other
reports have also implicated oxandrolone in increasing pulmo-
nary fibrosis.109 Therefore, if any signs of liver enzyme eleva-
tion appear in the plasma as well as any suspicion of pulmonary
problems, the use of this steroid should be ceased.
Propranolol
Propranolol is an important pharmacological -adrenergic
receptor blocker. During the hypermetabolism phase, the
-adrenergic receptor is overactivated, causing increased pro-
teolysis, hyperglycemia, and lipolysis. Studies have shown
that acute administration of propranolol reduces muscle wast-
ing, thereby improving lean body mass in postburn
patients.110,111 In addition, propranolol administration has been
shown to reduce lipolysis and improve glucose metabolism by
reducing insulin resistance.112,113 Increased lipolysis in burn
patients has been shown to elicit fatty liver through increased
fat delivery to the liver.37 Reductions in fatty liver resulting
from decreased lipolysis as well as reduced palmitate delivery
and uptake by the liver have been noted following propranolol
administration.112 Therefore, we recommend propranolol use
at a dose of 4 mg/kg/q24 given q6 hours for children and
10 mg tid in adults with an increased dose if required to reduce
heart rate to <100 bpm.
The anabolic agents discussed are currently the most
intensely studied and commonly used in the care of critically ill
trauma and burn patients. Having said this, new therapeutic
anabolic agents continue to be found and assessed for their
suitability in clinical care. Currently, a number of promising
agents (glucagon-like peptide, peroxisome proliferator-acti-
vated receptor agonists)114 are undergoing clinical trials in
the hopes of resolving postburn hyperglycemia.
8 Nutrition in Clinical Practice XX(X)
Summary and Conclusion
The devastating postburn metabolic and immunological altera-
tions make adequate nutrition supplementation pivotal in the
management of these patients. Failure to respond swiftly and
aggressively to these catabolic perturbations significantly
increases mortality rates in this patient population. Nutrition
supplementation alone is not sufficient to attenuate this hyper-
metabolic pathological state. Instead, nonnutrition therapies
are also needed in conjunction with nutrition supplementation
to reduce hypermetabolism and hypercatabolism in burns.
Despite the widespread use of nutrition and pharmacological
agents in burn patients, controversies still remain about their
use. Hence, there is much to learn about the safety and appro-
priate use of aforementioned therapeutic agents in the treat-
ment of burn patients.
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