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Chapter 2. Pathophysiology andHypermetabolic…
post-burn hypermetabolism, therapeutic agents that target
these responses have lagged behind.
45
Central Nervous System
The central nervous system (CNS) has an integral role in
activation of stress responses via relaying of afferent impulses
from the site of injury to the hypothalamus [115]. As a result,
hypothalamic inhibition of the pituitary is alleviated or alternatively, the hypothalamus produces hormones (e.g.,
corticotrophin- releasing hormone (CRH), growth hormonereleasing hormone (GHRH)) that stimulate production and
release of pituitary hormones [115]. These include anterior
pituitary corticotrophin (ACTH) and growth hormone (GH),
which ultimately have important metabolic consequences.
ACTH stimulates production of the stress hormone cortisol
in the adrenal cortex, which promotes liver gluconeogenesis,
hyperglycemia, and net muscle protein catabolism [116, 117].
Similar to cortisol, GH also increases blood glucose levels via
stimulation of glycogenolysis, promoting post-burn hyperglycemia and long-term growth abnormalities in pediatric burn
patients [115].
Importantly, the CNS has an integral role in driving the
post-burn sympathetic response. Acetylcholine release at the
splanchnic nerve-chromaffin cell junction provides a stimulus
for catecholamine secretion for the adrenal medulla and
binding to the respective receptors [118]. Epinephrine binds
to α1, α2, β1, and β2 adrenergic receptors, norepinephrine
binds to α1, α2, and β1, and dopamine binds to D1 and D2
receptors [115]. Activation of post-burn sympathetic responses
also may activate stress and inflammatory pathways including
p38 mitogen-activated protein kinase (MAPK), JNK, and
nuclear factor-kappa B (NF-kB), promoting inflammation
and immunosuppression after burn [119]. Catecholamines
also target various post-burn metabolic processes, driving the
initial stages of the hypermetabolic response [120]. However,
while elevated catecholamine levels after burn are associated
with stress, inflammation, and hypermetabolism, the exact
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R. Vinaik et al.
function of the CNS on burn-induced hypermetabolism is
still unknown at this time.
Management ofHypermetabolism:
Conservative Measures
Metabolic changes that occur after burn function in supplying energy support to preserve immune function, body tissues, and healing [121]. However, thermally injured patients
exhibit prolonged, consistent whole-body and muscle catabolism, necessitating nutritional and medical support. Clinicians
and scientists have targeted the post-burn hypermetabolic
response utilizing several different therapeutic approaches,
including conservative management and pharmacological
intervention. Key nonpharmacological strategies include
nutritional therapy and early mobilization and will be discussed in this section.
Nutrition—Calculating Energy Consumption
andNutrient Supplementation
Nutritional therapy aims to provide patients with sufficient
energy, fluids, and nutrients (e.g., protein) to maintain vital
organ and immune function and minimize further tissue loss.
In the late twentieth century, high caloric feeding was a therapeutic strategy. Wilmore etal. suggested 8000kcal/day, while
Curreri proposed a 25 kcal/kg body weight plus
40 kcal/%TBSA burn [122, 123]. While the latter was the
most frequently used formula between 1970 and 1980, Pennisi
created a more comprehensive formula in 1976 which
included an estimation of protein needs. Currently, there are
several formulas developed for critically ill patients, including
the Toronto, Schofield, American Society for Parenteral and
Enteral Nutrition (ASPEN), and Ireton-Jones formulae
(Table2.1). However, comparison of supplementation values
for a standardized patient (30years old, 72kg, 170cm, 40%
Chapter 2. Pathophysiology andHypermetabolic…
T . REE formulae and patient specications
Reference Specifications Formula
Harris &
Benedict
BMR
Curreri All patients (25kcal×weight (kg))+(40×%TBSA)
Pennisi Adults
Toronto
Formula
Davies and
Liljedahl
Male BMR×Activity factor×Injury factor
Female 66+(13.7×weight (kg))+
(5×height (cm))−(6.8×age)
665+(9.6×weight (kg))+
(1.8×height (cm))−(4.7×age)
Activity factor – Injury factor –
Confined to bed: 1.2 <20% TBSA: 1.5
Minimal ambulation: 1.3 20–40% TBSA: 1.6
>40% TBSA: 1.7
Calories (20kcal×weight (kg))+
(70kcal×%TBSA)
Protein (1g×weight (kg))+(3g×%TBSA)
Children
Calories (60kcal×weight (kg))+
(35kcal×%TBSA)
Protein (3g×weight (kg))+(1g×%TBSA)
All patients [−4343+(10.5×%TBSA)
+(0.23×kcals)+(0.84×Harris Benedict)
+(114×T(°C))−(4.5×days post-burn)]×
Activity factors
Activity factor
(non-ventilated) –
Confined to bed: 1.2
Minimal ambulation: 1.3
20kcal (weight (kg))+(70×%TBSA)
Activity factor
(ventilated)—1.2
(continued)
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T .
Reference Specifications Formula
Modified
Schofield
ASPEN All patients 25–35kcal/kg/day
IretonJones
Modified from Machado etal. (2011)
kcal: calorie intake in the past 24h
Harris Benedict: calorie requirement using the Harris benedict formula with
no stress or activity factors
T: body temperature
yrs: years
O: obesity=1/absent=0
S: male=1/female=0
TR: trauma present=1/no trauma=0
B: burn present=1/no burn=0
(continued)
Male BMR×Injury factor
10–18years=(0.074×weight (kg))+2.754
18–30years=(0.063×weight (kg))+2.896
30–60years=(0.048×weight (kg))+3.653
>60years=(0.049×weight (kg))+2.459
Female 10–18years=(0.056×weight (kg))+2.898
18–30years=(0.062×weight (kg))+2.036
30–60years=(0.034×weight (kg))+3.538
>60years=(0.038×weight (kg))+2.755
Injury factors –
<10% TBSA=1.2
11–20% TBSA=1.3
21–30% TBSA=1.5
31–50% TBSA=1.8
>50% TBSA=2.0
Nonventilated
Ventilated
629−(11×yrs)+
(25×weight (kg))−(609×O)
1784−(11×yrs)+(25×weight
(kg))+(244×S)+(239×TR)+804×B)
Chapter 2. Pathophysiology andHypermetabolic…
49
TBSA) using the different formulae demonstrated a wide
range, from 2099 kcal/day (Ireton-Jones) to 5229 kcal/day
(Modified Schofield) [124].
Currently, the appropriate caloric amount is still under
debate as is the composition of nutritional support, and
recent feeding regimens rely on resting energy expenditure
(REE) in order to provide sufficient energy supply and
nutrients [125–127]. Early enteral nutrition (within 12 hours)
ameliorates post-burn catabolism and improves outcomes,
but it is important to note that this is a delicate balance [128,
129]. Undernutrition reduces immunocompetence, delays
healing, and increases dependency on mechanical ventilation
and risk of infection while overfeeding (excess calories or
protein) is associated with hyperglycemia, organ fatty infiltration, and azotemia. This underscores the need to estimate
REE and accurately calculate caloric requirements [130].
REE can be estimated based on body mass, age, and gender
although caloric requirements based on these factors can
still be an overestimate [131, 132]. Energy requirements after
burn fluctuate, and static formulas often result in underfeeding during high energy consumption and overfeeding later in
the clinical course [133]. The gold standard for determining
energy expenditure is indirect calorimetry, which can be used
to confirm adequate nutritional support by calculating oxygen (O2) consumption and carbon dioxide (CO2) production
[132, 134, 135]. The ratio of CO2/O2 (respiratory quotient
(RQ)) is used to determine adequate feeding, and overfeeding results in an RQ >1.0 while normal metabolism is
between 0.75 and 0.90 [136].
After determining a specific caloric goal, ratios of the key
macronutrients (carbohydrates, proteins, lipids) need to be
determined. Carbohydrates are an important nutrient source
in burn patients due to their protein-sparing effects relative
to high-fat diets, as highlighted in clinical studies [137].
However, high-carbohydrate diets are limited by the ability
to oxidize and utilize glucose. Glucose administration >9mg/
kg/min cannot be oxidized sufficiently, and higher glucose
administration rates can lead to hyperglycemia, glycosuria,
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and dehydration [116, 138]. Hence, higher carbohydrate supplementation may not be feasible although this may be lower
than the estimated caloric expenditure.
Protein is also important in patients due to enhanced
muscle catabolism in response to burns, necessitating supplementation to maintain adequate wound healing and immune
function and allay lean body mass loss [139]. Administering
supraphysiological doses improves protein synthesis and
nitrogen balance although it does not eliminate catabolism
[140]. It is important to note that protein (1.5–2.0g/kg/day in
adults, 2.5–4.0g/kg/day in children) should be given with sufficient carbohydrates and fat to minimize use of protein as an
energy source rather than as nutrients to maintain muscle
mass and promote wound healing. In particular, glutamine
and arginine were found to play an important role after burn.
Glutamine provides energy for lymphocytes and enterocytes
and serves as a precursor for the antioxidant glutathione.
Clinically, glutamine supplementation improves burn patient
outcomes and minimizes length of hospital stay (LOS) [141,
142]. Conversely, while arginine supplementation improves
burn wound healing and immune responsiveness, it is potentially harmful overall and is not recommended in burn
patients [143].
Lipolysis is enhanced after burn although utilization of
lipids as an energy source is decreased [129, 144]. Rather,
liberated FFAs accumulate in organs such as the liver. Lipid
supplementations are recommended to minimize fatty acid
deficiency but in limited doses (no more than 15% total calories) since increased fat consumption can worsen immune
function. In addition to quantity, the fatty acid subtype needs
to be taken into consideration. Omega-6-containing formulas
can generate a pro-inflammatory response while formulas
with a greater proportion of omega-3 are associated with an
improved immune response, glycemic regulation, and patient
outcomes [145, 146]. Some enteral formulas have an omega-6:
omega-3 ratio from 2.5:1 to 6:1, while “immune enhancing”
formulas have a more balanced composition of 1:1 [133]. It is
important to note that although studies suggest that lower
Chapter 2. Pathophysiology andHypermetabolic…
omega-6 levels and sufficient lipid supplementation are beneficial, there is still debate with regard to enteral formula
composition and lipid quantity in burn patients [133].
In addition to macronutrients, micronutrient (vitamin
and trace element) supplementation is also crucial after
burns [147]. In particular, vitamins A and C improve epithelial growth and collagen cross-linking, respectively [148].
Vitamin D, which is involved in maintaining bone density, is
decreased after burn resulting in bone demineralization
[149]. Other nutrients that are lost in burns and have an
integral role in wound healing and immunity are iron (Fe),
copper (Cu), selenium (Se), and zinc (Zn) [150–152]. Fe and
Cu serve as a cofactor for oxygen scavengers such as superoxide dismutase and other forms of endogenous antioxidant defense [153]. Cu is necessary for collagen production
and wound healing, and Cu deficiency and corresponding
decreased levels of its transporter ceruloplasmin are implicated in immune dysfunction, arrythmias, and poor wound
healing in burn patients [154, 155]. Zn also has a function in
wound healing and at the molecular level, protein synthesis,
DNA replication, and immune cell function. Se similarly is
involved in cell- mediated immunity, and dietary Se influences leukocyte functions such as adherence, migration,
and cytokine secretion [156]. Additionally, several selenoproteins can regulate cellular redox processes and immune
cell activation [156]. Taken together, micro- in addition to
macronutrient supplementation is important in burn patient
management.
51
Environment, Early Excision, andExercise
Hypermetabolism may be an adaptive response to generate
energy to offset heat loss. Thus, raising ambient temperature
from 25°C to 33°C may obviate the need to increase core
body temperate, which increases by 2°C after major burn.
In patients with burns >40% TBSA, increasing ambient
temperature can diminish REE from a 2.0 to 1.4-fold
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increase [157]. In addition to environmental modulation,
patient factors are also important in managing post-burn
hypermetabolism. In particular, early excision (within 72h)
and wound coverage decrease burn-induced inflammation
and activation of stress responses. This in turn substantially
reduces REE and hypermetabolism, improving mortality
rates [7, 158, 159].
A key component of severe burns and accompanying
hypermetabolism is persistent skeletal muscle catabolism,
which is further exacerbated by prolonged bed rest and
physical inactivity. Rehabilitation programs are implemented
although muscle catabolism and poor muscle strength can
persist. However, resistance exercise programs can increase
muscle strength and hypertrophy and be safely incorporated
into routine burn care, mitigating frailty [132, 160]. In a study
in burned children, resistance exercise over a 12-week period
decreased REE and may attenuate sympathetic responses
[161]. This was accompanied by increased lean body mass by
over 20-fold in addition to enhanced muscle strength, total
work, and power [161]. Ultimately, enhanced muscle strength
and ability to do work allow for more rapid rehabilitation and
return to normal activities of daily leaving, improving
outcomes.
Management ofHypermetabolism:
Pharmacological Intervention
Although non-pharmacologic interventions are employed to
combat hypermetabolism, implementation of several key
medical interventions is critical for clinical efficacy. Currently,
there are various pharmaceutical agents used in burn care,
including propranolol, growth hormone (GH), insulin-like
growth factor 1 (IGF-1), insulin-like growth factor binding
protein-3 (IGFBP-3), insulin, metformin, and oxandrolone.
These therapeutics strategies are utilized to minimize catabolism and promote anabolism, ultimately improving burn
patient morbidity and mortality.
Chapter 2. Pathophysiology andHypermetabolic…
53
Propranolol
Prolonged, substantial catecholamine production is a hallmark of thermal injuries that ultimately contributes to the
hypermetabolic response. Increased catecholamine levels
contribute to generalized post-burn catabolism in addition
to increased REE, lipolysis, and muscle catabolism via stimulation of α and β receptors [40]. The non-specific β-blocker
propranolol is ideally administered post-resuscitation
(3–10 days after burn) to minimize pronounced
catecholamine- dependent changes [162]. Directly targeting
sympathetic pathways can reduce cardiac work by decreasing heart rate by 15–20% and mitigates blood loss during
grafting [13, 48, 163]. Moreover, treatment has supplementary benefits in addition to directly targeting sympathetic
pathways. For example, propranolol is associated with
improved wound healing, decreased healing time, and shorter
hospital LOS [163].
Studies have shown that propranolol is a potent anticatabolic agent and yields positive outcomes when combined
with recombinant human growth hormone (rhGH), which
will be discussed subsequently [137]. Combination therapy
can ameliorate hypermetabolism and inflammation while
eliminating the deleterious effects of rhGH monotherapy
[164]. In addition to anti-catabolic effects, propranolol has an
anabolic function as well. Treatment in severely burned children increases muscle protein balance by 82% above baseline
in concert with upregulation of genes involved in muscle
metabolism [48]. Long-term (1year) treatment in pediatric
patients significantly reduces bone loss, heart rate, and REE
without compromising immune function and increasing infection incidence [137].
Although there is a risk that enhanced endogenous catecholamine production combined with β-blockade could result
in unopposed α-adrenergic activity, vasoconstriction, and
ischemia, this has not been unequivocally demonstrated in
burn patients [165]. Other potential side effects, including
hypotension and bradycardia, can easily be diagnosed and
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managed in a burn intensive care unit. Despite potential
negative effects, there is sufficient evidence in pediatric burn
populations regarding efficacy of propranolol treatment.
While there are fewer studies establishing propranolol in
adult and elderly burn hypermetabolism management, clinical trials are currently ongoing [166, 167]. However, it is
important to note that propranolol administration is not
simple and effectively dosing is a challenge. Pediatric patients
are typically given 1–4mg/kg/day, while adults usually start at
10mg QID.The adult dose is increased in order to maintain
heart rate below 100bpm while maintaining blood pressure.
Recombinant Human Growth Hormone
Human GH is an endogenous anabolic hormone produced by
the pituitary gland that has receptors and binding proteins in
various tissues. Burn patients may exhibit disruptions in the
GH/IGF-1/IGFBP-3 axis likely as a consequence of excessive
pro-inflammatory cytokine production, favoring catabolism.
Thus, rhGH injection could be a possible therapeutic
strategy.
In adults, a 3-month rhGH regimen enhanced lean body
mass and muscle power while positively regulating IGF-1 and
adiponectin levels [168]. Other studies in children yielded
similar beneficial effects with regard to recovery of lean body
mass. As mentioned earlier, Hart etal. investigated long-term
(1 year) therapy with propranolol and rhGH after burn in
children, indicating that rhGH increases lean body mass,
height and weight gain, and bone mineral density compared
to placebo [169]. Importantly, long-term treatment increases
thyroid hormone-binding sites, ameliorating post-burn
growth arrest in children [170]. Similar results were seen in
another study by Branski etal. with the added finding of a
diminished hypermetabolic response [171]. Jeschke etal. also
demonstrated that rhGH administration in children significantly decreases hypermetabolic and hyperinflammatory
responses especially when combined with propranolol [164].
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