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Chapter 2. Pathophysiology andHypermetabolic…
Beyond beneficial effects in muscle protein kinetics, rhGH
treatment induces more rapid healing in children and adults
alike and minimizes scarring while improving outcomes such
as decreased hospital LOS [171, 172].
However, a key adverse event associated with rhGH treatment is hyperglycemia, which is of concern in burn patients.
Interestingly, beneficial outcomes seen with rhGH are not
reproducible in non-burn, critically ill patients. In fact, these
patients have hyperglycemia and insulin resistance associated
with a 40% increase in morbidity and mortality [173] .
Therefore, while rhGH has an anabolic effect, care should be
taken prior to implementation in patients. Currently, rhGH is
not a standard of care in burn or critically ill patients.
55
Insulin-Like Growth Factor 1/Insulin-Like Growth
Factor Binding Protein-3
Kim et al. demonstrated that rhGH treatment enhanced
IGF-1 levels, which is produced in the liver in response to
endogenous or exogenous GH. Therefore, the beneficial
effects of rhGH could be attributed to IGF-1 upregulation.
Similar to proinsulin, IGF-1 is a polypeptide whose principal
binding protein is IGFBP-3 [174]. IGF-1 in animal models
exhibits anti-inflammatory and anabolic effects and alleviates
stress responses. However, because of the side effects, IGF-1
is given as a complex with IGFBP-3in a 1:1 molar ratio. This
complex improves protein metabolism and diminishes catabolism without significantly impacting glucose levels (unlike
rhGH-associated hyperglycemia) [175]. The beneficial effects
on muscle maintenance can, in part, be attributed to improved
immune function and attenuated acute phase and inflammatory responses [57, 175–177].
However, similar to rhGH, IGF-1 alone is not effective in
critically ill, non-burn patients. This indicates that IGF-1 (and
by extension, rhGH) is primarily effective when administered
in conditions of significant IGF-1 deficiency; for example,
hypermetabolism-induced increased IGF-1 turnover. This
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R. Vinaik et al.
could be accounted for by lower levels of IGFBPs, especially
IGFBP-3, which is seen for up to 3years post-burn in pediatric patients and is associated with severe growth arrest [21].
Exogenous IGF-1/IGFBP-3 treatment functions by partly
reversing depressed TH1 and exaggerated TH2 cytokine
responses after burns, balancing pro- and anti-inflammatory
cytokines and improving organ function [178]. Treatment also
attenuates the hepatic acute phase response, indirectly affecting serum levels of proteins that influence the hypercatabolic
response [176, 177, 179, 180].
Although IGF-1 could be used to mitigate post-burn
hypermetabolism and catabolism, currently its use is limited
due to side effects such as hypoglycemia and poor efficacy
with IGF-1 monotherapy in critically ill, non-burn patients
[181, 182]. Dual therapy with IGF-1 and IGFBP-3 shows
some promise with regard to reduction in catabolism and
fewer hypoglycemic episodes [183]. However, IGF-1/IGFBP-3
administration is associated with adverse events such as neuropathies. At this point, further work is needed to optimize
IGF-1 or IGF-1/IGFBP-3 complex prior to implementation
for management of post-burn hypermetabolism [4].
Insulin
The hyperinsulinemic, hyperglycemic state after burn is associated with adverse clinical outcomes, and tight glycemic
control decreases infection and sepsis rates and improves
organ function [184, 185]. Insulin is an effective antihyperglycemic agent that is utilized in severely burned
patients due to its additional anabolic and anti-catabolic
effects. Insulin can attenuate hypermetabolism, evidenced by
decreased lean body mass loss, which serves as a marker to
monitor the hypermetabolic response [186]. Although the
mechanisms underlying its anti-catabolic effects have not
been elucidated as of yet, administration in burn patients
unequivocally increases muscle protein synthesis and attenuates lean body mass loss [20, 127].
Chapter 2. Pathophysiology andHypermetabolic…
Gore et al. demonstrated that hyperinsulinemia in burn
patients improves leg blood flow and muscle protein synthesis [184, 187]. Potentially, insulin mitigates hypermetabolism
by increasing IGF-1 and IGFBP-3, which facilitates suppression of proteolysis and activation of protein synthesis
[188, 189]. Additionally, insulin may exert anabolic effects by
suppressing IGFBP-1, thus increasing availability of IGF-1.
While high doses of insulin restore anabolism in critically
ill surgical patients, this introduces the risk of hypoglycemia
[190]. However, submaximal doses are sufficient to elicit anabolic effects while minimizing hypoglycemic episodes [191].
In addition to these beneficial effects, insulin is more cost
effective than rhGH or IGF-1 and has a clearly established
safety profile. If glucose levels are carefully monitored, insulin
can be administered to manage post-burn hypermetabolism.
57
Metformin
Metformin is a primary alternative to insulin for hyperglycemic regulation in severely injured patients. Similar to insulin,
metformin functions as both an anti-hyperglycemic and an
anabolic agent. Although the mechanisms underlying muscle
protein balance are still unclear, Gore etal. demonstrated a
relationship between elevated glucose levels and protein
catabolism [192]. Metformin likely regulates glucose levels by
diminishing synthesis of cyclic AMP, which is elevated after
burns and is a key potential mechanism in development of
post-burn hyperglycemia and insulin resistance [193]. By
improving insulin receptor sensitivity and attenuating postburn hyperglycemia, metformin may diminish net muscle
protein catabolism. Indeed, metformin treated patients
exhibit increased fractional synthetic rate of muscle protein
and improved net muscle protein balance [192, 194].
Metformin is compatible with insulin with regard to glycemic regulation and anabolic effects [195]. Additional advantages include cost-effectiveness and oral formulations, with
the added benefit that glucose levels need to be monitored
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less frequently once glucose and medication levels are stabilized. However, metformin can possibly induce lactic acidosis
and worsening of renal failure in high-risk patients [196].
Therefore, it should not be given to patients with poor lactate
elimination, such as those with renal or hepatic failure [197].
However, safety and efficacy trials in severely burned patients
indicate no significant worsening of renal or hepatic function
or lactic acidosis with metformin treatment [198].
Oxandrolone
The anabolic agent oxandrolone is a testosterone analog that
improves muscle protein catabolism via increased protein
synthesis and muscle mass gain and decreased weight loss.
Interestingly, oxandrolone has primarily anti-catabolic effects
in adults and anabolic effects in children [199]. Pediatric burn
patients treated with oxandrolone demonstrate upregulation
in several genes (e.g., transcription factors, muscle-associated
proteins, stress response proteins) and increased muscle protein balance [200, 201]. In adults, oxandrolone also restored
lean body mass in the acute and rehabilitation phase, augmented hepatic protein synthesis, and shortened hospital LOS
and donor site healing time [188, 202, 203]. Long-term administration decreases REE and hypermetabolism, increases lean
body mass by 6, 9, and 12 months post-burn, and increases
bone mineral content at 12 months compared to controls
[204]. Moreover, evidence suggests that oxandrolone may
have effects that persist for up to 5years after burn [205].
Although it is as effective in mitigating weight loss and has
similar benefits to agents such as rhGH, oxandrolone has an
improved side effect profile. Compared to rhGH, oxandrolone has less hyperglycemia and an attenuated hypermetabolic response [206]. Currently, the most common side effect
reported is hepatotoxicity although studies in burn patients
indicate no significant differences in liver dysfunction and
only a mild increase in transaminase levels in pediatric
patients [207–209].
Chapter 2. Pathophysiology andHypermetabolic…
59
Testosterone
The hypothalamic–pituitary–gonadal (HPA) axis reduces
the signal for production of testosterone under conditions
of severe stress such as burns [210]. In theory, testosterone
replacement should enable skeletal muscle anabolism. In a
study by Ferrando etal., exogenous testosterone administration in severely burned male patients resulted in a twofold reduction in muscle catabolism primarily due to
reduction in breakdown rather than alterations in protein
synthetic rate [211]. However, pediatric patients demonstrate an alternative mechanism of action of testosterone
therapy. In these patients, short-term testosterone treatment enhances protein synthesis rather than impacting
catabolism [212, 213].
In spite of these beneficial effects, there are limitations to
testosterone use in burn patients primarily due to the side
effect profile. This includes increased risk of cardiovascular
events, hepatotoxicity, erythrocytosis, and prostatic and dermatologic disorders [214]. Also, testosterone use is limited in
women due to potential androgenic effects. Due to its side
effect profile and the fact that there are no oral formulations,
alternative agents are used such as oxandrolone.
Conclusion
Hypermetabolism is an important response that has an
integral role in burn patient outcomes. While it may initially be an adaptive mechanism for post-burn survival,
there are several negative outcomes associated with it.
Although these consequences have been identified, hypermetabolism is still not completely understood. Delineating
the mechanisms underpinning this complex response is
imperative in order to successfully manage burn patients
in the clinical setting. Clinical features of the hypermeta-
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R. Vinaik et al.
bolic response include hyperglycemia and insulin resistance, hyperinflammation, catecholamine fluctuations, and
whole-body catabolism, and contribute to adverse outcomes. These detrimental effects target multiple organ
systems including cardiopulmonary, renal, gastrointestinal,
and immune systems and contribute to organ failure. While
several conservative and pharmacological advances in
clinical management focus on regulating hypermetabolism,
accurately determining and preserving nutritional status
and developing a consensus therapeutic approach is still
challenging.
Early excision and wound closure is an important initial
strategy that significantly improves burn patient mortality
rate. Important additional measures include environmental
temperature modulation and incorporation of resistance
exercises to aid in recovery and maintain lean body mass.
However, despite utility of conservative strategies, pharmacological intervention is a vital tool. Pharmacological agents
such as the β-blocker propranolol attenuate post-burn
hypermetabolism and inflammation and have a significant
anti- catabolic effect, especially when combined with agents
such as rHGH. Other important drugs include blood glucose regulators. Insulin administration to maintain blood
glucose levels below 130mg/dL significantly reduces morbidity, while metformin reduces muscle catabolism with the
added benefit of lower risk of hypoglycemic episodes.
Taken together, we show the broad long-term effects of
the hypermetabolic response after burns. Although the exact
initiating cause is not entirely defined, altered production of
stress-related mediators (catecholamines, glucocorticoids,
glucagon) can stimulate and maintain hypermetabolism,
which results in a profound catabolic state if not treated with
appropriate agents. While the conservative and pharmacological strategies discussed in this chapter are promising, further investigation is required at this point to elaborate and
improve burn care (Table2.2).
Chapter 2. Pathophysiology andHypermetabolic…
T . Summary of interventions
Intervention Summary Reference
Propranolol Anti-catabolic and anabolic
agent, beneficial when combined
with rhGH.Combination therapy
ameliorates hypermetabolism
and inflammation. Treatment
in children increases muscle
protein balance by 82%, longterm treatment reduces bone
loss, cardiac work (heart rate),
and REE without compromising
immune function and increasing
infection incidence.
Administration is not simple, and
effective dosing is a challenge.
Side effects such as hypotension
and bradycardia can easily
be diagnosed but needs to be
managed in a burn intensive care
unit. Despite negative effects,
sufficient evidence showing
efficacy in pediatric burns.
Clinical trials are currently
ongoing in adults.
Recombinant
Human
Growth
Hormone
RhGH diminishes the
hypermetabolic response,
enhances lean body mass and
muscle power in adults, increases
bone mineral density, height, and
weight in children.
A key adverse event is
hyperglycemia. RhGH is
currently not a standard of care
in burn or critically ill patients
and should not be given if the
patient has an ongoing infection
or is septic.
Arbabi
etal. (2004)
Breitenstein
etal. (1990)
Mohammadi
etal. (2009)
Herndon
etal. (2001)
Flores etal.
(2016)
Takala etal.
(1999)
Hart etal.
(2002)
Connolly
etal. (2003)
Jeschke etal.
(2008)
Branski etal.
(2009)
Kim etal.
(2016)
61
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T . (continued)
Intervention Summary Reference
Insulin Effective anti-hyperglycemic.
Attenuates hypermetabolism,
(decreased lean body mass
loss, increased muscle protein
synthesis).
More cost effective than rhGH
or IGF-1 and has a clearly
established safety profile.
However, high doses increase
hypoglycemia risk. If glucose
levels are carefully monitored,
Gore etal.
(2002)
Gore etal.
(2004)
Van den
Berghe
(2004)
Jeschke etal.
(2007)
Pidcoke
etal. (2014)
insulin can be administered
to manage post-burn
hypermetabolism.
Metformin Anti-hyperglycemic and
anabolic agent. Compatible with
insulin with regards to glycemic
regulation and anabolic effects.
Cost-effective, oral formulations
available, glucose needs to be
monitored less frequently once
medication levels are stabilized.
Salpeter
etal. (2003)
Gore etal.
(2005)
Riesenman
etal. (2007)
Sears and
Perry (2015)
Can induce lactic acidosis and
worsening of renal failure.
Should not be given to patients
with poor lactate elimination
(renal or hepatic failure). No
significant worsening of renal/
hepatic function or lactic acidosis
in burn patients. Attractive
strategy to manage burn-induced
hypermetabolism.
(continued)
Chapter 2. Pathophysiology andHypermetabolic…
T . (continued)
Intervention Summary Reference
Oxandrolone Acute and long-term
administration decreases REE
and hypermetabolism, increases
lean body mass and bone
mineral content.
Improved side effect profile
compared to rhGH (less
hyperglycemia, hypermetabolic
response). Most common side
effect is hepatotoxicity, although
no significant differences in
liver dysfunction and only mild
increase in transaminase levels
in children. Hepatic function
monitoring is recommended.
Testosterone Administration in severely
burned adult male patients
decreases muscle catabolism and
enhances protein synthesis in
pediatric patients.
Limitations due to the side effect
profile (cardiovascular events,
hepatotoxicity, erythrocytosis,
and prostatic and dermatologic
disorders) and androgenic
effects. Alternative testosterone
derivatives preferred.
Barrow etal.
(2003)
Wolf etal.
(2003)
Demling
(2005)
Jeschke etal.
(2007)
Pham etal.
(2008)
Miller and
Btaiche
(2009)
Porro etal.
(2012)
Cochran
etal. (2013)
Ferrando
(1999)
Spratt (2001)
Ferrando
etal. (2007)
Basaria etal.
(2010)
63
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