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Chapter 2. Pathophysiology andHypermetabolic…
F . Lipolytic and proteolytic byproducts as gluconeogenic
and glycolytic/TCA substrates
35
production, and (3) enhancing adipose lipolysis and muscle
proteolysis to provide gluconeogenic and glycolysis/TCA
substrates like glycerol, alanine, and lactate (Fig.2.2).
In burn patients, the rate of glucose production in the liver
is around twofold greater than in healthy controls [14, 43].
This increased glucose production is excessive for tissue use
and leads to the “diabetes of stress.” [14, 44] Moreover, unlike
in healthy individuals, exogenous glucose infusion does not
fully attenuate hepatic gluconeogenesis in burn patients
(only about 50%) [43]. While the exact cause is not entirely
defined, it appears that burn patients undergo a “double hit”
where both central and peripheral insulin sensitivity are
impaired after injury, resulting in poor glucose control. More
specifically, insulin exerts a diminished ability to suppress
hepatic glucose output (central insulin resistance) and/or a
diminished ability to stimulate glucose disposal into skeletal
muscle (peripheral insulin resistance) [44]. Therefore,
although glucose remains a preferred substitute for tissue
energy post-burn, there is a well-defined limit to its use given
the insulin resistance. The result of this metabolic abnormality is (1) hyperglycemia; (2) profound catabolism; (3)
increased ectopic fat deposition; and (4) wasted energy.
Of major importance is recent evidence suggesting that
impaired glucose metabolism post-burn is detrimental and
contributes to adverse clinical outcomes after injury. Studies
have shown that hyperglycemia not only leads to profound
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R. Vinaik et al.
wasting and cachexia in severely burned patients but is also
linked to increased incidence of infection, pneumonia, sepsis,
and even death [10–14, 21, 45, 46]. These findings were further
supported by a prospective randomized trial, which demonstrated that glycemic control is beneficial for post-burn organ
function and morbidity outcomes. Retrospective cohort studies also confirmed the survival benefits of glycemic control in
severely burned patients [12, 46]. Together, these studies
clearly highlight the significant clinical challenges associated
with post-burn insulin resistance and hyperglycemia and the
importance of treatment after injury.
Lipid Metabolism
Lipid metabolism is another key metabolic pathway that is
significantly altered during the post-burn hypermetabolic
period. As with other forms of trauma, the rise in post-burn
catecholamine levels leads to activation of adipose tissue
lipolysis, mainly via β2 and β3 adrenergic stimulation [47, 48].
Lipolysis is defined as the enzymatic breakdown (hydrolysis)
of triglycerides into free fatty acids (FFAs) and glycerol molecules. These substrates are then released into the circulation
to be used as fuel by other tissues in the body through betaoxidation, gluconeogenesis, and glycolysis [49]. Similar to
glucose however, the amount of exogenous fat that can be
utilized as an energy substitute after burn is limited [15, 50].
In fact, only 30% of FFAs at most is oxidized for fuel, while
the remaining 70% is simply recycled. This is a marked difference from starvation during which 90% of lipolysis-derived
FFAs are used for fuel [50]. Unfortunately, burn-induced
lipolysis and FFA mobilization have been linked to a number
of detrimental complications, including insulin resistance and
multi-organ dysfunction. Specifically, increased FFA levels
may overwhelm glucose transport activity after injury, which
further impairs insulin-mediated glucose uptake contributing
to post-burn insulin resistance [5, 50, 51]. This has been supported by research in type 2 diabetes, demonstrating that
Chapter 2. Pathophysiology andHypermetabolic…
elevated FFA levels are predictive for the incidence and
severity of the disease [52, 53].
Another major consequence of the post-burn lipolytic
response is increased fatty infiltration into vital organs, especially the liver. Liver fatty infiltration and dysfunction, or
hepatic steatosis, remain a leading cause of morbidity and
mortality in burn patients [21]. A clinical analysis conducted
by Kraft etal. demonstrated that a strong correlation exists
between FFA and hepatic fat content after burn injury [54].
This data is in agreement with post-burn pathology examinations and spectroscopy reports showing that hepatic triglycerides are increased by three- to fivefold in severely burned
children [55, 56]. In fact, these authors also found that in
severely burned children, elevated triglycerides are associated
with worsened organ function and glucose metabolism and
increased incidence of infection, sepsis, and poor outcomes
[54]. Thus, while adipose tissue was previously ignored for a
long time, it is becoming increasingly evident that this organ
plays a very central role in meditating post-burn hypermetabolic responses. Though this relationship is now clear, the
mechanisms by which lipolysis-derived lipids induce these
post-burn metabolic disturbances are still not entirely defined.
37
Protein Metabolism
The main source of fuel in the burned patient is protein/
amino acids from skeletal muscle. Chronic catabolism of skeletal muscle is pathognomonic of severe burn trauma, which
leads to marked wasting of muscle protein and consequently
of lean body mass (LBM) within days after injury [7, 26, 44].
The prolonged erosion of LBM and resultant wasting leaves
burn survivors cachectic and debilitated. This metabolic
abnormality in turn significantly delays wound healing and
contributes to long-term morbidity after injury [44]. While
the specific mechanism is unclear, likely mediators are stress
hormones, cytokines, and oxidants. The underlying pathophysiology was shown to be a substantial increase in muscle
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protein breakdown along with no or only a minor compensatory increase in muscle protein synthesis leading to muscle
loss [56]. From a mechanistic view, burn injury induces a
concurrent increase in both skeletal muscle protein synthesis
(MPS) and breakdown (MPB) rates. However, MPB rates
significantly surpass MPS rates, resulting in significant net
loss of total body protein [56]. Moreover, increasing protein
intake does not further increase muscle protein synthesis,
indicating that the catabolic drive cannot be overcome with
more substrate synthesis [57]. The exception would be addition of an anabolic agent, such as growth hormone or testosterone, which in fact would be more likely to overcome the
net amino acid effect [57]. Medical management of hypermetabolic changes will be discussed in Management of
Hypermetabolism: Pharmacological Intervention section.
Interestingly, recent evidence suggests that defects in skeletal muscle protein kinetics can persist for over a year after
burn injury. Indeed, studies have shown that lean body mass
is reduced for up to 2–3 years post-burn. In severely burn
patients (>30% TBSA), this cachectic state can be observed
for several years after injury [26]. The clinical consequences
of persistent protein catabolism can be quite severe, depending on the degree of muscle protein loss [58]. A 10–15% loss
in LBM has been shown to decrease wound healing, while a
further increase in LBM loss ~30% is associated with significant increases in infection rates, profound weakness, pressure
sores, and diminished wound healing [59, 60]. An LBM loss of
40% or greater usually becomes fatal [60]. Mortality in these
burn patients is further augmented by severe muscle weakness, which can prolong mechanical ventilation requirements,
inhibit sufficient cough reflexes, and delay mobilization in
protein-malnourished patients [61]. Decreases in muscle
mass may also be responsible for the delay in growth commonly observed in pediatric burn patients, even at 2 years
post-burn [62]. Furthermore, given that skeletal muscle is
responsible for 70–80% of whole-body insulin-stimulated
glucose uptake, profound muscle wasting may further augment persistent insulin resistance after injury [20]. Modulation
Chapter 2. Pathophysiology andHypermetabolic…
of this hypercatabolic response after burn injury is thus paramount for the restoration of normal metabolic structure and
function in severely burned patients.
39
Targeting Organ Systems: Cardiac, Renal,
Gastrointestinal, andImmune Systems
Cardiac
Burns are associated with poor myocardial function after
injury as a result of impaired contractility and right heart
overload [63, 64]. Increased systemic and pulmonary vascular
resistance increases afterload for the left and right heart,
respectively. While the left ventricle can compensate and sustain cardiac output due to post-burn adrenergic stimulation,
the right ventricle lacks the capacity to compensate for the
increased afterload. Burns greater than 45% TBSA can cause
contractile issues and in severe conditions, desynchronization
of the ventricles [65]. Aggressive early fluid resuscitation
does not completely correct for left ventricular defects, suggesting that hypovolemia may not be the only mechanism of
impaired post-burn cardiac function [63, 65, 66]. However,
early, sufficient fluid therapy is important in ameliorating
myocardial depression in burns, and animals given no resuscitation exhibit persistent myocardial depression [67]. Horton
etal. demonstrated decreased left ventricular contractility in
guinea pig hearts within 24 h post-burn, which was significantly reversed with adequate resuscitation [68–70].
The underlying mechanism by which post-burn shock
impairs myocardial function is still unclear [71]. However, oxygen-derived free radicals may have a key role in myocardial cell
membrane dysfunction. When given in conjunction with adequate fluid resuscitation (2–4mL/kg/%TBSA), a combination
infusion of superoxide dismutase and catalase (free radical
scavengers) improves post-burn poor ventricular contractility.
However, antioxidant infusion did not alter or obviate the volume needed for fluid resuscitation after burn [72].
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Renal
Rebal function decreases due to reducedcardiac output and
decresed renal blood flow leading to a reduiced glommerular
filtration rate. Additionally, stress-induced hormones that
mediate fluid balance such as angiotensin, aldosterone, and
antidiuretic hormone further limit renal blood flow and compound effects seen due to poor cardiac output. These changes
result in oliguria that can worsen and culminate in acute
tubular necrosis and ultimately, renal failure [71]. Furthermore,
inflammatory mediators such as cytokines (e.g., TNF, IL-1),
eicosanoids (e.g., prostaglandins), and platelet-activating factor are released early post-burn [73]. They increase vascular
permeability and are involved in disseminated intravascular
coagulation that results in formation of microthrombi in
renal structures, further interfering with normal renal function. However, early, adequate resuscitation may decrease
risk of renal failure, which parallels cardiac outcomes (e.g.,
improved cardiac function and output) [74].
Acute renal failure in burn patients is accompanied by
increased morbidity and higher mortality rates and is
detectable by reduced urine output despite adequate resuscitation in oliguric renal failure. Early renal support via incorporation of dialysis during the recovery period is key [75].
Dialysis regulates serum electrolytes and allows for large
volumes of nutritional supplementation and removal of
excess water or toxic substances when combined with hemofiltration in burn patients [75–77].
Gastrointestinal
Gastrointestinal (GI) changes in burns detrimentally impact
nutritional status through several mechanisms. Burns induce
mucosal atrophy within 12h of injury directly proportional to
burn size, increase intestinal permeability, and alter digestive
absorption [78, 79]. The mucosal brush border undergoes atrophy and apoptosis of the epithelial lining, and cytoskeletal
Chapter 2. Pathophysiology andHypermetabolic…
changes associated with apoptotic cell death are most pronounced at 18 h after injury [80]. Interruption in the intact
mucosal barrier in turn enhances intestinal permeability to
macromolecules, correlated with the extent of the burn [81,
82]. This includes enhanced permeability to molecules such as
PEG3350, lactulose, and mannitol, and these effects are compounded by infection [83]. Importantly, altered permeability
of the gut mucosa is closely related to blood flow. Systolic
hypotension in severe burns (40% TBSA) and decreased
intestinal blood flow after burn are associated with increased
intestinal permeability early (5h) after injury [84, 85]. In addition to increased permeability to dextrans, impaired intestinal
blood flow and mucosal viability allow for augmented permeability to opportunistic agents such as Candida [85].
While burn injuries increase transport of the aforementioned, they are also accompanied by reduced glucose, amino
acid, and fatty acid uptake and decreased brush border lipase
activity within a few hours after injury [86]. These changes
return to normal by 48–72 h after injury, which parallels
mucosal atrophy. Thus, treating mucosal atrophy to ensure
adequate nutrition for burn patients is vital. In order to ameliorate atrophy, early enteral nutrition and administration of
glutamine and various antioxidants within 8–12h can improve
intestinal inflammation and function.
41
Immune System
Burns paradoxically cause systemic hyperinflammation and
immune compromise, increasing risk for infectious complications such as bacterial, fungal, and viral infections. Impaired
immune function is proportional to burn size in burns greater
than 20% TBSA, and susceptibility to infection is a byproduct of impaired activity of various immune cells including neutrophils, macrophages, and T and B lymphocytes [71].
Interestingly, neutrophil count is initially increased afterburn
due to decreased apoptosis [87]. However, although neutrophil count is increased, these cells exhibit impaired diapede-
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sis, chemotaxis, and phagocytosis. A deficiency in p47-phox
and p67-phox oxidase components and associated impaired
respiratory burst as well as compromised actin polymerization and depolymerization may account for the aforementioned outcomes [88, 89]. By 48–72 h, neutrophil counts
decrease similar to macrophages, which are diminished after
burn [90].
T lymphocyte function is similarly decreased after severe
burns. This is due to polarization from the T-helper 1 (TH1) to
TH2 response and is correlated with increased mortality rate
[91, 92]. The TH1 response is involved in cell-mediated
immune defense while the TH2 response is important for antibody responses and is characterized by increased interleukin 4 (IL-4) and IL-10 production. Interestingly, administration
of anti-IL-10 antibodies and growth hormone partially
reverses the TH2 response and improves mortality rates in
burn animal models [93, 94]. In addition to increased TH2
responses, burn injury impairs cytotoxic T cell activity, which
enhances infection risk. This can be ameliorated by early
wound excision, which will be discussed in the subsequent
section on management of post-burn hypermetabolism [95].
Adipose Tissue
Originally, adipose tissue was simply regarded as a passive
energy reservoir, however research over the past two decades
has led to a major shift in our understanding of its role in
health and disease. Adipose tissue (AT) is now considered to
be a remarkably complex endocrine organ capable of regulating a variety of diverse biological functions [96]. In addition
to secreting a plethora of adipocyte-derived factors known as
adipokines, AT plays a major part in inflammation, mechanical organ protection, and thermoregulation [96, 97]. Given its
central role as a metabolic-endocrine-immune organ, adipose
dysfunction is associated with a number of detrimental burnrelated metabolic phenomena, and thus, understanding its
biology appears crucial [98].
Chapter 2. Pathophysiology andHypermetabolic…
43
Traditionally, AT has been categorized into two distinct
types, namely white adipose tissue (WAT) and brown adipose
tissue (BAT) [98]. The main function of WAT is to store
excess energy in the form of TGs (triacylglycerols), while
BAT is specialized for thermogenesis and dissipates energy as
heat through UCP1 (uncoupling protein 1)-mediated uncoupling of oxidative phosphorylation from ATP synthesis [99].
These distinct functions of the classic BAT and WAT are due,
at least in part, to their different developmental origins.
Based on lineage tracing experiments performed in mice,
BAT seems to arise from Myf5 (myogenic factor 5)-expressing precursors—a property normally attributed to skeletal
muscle [98]. Thus, brown preadipocytes express a skeletal
muscle gene signature while white preadipocytes do not [98,
99]. In terms of morphology, classic brown adipocytes are
characterized by a small multilocular lipid droplet structure,
an abundance of mitochondria, and the expression of the
mitochondrial brown fat marker, UCP1, which is produced in
the inner mitochondrial membrane. Rodents and humans
both possess BAT; however, whereas BAT depots remain
throughout life in mice, human BAT diminishes with age. In
contrast, WAT is found dispersed throughout the body in
both humans and rodents, with the subcutaneous (inguinal in
rodents) and visceral (epididymal) being the largest fat
depots in the body [99]. These white adipocytes are characterized by unilocular morphology, reduced mitochondrial content, and the lack of UCP1 expression [99].
WAT has long been considered to only exist in the aforementioned classifications, and emerging evidence has
revealed that a complex cellular heterogeneity exists even
within a single fat pad [99]. Indeed, it was recently discovered that certain depots of WAT could adopt BAT characteristics when subjected to certain physiological stimuli in a
process termed “browning” [100, 101]. This results in the
recruitment of “brown-in-white,” or beige adipocytes that
are characterized by a multilocular appearance, increased
mitochondrial biogenesis, and the expression of UCP1—the
master regulator of non-shivering thermogenesis [98–100].
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The dynamic nature of the adipose organ allows the body to
adequately respond to both changes in nutrient supply and
ambient temperature by mobilizing free fatty acids in periods of energy demand and storing excess as triglycerides
when energy is no longer needed [98]. Owing to its high
degree of plasticity, WAT browning has garnered significant
attention over the past decade for its potential to be
exploited for the treatment of obesity and type II diabetes
[102, 103]. Numerous studies have demonstrated that
enhanced thermogenesis in conditions of energy surplus (i.e.,
obesity) has beneficial effects on whole-body metabolic
homeostasis including improved insulin sensitivity, increased
resting energy expenditure, and enhanced weight loss [102].
While beneficial in obesity and diabetes, these attributes can
be detrimental in cancer and burns [103]. In fact, in these
hypermetabolic conditions, WAT browning has been shown
to drive the progression of cancer- associated cachexia, a
state characterized by severe weight loss and muscle catabolism [104]. Furthermore, evidence suggests that WAT browning may promote lipolysis and organ fatty infiltration in burn
patients [105]. Indeed, hypermetabolic burn patients demonstrate elevated levels of circulating FFAs due to the constitutive activation of adipose tissue lipases, such as hormone
sensitive lipase (HSL) following injury [106]. These findings
were corroborated in a recent study from our group demonstrating browning-induced lipolysis facilitates hepatic steatosis and dysfunction in post-burn mice, thereby increasing
morbidity and mortality [107].
Interestingly, in both conditions of cancer and burns where
WAT browning has been implicated in persistent hypermetabolism and poor outcomes, the inflammatory cytokine IL-6
was identified as a major initiator of this pathological cascade
of events [108–110]. In the context of burns, increased levels
of bone marrow derived IL-6 have been shown to correlate
with the magnitude of injury and organ failure, and genetic
deletion of IL-6in mice attenuates post-burn hypermetabolism via reductions in WAT browning and whole-body energy
metabolism [111–114]. Despite all these findings that have
implicated both WAT browning and IL-6 as major drivers of
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