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CHAPTER3 Pathophysiological response toburns
Systemic changes
Multisystem changes occur following large burns (>20– 30% TBSA).
Cardiovascular function and burn shock
Burn shock occurs when organ function is compromised by reduced perfusion. The mechanisms leading to burn shock are a complex interplay
between hypovolaemia and several inammatory mediators released postburn, such as histamine (see Table 3.1).
Heat disturbs vascular endothelial and cell membrane integrity. Increased
microvascular permeability allows leakage of uid from the intravascular
space, which becomes hypovolaemic, to the interstitial space, where it
causes oedema. Insensible uid losses are also increased secondary to
evaporation following loss of epithelial barrier function. Homeostatic compensation is attempted by a rise in peripheral vascular resistance. These
changes contribute to the reduction of cardiac output (CO) immediately
post burn. However, CO falls before hypovolaemia occurs, suggesting a
simultaneous direct neurogenic response. Further, the myocardium may
be depressed by a mediator released by burn wounds, although this is
not yet fully characterised. Cardiac dysfunction in the rst two days (ebb
phase) further stimulates release of inammatory mediators – a positive
feedback cycle.
The kidneys receive 25% of cardiac output and are therefore sensitive
to reductions in circulating volume. Hypovolaemia leads to pre- renal acute
kidney injury and, potentially, renal failure which can have a mortality rate
of 88% for adults and 56% for children.
Early and adequate uid resuscitation is crucial in ameliorating the eects
of burn shock. However, since inammatory mediators including a myocardial depressant factor contribute to burn shock, correcting hypovolaemia
alone does not entirely obviate the problem. Further, although patients
with extensive burn require large amounts of uid, resuscitation should be
closely monitored since restoration of circulating volume can exacerbate
oedema caused by hyperpermeable vessels.
Eect onmetabolism and inammation
A stereotyped neuroendocrine response occurs following trauma. This response is possibly an evolutionary adaptation to mobilise energy sources,
primarily glucose for the ‘ght or ight’ response. Neural excitability results in increased secretion of catabolic hormones such as cortisol and
glucagon, anti- insulin hormones such as growth hormone (GH) and catecholamines. In concert, these hormones cause hyperglycaemia by inducing
glycogenolysis and gluconeogenesis. Gluconeogenic substrates are derived
from lipolysis and proteolysis partially explaining lean muscle loss and cachexia. This stress response to trauma is clinically indicated by tachycardia,
pyrexia and elevation of serum neutrophil and inammatory markers, e.g.
CRP (C- reactive- protein).
A systemic immunoendocrine response also occurs following large
burns and other critical illnesses. Transcriptome analysis shows that similar
genes are activated secondary to endotoxaemia, blunt trauma, and burns.
However, the response to burns is massively amplied and proportionate
to burn size. Post- burn immunoendocrine changes persist beyond wound
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SYSTEMIC CHANGES
Table3.1 Mediators ofburn injury
Mediator Role
Histamine Released from mast cells and increases early phase
Prostaglandins Derivatives of arachidonic acid released from burned
Thromboxane Produced locally by platelets
Kinins Local inammatory mediator that contributes to uid shifts
Serotonin Released early following burn injury
Catecholamines Adrenaline and noradrenaline released is augmented
Oxygen radicals Activated neutrophils release oxygen free radicals including
Platelet
aggregation factor
Angiotensin II and
vasopressin
Data sourced from Jeschke M.Pathophysiology of burn injur y, p. 13– 29, in Jeschke MG etal.
(eds) Burn care and treatment. Vienna, Austria:Springer. Copyright © 2013; and Keck M, etal.
Pathophysiology of burns. Wiener Medizinische Wochenschrift 159(13– 14):327– 36. Copyright ©
2009 Springer- Verlag Wien.
microvascular permeability by inducing gap formation
between endothelial cells
Increases capillary pressure and uid extravasation by
dilating arterioles and constricting venules
tissue and inammatory cells such as activated
macrophages and neutrophils
Vasodilatory and increase microvascular permeability
Can cause progression of partial- thickness to full- thickness
injury through vasoconstriction
by increasing venular permeability
Contributes to the rise in peripheral systemic resistance by
constricting the smooth muscle of large vessels
following burn injuries
These catecholamines reduce capillary pressure by
constricting arterioles. They may also limit histamine- and
bradykinin- induced capillary permeability. These two
actions encourage uid reabsorption from the interstitium
Potentiate hypermetabolism and hyperdynamism of the
circulation
the superoxide anion, hydrogen peroxide and hydroxyl ion
These contribute to uid shifts by damaging microvascular
endothelial cells and thus increase vascular permeability
Contributes to oedema by increasing capillary permeability
Regulators of uid balance and potent vasoconstrictors of
terminal arterioles
Increased release following burns
Angiotensin II implicated in selective gut mucosal ischemia
with subsequent translocation of bacteria and endotoxins,
sepsis, and potential multi- organ failure
Vasopressin, with catecholamines, is likely largely
responsible for increased system vascular resistance which
increases left heart afterload and, therefore, cardiac work
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CHAPTER3 Pathophysiological response toburns
closure for up to 3years. These changes are associated with adverse outcomes such immune incompetence and associated sepsis, increased fracture risk, growth retardation, reduced organ function, impaired wound
healing, and death.
The primary mediators of the hypermetabolic response are catecholamines, glucocorticoids, and inammatory cytokines, such as the pro- inammatory interleukins (IL) 1 and 6. These mediators remain elevated for
up to 36months post burn. Jeschke etal. compared several hypermetabolic
and inammatory parameters in 977 burned children (>30% TBSA) and
107 age- matched controls. Predicted resting energy expenditure (REE)
was signicantly greater in burned children from injury up to 2 years
post burn, indicating prolonged hypermetabolism. Up to 2000- fold rises
in proinammatory cytokines (IL 6 and 8) and chemokines (granulocytecolony stimulating factor (CSF) and monocyte chemoattractant protein- 1)
were recorded for 36months. Levels of catecholamines, glucocorticoids,
acute- phase proteins, and other cytokine were also elevated to varying extents and lengths of time (see Table 3.2).
Serum hormone panels are also deranged following large burns. For
example, growth hormone, parathormone, oestradiol, and testosterone
levels may be reduced whereas progesterone levels are elevated. Insulin
levels are signicantly elevated but sustained hyperglycaemia suggests an
insulin- resistant state. Elevated levels of catabolic hormones such as catecholamines, cortisol, and glucagon, as well as increased glycolysis and
gluconeogenesis, also cause hyperglycaemia which is linked to immune dysfunction and increased risk of infections.
Table3.2 Summary ofhypermetabolic and inammatory derangements
following large burns (>30% TBSA)
Magnitude of
Catecholamines Urinary adrenaline 5- fold 18
Urinary noradrenaline 10- fold 2
Glucocorticoids Serum and urinary cortisol Up to 10 fold 36
Cytokines G- CSF, MCP- 1, IL- 6, IL- 8 Up to 2000 fold 36
IL- 1β, - 2, - 5, - 7, - 10
and - 17, TNF- α, IFN- γ,
GM- CSF
Acute- phase
proteins
G- CSF, granulocyte- colony stimulating factor; MCP- 1, monocyte chemoattractant protein- 1;
TNF- α, tumour- necrosis factor- alpha; IFN- γ, interferon- gamma; GM- CSF, granulocyte-
macrophage; CRP, C- reactive protein; IL- interleukin.
Data sourced from Jeschke MG, etal. Long- term persistence of the pathophysiologic response
to severe burn injury. Plos One 2011;6(7):e21245. Copyright © 2011 Jeschke etal. This is an
open- access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
CRP 13- fold 9
dierence
up to 20- fold Most of the
Duration
(months)
36month
study period
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SYSTEMIC CHANGES
Table3.3 Eects oflosses oflean body mass (LBM)
Magnitude of LBM loss (%) Eects
10 Immune dysfunction
20 Decreased wound healing
30 Increased risk for pneumonia and pressure sores
40 Possible death
Body composition and organ changes secondary tohypermetabolism
The hypermetabolic and hyperinammatory stress response produces
long- term changes in body composition and organ function.
Bone mineral content, lean body mass, fat content, height, and weight
were all signicantly reduced in burned children for 36months post burn.
Loss of lean body mass results from muscle protein catabolism which
is increased to provide gluconeogenic substrates. However, since the
sequelae of low LBM can be fatal (see Table 3.3), pharmacological and nutritional interventions are important to ameliorate proteolysis. Asimilarly
multifaceted approach including anabolic agents— such as oxandrolone and
growth hormone (GH)— and physical therapies is required to correct postburn osteopenia.
In burnt children, the liver remains almost double the size of controls
with correspondingly elevated transaminases, alkaline phosphatase, and reduced albumin. Hepatomegaly is associated with increased septic susceptibility and mortality risks.
Eect onother systems
Burns can also adversely aect other systems directly or indirectly (see
Table3.4).
Gastrointestinal mucosal atrophy occurs early and aects absorption
of glucose, fatty acids, and amino acids. Intestinal permeability is also increased, increasing the risk of sepsis. Furthermore, intestinal blood ow
decreases. These changes, along with post- burn ileus, reduce the body’s
capacity to absorb nutrients required to support the hypermetabolic states.
Early enteral feeding is crucial to ameliorate these changes in an eort to
avoid potentially catastrophic malnutrition.
The immune system is also globally depressed following burns. The
scale of immune depression is proportional to burn size. Burn patients,
by virtue of lost skin barrier function, are susceptible to microbial colonization. Immune incompetence further reduces the capacity to mount
responses. Patients become susceptible to a range of infective complications which can be fatal. Sepsis remains the largest cause of post- burn
mortality.
Pulmonary function is also adversely aected by burn- induced oedema,
regardless of whether inhalation injury is present. Burns increase pulmonary
vascular resistance and wedge pressures. This, combined with neutrophil
and TNF- α- mediated increases in pulmonary microvascular permeability,
encourages uid shifts. Both hypoprotenaemia, from plasma protein loss
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CHAPTER3 Pathophysiological response toburns
through the burn wound, and overzealous uid resuscitation also increase
risk of pulmonary oedema. Reduced airway compliance and impaired gaseous exchange occurs. Respiratory function could also be aected by proteolysis of intercostal and accessory muscles of respiration secondary to
hypermetabolism.
Table3.4 Summary ofthe eects ofburn injury onkey systems
Cardiovascular
Early phase Hypermetabolic phase
Hypoperfusion Hyperperfusion
i Capillary permeability Oedema
i Peripheral vascular resistance Cardiac arrhythmias
d Cardiac output Mycocardial dysfunction
Renal
Early phase Hypermetabolic phase
Hypoperfusion Hyperperfusion
dGlomerular ltration rate iGlomerular ltration rate
Acute renal failure
Respiratory Gastrointestinal
Pulmonary hypertension Paralytic ileus
i Airway resistance Gastric stasis
d Compliance GI ulceration
GI haemorrhage
d Mesenteric perfusion
d Nutritional absorption
Bacterial translocation
Hepatic hypoperfusion
https://t.me/med1917
FURTHER READING
Further reading
Jeschke M. Pathophysiology of burn injur y. In Jeschke MG, Kamolz L- P, Shahrokhi S (eds) Burn care
and treatment. Vienna:Springer, 2013; pp. 13– 29.
Jeschke MG, Gauglitz GG, Kulp GA, etal. Long- term persistence of the pathophysiologic response
to severe burn injury. Plos One 2011;18;6.
Jeschke MG, Mlcak RP, Finnerty CC, etal. Burn size determines the inammatory and hypermetabolic
response. Critical Care 2007;11:R90.
Keck M, Herndon DH, Kamolz LP, et al. Pathophysiolog y of burns.Wiener Medizinische
Wochenschrift 2009;159:327– 36.
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Chapter4
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Hypermetabolic response
toburns
Hypermetabolic response to burns 30
Strategies to attenuate hypermetabolism
and catabolism 32
Summary 34
Further reading 34
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CHAPTER4 Hypermetabolic response toburns
Hypermetabolic response toburns
Although improvements in clinical care have been made over the past three
decades and these improvements have translated into reduced morbidity
and mortality, a large thermal injury remains one of the most disastrous
injuries today.
The burn survivor experiences not only several psychosocial stressors
and disgurement, but also a unique metabolic response to the trauma that
does not resolve with burn wound closure and healing. This problem has
been best studied in paediatric burn patients.
These hypermetabolic and catabolic responses are seen in patients with
burns over more than 30% of the total body surface area (TBSA). Two
phases are observed:
• The ‘ebb’ phase starts immediately after a burn, lasts 2– 3days, and is
characterized by a ‘shock state’ with decreases in cardiac output, oxygen
consumption, metabolism, and glucose tolerance
• The ‘ow’ phase starts approximately 5days after a burn. This phase
can last up to 3years (the maximum follow- up period reported)
in paediatric patients with >30% TBSA burned. The ow phase is
characterized by persistent hypermetabolic and inammatory responses,
leading to catabolism and loss of function, which delay re- integration of
the burn survivor into society
Findings:
• Metabolism:Indirect calorimetry is used to quantitate hypermetabolism.
The resting metabolic rate increases immediately post burn to 180%
of the basal rate during the acute phase, is 110% at 12months, and
remains elevated up to 3years post burn. Heightened glycogenolysis,
gluconeogenesis, and lipolysis create an environment of elevated
glucogenic precursors, resulting in hyperglycaemia and insulin resistance.
Hyperglycaemia itself is associated with a higher infection rate, which
in turn exacerbates metabolism and catabolism. Serum triglycerides
and glucose levels increase gradually during the ow phase and remain
elevated even after wound healing is complete. These elevations, which
can also last for up to 3years, are associated with peripheral lipolysis
and insulin resistance
• Body composition:Catabolism (characterized by muscle wasting, a
negative nitrogen balance, weight loss, and decreased bone mineral
content) can be so severe that growth arrest can result. Metabolic
studies have shown that muscle protein is broken down to fuel the
hypermetabolic response. Without intervention, a lethal loss of
20– 25mg/ m2 nitrogen can be reached in 2– 3 weeks after a
severe burn
• Organs:Cardiac output increases after the ebb phase. Studies in
paediatric patients with >30% TBSA burns have shown that cardiac
output remains increased for up to 12months after a burn before
returning to age- matched, non- burned, normal values. An increase in
liver size, as measured by ultrasound, occurs in paediatric burn patients
and does not return to normal even after 3years
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HYPERMETABOLIC RESPONSE TOBURNS
• Inammatory response:Many cytokines and acute- phase proteins are
elevated after a burn. Dramatic changes have been observed for IL- 6,
IL- 8, G- CSF, and MCP- 1, with increases of up to 2,000- fold compared
to non- burned control levels. GM- CSF, INF- γ, TNF- α, IL- 1β, IL- 2, IL- 5,
IL- 7, IL- 10, and IL- 17 increase signicantly above control levels and have
been found to remain elevated for most of the 3- year follow- up period.
Alterations in serum acute- phase proteins include elevations of serum
complement C3, haptoglobin, α1- acidglycoprotein, and CRP, with
decreases in α2- macroglobulin. Expression of serum constitutive hepatic
proteins such as transferrin, retinol- binding protein, and pre- albumin are
lower in burn patients than in controls. Hepatic enzymes are elevated
with concurrent decreases in albumin
• Hormonal imbalance:Urinary catecholamines and cortisol are elevated
immediately after a burn and remained elevated. Norepinephrine is
elevated up to 540days post burn. Decreases in growth hormone,
insulin growth factor- 1, insulin- like growth factor binding protein- 3, and
parathyroid hormone occur as well
Additionally, infections and sepsis are associated with signicant increases
in metabolism and oxygen consumption, which may underlie adverse outcomes after a burn.
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