Chăm Sóc Và Điều Trị Bỏng Toàn Diện (Total Burn Care – Tập 5)

235.e2 21  •  Biomarkers in Burn Patient Care
53. Davis CS, Janus SE, Mosier MJ, et al. Inhalation injury severity
and systemic immune perturbations in burned adults. Ann Surg.
2013;257(6):1137-1146.
54. Maile R, Jones S, Pan Y, et al. Association between early airway dam­
age-associated molecular patterns and subsequent bacterial infection
in patients with inhalational and burn injury. Am J Physiol Lung Cell
Mol Physiol. 2015;308(9):L855-L860.
55. Cancio LC, Salinas J, Kramer GC. Protocolized resuscitation of burn
patients. Crit Care Clin. 2016;32(4):599-610.
56. Lawrence A, Faraklas I, Watkins H, et al. Colloid administration nor­
malizes resuscitation ratio and ameliorates “fluid creep”. J Burn Care
Res. 2010;31(1):40-47.
57. Pham TN, Cancio LC, Gibran NS. American Burn Association
practice guidelines burn shock resuscitation. J Burn Care Res.
2008;29(1):257-266.
58. Foldi V, Lantos J, Bogar L, et al. Effects of fluid resuscitation methods on
the pro- and anti-inflammatory cytokines and expression of adhesion
molecules after burn injury. J Burn Care Res. 2010;31(3):480-491.
59. Howell E, Sen S, Palmieri T, et al. Point-of-care B-type natriuretic
peptide and neutrophil gelatinase-associated lipocalin measurements
for acute resuscitation: a pilot study. J Burn Care Res. 2015;36(2):
e26-e33.
60. Hong DY, Lee JH, Park SO, Baek KJ, Lee KR. Plasma neutrophil gela­
tinase-associated lipocalin as early biomarker for acute kidney injury
in burn patients. J Burn Care Res. 2013;34(6):e326-e332.
61. Lee HE, Lee SH, Baek M, Choi H, Park K. Urinary measurement of neu­
trophil gelatinase associated lipocalin and kidney injury molecule-1
helps diagnose acute pyelonephritis in a preclinical model. J Biomark­
ers. 2013;2013:413853.
62. Finnerty CC, Jeschke MG, Branski LK, et al. Hypertrophic scar­
ring: the greatest unmet challenge after burn injury. Lancet.
2016;388(10052):1427-1436.
63. Forsberg JA, Potter BK, Polfer EM, Safford SD, Elster EA. Do inflam­
matory markers portend heterotopic ossification and wound failure
in combat wounds? Clin Orthopaed Related Res. 2014;472(9):2845-
2854.
64. Hawksworth JS, Stojadinovic A, Gage FA, et al. Inflammatory
biomarkers in combat wound healing. Ann Surg. 2009;250(6):
1002-1007.
65. Simonetti O, Lucarini G, Cirioni O, et al. Delayed wound healing in aged
skin rat models after thermal injury is associated with an increased
MMP-9, K6 and CD44 expression. Burns. 2013;39(4):776-787.
66. Yin H, Li X, Hu S, et al. IL-33 accelerates cutaneous wound healing
involved in upregulation of alternatively activated macrophages. Mol
Immunol. 2013;56(4):347-353.
67. Murad A, Nath AK, Cha ST, et al. Leptin is an autocrine/paracrine
regulator of wound healing. FASEB J. 2003;17(13):1895-1897.
68. Sander AL, Henrich D, Muth CM, et al. In vivo effect of hyperbaric
oxygen on wound angiogenesis and epithelialization. Wound Repair
Regen. 2009;17(2):179-184.

236
Hematology, Hemostasis,
Thromboprophylaxis, and
Transfusion Medicine in
Burn Patients
DEREK CULNAN, KAREL D. CAPEK, CHARLES VOIGT, and
KUZHALI MUTHUMALAIAPPAN
22 
Subsequently, anemia is characterized as the anemia of
critical illness and develops from inadequate nutrition,6,7
stunted erythropoiesis,8 or phlebotomy and dressing
changes.8 Specifically, bone marrow dysfunction leading
to dampened erythropoiesis has been explored in autopsy
studies and in the mouse model of burn injury in vitro.8
In an autopsy study of patients who died from myocar­
dial infarction, sepsis, or burns, the bone marrow of burn
patients contained significantly fewer erythroblasts com­
pared to the other groups.9
Acute blood loss results in at least 2% blood volume loss
per percent body surface area excised; thus during major
burn excisions, there is significant blood loss often requiring
massive transfusions (MTs).10 MT is defined as the transfu­
sion of packed red blood cells (pRBCs) of 10 units or more
within 24 hours of admission.11 While acute surgical blood
loss is obvious and prominent during the treatment phase,
burn patients suffer a prolonged anemia of critical illness
during their recoveries, which is insidious. The anemia of
critical illness is the inability of RBC production to meet
RBC demand and losses during critical illness.12,13 More
than 50% of transfusions during a burn patient’s hospital
course may be caused by the anemia of critical illness.14
It has been equated to an acute form of the anemia of
chronic disease15–17 and anemia of inflammation in con­
junction with nutritional deficiencies.12 Acute blood loss
anemia is controlled with surgical technique, while the
anemia of critical illness can be restrained with reduced
phlebotomy, decreased blood loss with dressing changes,
improved nutrition, and resolving the critical illness by
covering the patient with skin, thereby abating his disease.
Prevention of anemia is accomplished through alteration
of its sources, acute blood loss, and the anemia of critical
illness, while the mainstay of treatment for both types of
anemia is the transfusion of pRBCs.
Hemostasis in Burn Patients
Controlling blood loss and hemorrhage during burn care is
important to prevent episodes of hemorrhagic shock and
limit total transfusion need. While Barbosa and Rowel dem­
onstrated that a 6-h RBC transfusion requirement is one of
the mortality predictors in MT trauma patients, it is unclear
Introduction
Severe burn injury causes a myriad of hematologic per­
turbations. Burn excision as well as substantial in-hospital
phlebotomy causes severe blood loss anemia and even
hemorrhagic shock, requiring substantial transfusion.
Large-scale fluid resuscitation and shock cause a signifi­
cant coagulopathy. Surgical extirpation can similarly cause
a significant dilutional coagulopathy requiring transfu­
sion. Hematopoiesis, the generation of new blood cells, is
directed away from red blood cell (RBC) production toward
myeloid blood cell production by the hyperinflammatory
cytokine cascade. The hyperinflammatory nature of burn
injury further makes the patient hypercoagulable, generally
requiring significant anticoagulation or thromboprophlyac­
tic therapy. Providing total burn care requires knowledge of
hematology, hemostasis, thromboprophylaxis, and transfu­
sion medicine to overcome the substantial pathophysiology
experienced by these patients.
Etiology of Anemia in
Burn Patients
Anemia is the condition occurring when the RBC concentra­
tion, or hemoglobin (Hb) concentration, falls below normal
laboratory limits for healthy adults. These normative values
do not correlate with sufficient oxygen delivery. Weiskopf
and Feiner classically demonstrated normal oxygen delivery
despite dramatic acute anemias while examining Hb con­
centrations as low as 5 g/dL in euvolemic subjects.1 Anemia
is common in burn patients, especially in those with severe
thermal injuries. Burn patients suffer from anemia due to
acute surgical blood loss and the anemia of critical illness.
This can occur in patients with as little as 10% total body
surface area (TBSA) burned.2 A mild reduction of RBCs
mass is of little clinical significance3; when the concen­
tration is significantly reduced, or total blood volume loss
is beyond 30%, it becomes clinically relevant, leading to
impaired end-organ perfusion and oxygenation.4 The initial
2 weeks post-burn feature anemia mainly resulting from
blood loss through the burn wound, dilution due to resus­
citation, and surgical blood loss from repeated débridement
to prepare the wound bed with well-vascularized tissue.5

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
237
needs and the expenses incurred by blood typing and cross-
matching,47 a preoperative estimate of 1.78 units of pRBCs
per 1000 cm2 of burn wound excised best utilizes blood bank
resources.48
Coagulopathy in Burn Patients
In addition to anemia, thermal injuries are associated with
systemic coagulopathy, and the hemostatic changes seen
in patients with severe burns appear similar to those in
patients with other major traumas. The severity of the burn
correlates with the extent of hemostatic changes49,50; typi­
cally only severely burned patients (≥30% TBSA) develop
extensive coagulopathy.51–53 However, no consensus cur­
rently exists on the definition of coagulopathy in burn
injuries.54 Despite being documented since the 1970s, the
physiology of coagulopathy in burns is still ill-defined.49
However, coagulopathy of thermal trauma does present
with characteristics common to sepsis-induced coagulopa­
thy: decreased levels of antithrombin and other native anti­
coagulants, elevated levels of activated factor VII, fibrinogen
degradation products, plasminogen activator inhibitor-1
(PAI-1), and thrombin-antithrombin complex (TAT).53 The
three types often discussed in burn- and trauma-related lit­
erature are trauma-induced coagulopathy (TIC), dissemi­
nated intravascular coagulation (DIC), and acute traumatic
coagulopathy (ATC).54 Acute coagulopathy of trauma shock
has largely been subsumed under TIC.55 Caused by trauma,
TIC is characterized by coagulation activation, hyperfibri­
nolysis, and consumption coagulation.56 The main patho­
physiology of TIC is DIC .55,57,58 Specifically DIC presents
as the fibrinolytic phenotype in the early, acute phase of
trauma and burn54,56,58,59, whereas the thrombolytic pheno­
type is associated with sepsis-induced DIC, which presents
later in the clinical course of burn pathophysiology.56 As
defined by the Scientific and Standardization Committee of
the International Society on Thrombosis and Hemostasis,
DIC is an acquired syndrome characterized by the intra­
vascular activation of coagulation with loss of localization
originating from and causing damage to the microvascula­
ture, potentially leading to multisystem organ dysfunction
(MOD).55,60 DIC is characterized not by the significant bleed­
ing, transfusion requirements, and fourfold higher mortal­
ity associated with TIC,54,61 but by excessive thrombosis,
unchecked inflammation and MOD, insufficient anticoag­
ulation mechanisms, and increased fibrinolysis.58 Indeed,
early coagulopathy is associated with increased incidence
of ventilator-associated events among burn patients.62 MTs
are administered more frequently in patients with DIC.63
ATC is associated with the depletion of fibrinogen, platelet
dysfunction, and activation of protein C.64 This particular
coagulopathy is not secondary to other conditions, such as
hypothermia, and markers for it can be discerned within 30
minutes of the inciting thermal event.65,66 In the pediatric
population, ATC is defined by an international normalized
ratio (INR) of 1.3 or greater, and those who present with
fibrinolytic shutdown are more likely to develop deep vein
thrombosis (DVT), especially because prophylactic antico­
agulant administration is not recommended in the pediatric
population due to their lower rates of venous thromboem­
bolism (VTE).67 Coagulopathy seen in burns is mediated by
if these findings extend to controlled blood loss during a
burn extirpation.18 In these cases, a skilled anesthesiolo­
gist can match the transfusion rate and blood product mix
to the bleeding rate, thus preventing hemorrhagic shock,
maintaining euvolemia, and avoiding coagulopathy while
the surgeon removes burned and diseased tissue and
engrafts the patient.
As with burn-susceptible infections, preventing burn-
derived anemia from developing is more optimal than treat­
ing the anemia or subsequent sequela. Several methods have
been established to mitigate acute surgical blood loss, includ­
ing epinephrine tumescence, thrombin-soaked dressings, and
tourniquet use.19 Additionally, excision with electrocautery
at a fascial or subcutaneous level can limit blood loss signifi­
cantly in large, full-thickness burns.20 Regardless of excision
methodology employed, many studies found the injection of
dilute epinephrine into the subdermal space promoted vaso­
constriction and reduced blood loss during surgical man­
agement of the wound.21–24 In a pediatric trial, epinephrine
tumescence alone decreased blood loss from 3.5% to 5% to
0.98% of total blood volume per percent of body excised
and grafted.24 Importantly sufficient time must be allotted
for the epinephrine to take effect, with an ideal interval of 25
minutes.25 Epinephrine tumescence has no significant hemo­
dynamic consequences, nor does it alter wound healing.26–30
A recent study confirmed that subcutaneous epinephrine
injection had no adverse effect on perfusion, pain, or scar
quality versus the saline-administered control group.26 Of
interest lately has been tumescent infiltration of lidocaine
and epinephrine by clysis. Gumus showed that this technique
resulted in more facile excision with diminished blood loss.31
Similarly, clysis has been demonstrated to reduce the need
for blood transfusions.32 The use of thrombin-soaked pads
for additional hemostasis support postoperatively has been
studied in the context of epinephrine tumescence and pro­
vides supplementary hemostasis by reducing unnecessary
ooze from the dressing site.19,33–35 New silicone gel dress­
ings also significantly reduced the amount of blood loss per
percent excised and the amount of blood transfused.36,37 We
employ nonadherent dressings (Telfa) soaked with epineph­
rine intraoperatively. This facilitates hemostasis and does not
restart the bleeding upon removal of the pads, as often occurs
with epinephrine-soaked laparotomy pads that avulse the
clots they helped induce on the wound surface when they are
removed. Finally the use of an extremity tourniquet during
excision and débridement can decrease acute surgical blood
loss without compromising graft adherence.19,38–41 Kragh
et al. found tourniquet use efficacious in both adults42 and
children.43 In combination, all three techniques (epineph­
rine tumescence, thrombin-soaked dressings, and tourniquet
use) can reduce intraoperative transfusion from 3.3 to 0.1
units per operative case with 96% graft take and total units
transfused from 15.7 to 7.9 units per patient.34 However
recent analysis indicates that utilizing the epinephrine-
tumescent technique obviates the need for tourniquets.44
Of note, administration of topical bovine thrombin must be
avoided in burn patients with prior exposure because they
have been shown to develop coagulation derangements and
severe bleeding complications from an acquired factor V defi­
ciency.45 Mullins et al. reported safe and effective hemostasis
through recombinant human thrombin applied as a spray.46
Due to rampant overestimations of operative transfusion

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
238
may mask bleeding, and repeated measurements are
necessary to use Hb levels diagnostically as a marker for
bleeding. Notably, low initial Hb is considered an indica­
tor for hemorrhage-associated coagulopathy.68 However,
assessing specific coagulation markers has proved both
time-consuming and expensive, and typical laboratory
tests, such as PTT, are limited in diagnostic value.52,53,88
The markers of the various coagulopathies seen in burns
present similarly to the coagulopathy seen in patients with
sepsis and severe trauma.53,89,90 Among the coagulopathic
changes are increased levels markers of thrombin activa­
tion, activated factor VII (FVIIa), thrombin-antithrombin
complex (TAT) and inhibited fibrinolysis with increased
levels of PAI-1, as well as decreased levels in proteins C and
S, fibrinogen, and antithrombin.53,90–93 In the first day post-
burn, patients with severe burns show marked decreases in
fibrinolysis51,53,72 as well as platelet activity.94 Lavrentieva
et al. demonstrated that, in the early post-burn phase (day
3 to day 7 post-burn), survivors could be distinguished from
nonsurvivors by the levels of natural coagulation inhibi­
tors (i.e., proteins C and S and antithrombin), fibrinolytic
factors (i.e., PAI-1 and tissue-plasminogen activator), and
TAT, a marker of thrombin generation, but not at admission
when both groups presented with statistically similar levels
in all parameters.72 While van Haren et al. also found that
severely burned patients become hypercoagulable follow­
ing admission despite pharmacologic thromboprophylaxis,
they determined that thromboelastography (TEG) was a
more reliable indicator of coagulopathy than were coagu­
lation markers.89 Interpretation of TEG data is reviewed in
Fig. 22.1. Furthermore, TEG provides diagnostic answers
in a much shorter time than standard laboratory testing,
resulting in faster goal-directed therapies.91,95 The major­
ity of burn centers worldwide used standard coagulation
tests,96 but the move to using TEG is warranted. With the
advent a portable fibrinogen analyzer, fibrinogen levels can
be measured in mere minutes.97 Low levels of fibrinogen
have been shown to be predictors for MTs98; Hayakawa
et al. demonstrated that fibrinogen reached critical diag­
nostic levels (150 mg/dL) sooner than other coagulation
parameters,63 making it a key factor in determining blood
product needs as well as being a coagulation indicator. More
recently, other studies showed higher levels of fibrinogen
(211 mg/dL and 190 mg/dL) functioned as useful predic­
tors of MT.98,99
Not only is there limited consensus on the diagnosis of
the type of coagulation associated with burns, there is no
agreement on the therapies used to respond to the condi­
tion when it presents.96 It is accepted that the activation of
fibrinolysis is inadequate to offset the excessive fibrinogen
formation in the early post-burn phase in patients severely
burned.72 Hemostasis depends on fibrinogen for clot forma­
tion and platelet aggregation, and the depletion of fibrino­
gen correlates with poor outcomes.100 While fibrinogen is
the coagulation protein with the highest plasma concen­
tration, plasma transfusions do not correct the fibrinogen
depletion seen in TIC and ATC unless massive volumes are
infused.101 Current European Trauma Guidelines suggest
the administration of fibrinogen concentrate or cryopre­
cipitate if a trauma patient presents with both significant
bleeding and thromboelastometric signs of functional
fibrinogen deficit or a fibrinogen concentration (FIB) of
preexisting conditions (e.g., age and comorbidities) as well
as environmental (e.g., ambient temperature) and thera­
peutic factors (e.g., pre-hospital fluid administration).68
As demonstrated in multiple studies, the timing and
onset of coagulopathy correspond with the severity of the
burn,49,52,69,70, and TIC may present without initial hyperco­
agulopathy.71 Few burn patients present with coagulopathy
at admission, but a large number develop it within a day
post-burn.49 In fact, at admission, no statistically significant
differences were observed between nonsurvivors and survi­
vors in coagulation and fibrinolysis markers.72 The inciting
causes of coagulopathy in burned patients include tissue
hypoperfusion from fluid resuscitation, systemic inflamma­
tory response syndrome (SIRS), blood loss from surgical
excision, hypothermia, endothelial damage, consumption
and/or dilution of coagulation factors, and acidemia.53
Tejiram et al. effectively reviewed the myriad of changes
seen in the clotting dynamics of burn patients and related
more subtle factor changes as possible markers of mortal­
ity than partial thrombin time (PTT) and INR, which were
normal in their cohort.73 Classically, hypothermia, acido­
sis, and coagulopathy are collectively known as the lethal
triad,71,74,75 corresponding to MTs and mortality in burn
and trauma patients.
Prevention of hypothermia in the operative theater is
completely within the purview of the operative team and
the operating room in the same way that the temperature
of a steak is completely within the purview of the chef and
the oven. As a manifestation of the First Law of Thermo­
dynamics, a patient cannot cool beyond the temperature
of the operating room. The clinical practice guideline in
many burn centers is to maintain the ambient temperature
of the ICU and operating rooms at 86–104°F (30–40°C)
as a component of standard of care in the treatment of
burn patients.76,77 Maintaining sufficient heat in the oper­
ating room to prevent hypothermia is essential. In patients
undergoing surgery, inadvertent perioperative hypothermia
resulted from 50% to 90% of the cases.78 Singer et al. deter­
mined hypothermia to be associated with high mortality,
although it was much more commonly found in patients
with large burns.76,77 In fact, it has been shown that
hypothermia, the condition where the core temperature
falls below 36°C (96.8°F),79 is not associated with exter­
nal factors at the time of the burn, but correlates to burn
severity and patient physiological status.80 Burn patients
are most vulnerable during excisional surgery due to opera­
tive heat loss81 concurrent with evaporative water loss82 or
massive fluid therapy.53,77,83
Acidosis is an ever-present threat for the recovering burn
patient. Lactic acidosis from shock states occurs transiently
during recovery and surgery and exacerbates bleeding, as
does hypercarbia. Uremia causes an anion gap acidosis and
reduces platelet aggregation, which can be reversed with
desmopressin.84 Hyperchloremia of normal saline admin­
istration is an effect of hemodilution or a decrease in renal
excretion of H+.85 While administration of natural saline is
associated with hyperchloremia-induced metabolic acido­
sis,86 Ringer’s lactate, the other crystalloid solution typi­
cally used, correlates with metabolic alkalosis.87
Diagnosis of coagulopathy depends on detection. The
INR measured upon admission is the basis for the diagno­
sis of acute traumatic coagulopathy.49,64 Initial Hb levels

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
239
randomized controlled trial, Roberts et al. demonstrated
a reduction of blood loss and mortality with TXA use in
trauma patients.102 Not only does TXA safely and signifi­
cantly reduce the mortality rates of trauma patients with,
or at risk of, substantial bleeding when administered early
in the course of treatment,103 but its de minimis side-effect
profile in conjunction with its low cost and ease of use have
less than 1.5–2 g/L.68 Topical hemostatic agents such as
thrombin spray rely on plasma FIB to effect hemostasis in
operative wounds.
Limiting fibrinolysis is another important method to
control blood loss during burn excisions. Tranexamic acid
(TXA), a synthetic derivative of lysine, has found great
utility in treating burn patients. In the landmark CRASH2
TEG instrument
Normal Hemostasis
Normal Hemostasis
Hemorraghic
Fibrinolytic
Thrombotic
TEG tracing
Torsion wire
Coagulation
Fibrinolysis
MA
K
R

EPL
Pin
0.36 ml whole
blood (clotted)
Low clotting
factor function
Enzymatic
hypercoagulability
Platelet
hypercoagulability
Platelet
hypercoagulability
Low clotting factors,
low platelet function
Primary fibrinolysis
Secondary fibrinolysis
Low fibrinogen
level
Low platelet
function
A
B
C
D
E
4°45
Heating
element,
sensor and
controller
Cup
Fig. 22.1  Panel 1 depicts the thromboelastography (TEG) device, in which a cuvette of whole sample blood is incubated with a pin and torsion wire
rotates within the sample. The tracing depicted in Panel 2 reflects the force required to spin the pin over time as the fibrin strands form a clot which
resists pin movement. R (reaction time) in minutes reflects the latency time to initial fibrin formation. Elevations are typically treated with frozen fresh
plasma (FFP) or reversal of anticoagulants, which delay initiation of clot formation. K (kinetics) is the time taken to achieve a clot strength of 20 mm.
α is the angle between R and K and measures the speed of fibrin build up and cross-linking, which reflects the availability of fibrinogen; defects are
typically treated with cryoprecipitate. TMA (time to maximum amplitude) is another measure of speed to fibrin build up. MA (maximum amplitude)
represents the ultimate strength of the fibrin clot and overall stability and is a measure of platelet action and stabilization of the clot. Deficits in MA
are typically treated with platelets or ddAVP to augment platelet aggregation. FPL, A30, or LY30 reflects the amplitude of the clot strength at 30 minutes
as a measurement of fibrinolysis. Fibrinolytic patterns are treated with TXA typically. (A) Normal TEG tracing. (B) Low clotting factor availability causing
a decreased α-angle. (C) various pathological hemorrhagic TEG tracings. (D) Fibrinolytic TEG tracings. (E) Various thrombotic TEG tracings. (From Mauf­
frey C, Cuellar DO, 3rd, Pieracci F, et al. Strategies for the management of haemorrhage following pelvic fractures and associated trauma-induced coagulopa­
thy. Bone Joint J. 2014;96–B(9):1143–1154.299)

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
240
accepted and employed constants are adult men 75 cc/kg,
adult women 65 cc/kg, infants 80 cc/kg, term infants
85 cc/kg, and premature neonates 95 cc/kg. Gross initially
described the mathematics of the formula in 1983114; we
have derived an equation estimating allowable operative
blood loss with which we estimate blood loss for all our
operations.115 Fig. 22.2 reflects the formula we utilize, and,
although patient conditions, such as venous capacitance
and changes in vascular tone, can significantly alter blood
volume of distribution, this formula has proved the best
estimator of blood loss in our experience.
Due to blood type and cross-match expenses and overes­
timation of operative transfusion needs47 a preoperative
estimate of 1.78 units of pRBCs per 1000 cm2 of burn
wound excised best utilizes blood bank resources.48 However,
even since publication of the prior edition of this book,
studies show 25% of patients received cross-match orders
exceeding national guidelines, with surgeons being most
responsible for this overestimation.116 Interestingly, change
in hematocrit, not Hb, is considered the most reliable indica­
tor for continuing blood loss,117 and, at admission, is the
best predictor of 24-hour blood product requirements,118 as
well as being associated with signs of shock and hemor­
rhage in trauma patients, both adult119 and pediatric.120
Additionally multiple studies have found massive blood
transfusion in trauma, surgery, and critical care to be a
predictor of SIRS, multiple organ failure, and increased
infection and mortality,74 although it is unclear if the need
for significant transfusion is a marker for disease severity
rather than the transfusion itself being the etiologic cause.
In the setting of active operative hemorrhage, transfu­
sion rates should match the rate of blood loss. Estimation
of ongoing rates of bleeding and matching transfusion rates
requires careful coordination between the anesthesia and
operative teams. MT protocols have been demonstrably life-
saving in these cases.121 In the setting of operative hemor­
rhage, the standard transfusion ratio is 1 pRBC to 1 flash
frozen plasma (FFP).121 Electrolytes must be monitored to
prevent hypocalcemia instigated by the citrate anticoagu­
lant in the blood products. As was demonstrated in the
PROPPR study, major trauma centers were unable to deliver
adequate amounts of thawed plasma for MT sufficiently
quickly, so a burn team anticipating significant blood loss
intraoperatively is well advised to order appropriate amounts
of blood products prior to initiating the surgery.122 With
modern rapid infusers, such as the Belmont, capable of
transfusing warmed, mixed blood products at rates of
500 cc/min, there is little reason for insufficient transfusion
rates during a burn extirpation.
made it an integral component of resuscitation protocols
worldwide.104 However, the benefits of TXA are seen only
when administered within 3 hours of injury; after that
window, it has been shown to increase mortality.65,105 Thus
it is most efficacious to treat acute traumatic coagulopa­
thy. Fibrinolysis is less likely to be fully activated the sooner
patients receive TXA; fibrinolysis continues unceasingly
once activated, and only restoration of endogenous anti­
fibrinolytic elements can then abate the activity.106 Some
practitioners feel that the potential risk is too great for use in
patients whose bleeding is not life threatening.107 Although
reports exist highlighting the prothrombotic effects result­
ing from each antifibrinolytic drug,65 we advocate the use
of TXA perioperatively for large burn excisions.
Transfusion of Blood Cells
Burn patients have many disparate indications for transfu­
sion. In the setting of active operative hemorrhage, the
rapid transfusion of pRBC, plasma, and other products is
essential to prevent hemorrhagic shock. In the postopera­
tive period, transfusion is necessary to treat blood loss
anemia, coagulopathies, and consumptive thrombocytope­
nias. As a component of resuscitation, plasma transfusion
is often required to treat coagulopathies resulting from con­
sumption and under-production of factors, as well as for
volume expansion, as discussed in Chapter 8 on the patho­
physiology of burn shock and burn edema and in Chapter
9 on fluid resuscitation and early management. Under­
standing the vastly disparate indications for transfusion in
burn patients allows clarity in the urgency and aggressive­
ness of transfusion used in these patients with ever-
changing status.
The first major indication for transfusion is intraoperative
blood loss during burn wound excision. The anesthesia
team must monitor overall preload while estimating blood
loss to prevent hypovolemia and hemorrhagic shock. Surgi­
cal control of hemorrhage is critical, but large blood loss is
expected, especially in the setting of large burns. Surgical
blood loss has been estimated and measured in a variety of
ways,33,108–112 but reports based on surgical and anesthesia
team estimates113 are simple and reliable. Following serial
hematocrit value along with hemodynamic markers is a
standard method of monitoring blood loss and transfusion
success. Various formulae have been developed to calculate
the estimated blood loss. Total blood volume is estimated
using the patient’s weight, preoperative and postoperative
Hb, and presumed normal adult Hb of 70 cc/kg. Generally
Fraction of
blood loss
A = Expected blood volume
B =
Patient weight  Expected blood volume/kg
Blood transfusion
volume


(HCTpre-op – HCTpost-op)
HCTpre-op
Fig. 22.2  An algebraic formula to estimate surgical blood loss. In the first group of terms, labeled A, the patient’s weight is multiplied by the expected
blood volume for age: adult men 75 cc/kg, adult women 65 cc/kg, infants 80 cc/kg, term infants 85 cc/kg, and premature neonates 95 cc/kg. The
second portion of the equation utilizes preoperative and postoperative hemocrit (Hct) to derive the fraction of blood lost to account for the observed
change in Hct. Finally, blood transfused is added in to account for intraoperative transfusion effects.

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
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and using pathogen-inactivated plasma reduces the risk
of transmitting infectious diseases.68 The indicators for
increased transfusions of FFP and pRBC were high TBSA
and use of argatroban anticoagulation.142
Except in the setting where MTs are indicated, greater
ratios of FFP and platelets to pRBCs correlate to longer ICU
stays and higher mortality rates.143 When high ratios of
FFP to pRBC are unable to be transfused, it has been dem­
onstrated that resuscitating patients with a minimum of
1 L crystalloid per unit pRBC leads to improved mortality
rates.144 However, a recent study showed that TBSA burn
and patient age independently correlated to mortality, not
RBC or plasma transfusions.142 Blood product resuscitation
was not hemostatic, and coagulopathy and thrombocytope­
nia combined may contribute to intraoperative hemorrhage,
which blood product transfusions would be inadequate to
correct.145 Brakenridge and coworkers showed that, despite
prior reports of associations between FFP and large-volume
crystalloid transfusions with MOD, it was the MT volumes of
pRBC that correspond to MOD, not blood products.146 Blood
component ratios failed to predict inflammatory complica­
tions, whereas injury severity, sex, and total pRBC volume
did.147 Additionally transfusion of stored pRBC correlates
with increased complications due to microparticles released
from RBCs able to induce cellular dysfunction.148 The poor
quality of stored erythrocytes has been documented with
dynamic microscopy.149 Furthermore, recent data would
suggest different protocols for transfusion in the operat­
ing room (acute blood loss) versus in the setting of critical
illness (bedside).150 A series of studies examining different
ratios of FFP to pRBC transfusions have yet to demonstrate
any difference in transfusion volume for burned pediatric
patients.10,151 Last, it has been demonstrated that transfu­
sion protocols for adults are not efficacious in children;152
a new score should be developed for transfusions in the
burned pediatric population.
Recently, platelet-rich plasma (PRP), in which the platelet
concentration is above baseline in blood plasma, has come
under consideration for use in transfusing burn patients
because its hemostatic antimicrobial effects have shown
promise in wound healing in animal studies.153 The con­
centration of growth factors and number of platelets dictate
the clinical efficacy of PRP.154 It is not transfusions of pRBCs
but rather of platelets that have recently been correlated to
nosocomial infections in the critically ill.155 Platelet trans­
fusion is not without complications because platelets are
stored at room temperature, thereby facilitating higher rates
of bacterial contamination than for other blood products.
One in 1000–3000 platelet units may be bacterially con­
taminated;156 one-sixth of these episodes result in a septic
event.157 In a study of blood bank utilization by a burn
unit, 15% of all admitted patients received platelets with
either pRBCs or FFP.47,156 Given that cryopreserved plate­
lets demonstrate superior hemostatic activity over liquid
platelets, studying the efficacy of storing platelets at cold
temperatures for burn units is warranted.158,159 Last, imme­
diate administration of pRBCs, plasma, and platelets upon
admission has been shown to benefit patient outcome.121
Commonly coincident with sepsis,160 thrombocytope­
nia requiring platelet transfusion is rare in burn patients.
Often platelet counts and function are stable unless there
is an infectious or septic event. In coagulopathic patients
In the ICU, blood transfusions are typically unneces­
sary to treat or prevent hemorrhagic shock; rather, they
are warranted for less emergent indications, such as blood
loss anemia, coagulopathy, or volume expansion. Tradition­
ally a defined Hb trigger of 10g/dL or hematocrit of 30%,
the “10-and-30” rule, has guided transfusion practices.123
These triggers continue in many centers worldwide.123
However large-scale works in critical care literature124 and
smaller, retrospective reviews of adult125 and pediatric126
burn patients have established the benefits of a lower, more
restrictive transfusion trigger, indicating that some patients
had been receiving blood to no benefit.123 The Society of
Critical Care Medicine addressed transfusions in the inten­
sive care setting. For critically ill patients, a restrictive strat­
egy was found as efficacious as the conventional liberal one,
so in patients with evidence of hemorrhagic shock, hemo­
dynamic instability, or acutely bleeding, an Hb trigger of
less than 7 g/dL indicates for transfusion, and this should be
given as single units in the absence of acute bleeding.127,128
Recent research supports the theory that pRBC transfusions
should not rely on the use of standardized triggers, but
rather be tailored to the burn patient’s blood volume status,
acuity of blood loss, and perfusion requirements.2
Transfusion needs increase with burn size,5,47,129,130 as
do complications. Each 1% increase in TBSA of burn has a
corresponding 6% increase in mortality risk.131 In a large
study of transfusion trends in burn patients, those with
20% or greater TBSA required 13.7 ± 1.1 units, whereas
those with 50% or greater TBSA required more than 30
units of pRBCs.129 Burn patients often receive multiple
transfusions; in one study, more than half the transfu­
sions resulted from anemia of critical illness (nonsurgi­
cal).5 While pRBC transfusion rapidly and reliably corrects
anemia, it is associated with many of the consequences of
bloodborne transmission, including hepatitis B, hepatitis C,
and HIV. While the infectious transmission rate has signifi­
cantly decreased with improved screening methods,132,133
it is markedly higher in low- and middle-income countries
than in high-income countries like the United States (0.1%
and 0.003%, respectively).134 More importantly, pRBC
transfusion is associated with immunomodulation, includ­
ing increased infectious morbidity,135 with a 13% increase
in risk of developing an infection per unit of blood trans­
fused.129 Muszynski et al. nicely reviewed the extensive
hyperinflammatory and severe immunosuppressive effects
of blood transfusions and related these data to critical care
outcomes.136
Other significant consequences include transfusion-
related acute lung injury (TRALI), which is difficult to diag­
nose in burn patients because simultaneous lung injury
from resuscitation or inhalation injury may contribute
to TRALI diagnostic criteria,137 and ABO incompatibility,
which can be rapidly fatal.138 Implementation of restrictive-
transfusion strategies in which pRBCs are transfused only
for hemodynamic instability or at lower Hb concentrations
has reduced overall transfusion and infection rates, benefit­
ting both cost and survival.68,125,126 FFP transfusion is also
associated with TRALI139 in burn patients, and early trans­
fusion of FFP correlates with increased incidence of other
deleterious effects post-burn.140 However by not adminis­
tering plasma from women with a history of pregnancy,
the risk of TRALI from FFP is significantly mitigated,141

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
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Pharmacologic anticoagulants fall under four major
classes: antithrombin-III (AT-III) activators, such as UFH;
factor X inhibitors, such as LMWHs; direct thrombin inhibi­
tors (DTIs), such as argatroban; and vitamin K antagonists,
such as warfarin. The ideal phamacoprophylactic agent for
a burn patient has a short half-life allowing dose titration
and operative interventions, the ability to monitor result­
ing effects with laboratory values, an available reversal
agent, and limited nursing workload. Warfarin is not used
for prophylaxis in hospitalized burn patients due to its long
half-life, which requires days to take effect and reestablish
normal coagulation, all of which complicates operative
management.175 DTIs carry a high risk of bleeding and are
irreversible so typically are employed only in the rare setting
of antibody-confirmed heparin-induced thrombocytopenia
(HIT) when treating burn patients.176 Most VTE prophylaxis
and treatment in burn patients are carried out using UFH
or LMWH.
UFH exerts the principal part of its action by binding to
and activating AT-III, the most abundant anticoagulant in
the plasma. AT-III, in turn, breaks down activated throm­
bin, thereby terminating the propagation of coagulation.
A minor portion of AT-III’s action is attributable to inac­
tivating factor X, the central factor joining the intrinsic
and extrinsic coagulation cascades. Anticoagulant activ­
ity can be monitored, with a PTT targeting time of 30–41
seconds for prophylaxis and 60–80 seconds for therapeutic
anticoagulation.53 UFH can be administered either subcu­
taneously or via a continuous intravenous infusion. Subcu­
taneous dosing of 5000 units every 8 hours is considered an
effective prophylactic dose; however in burn patients with
unpredictable subcutaneous absorption and variable cre­
atinine clearances due to hypermetabolism, this route is far
less predictable. In our critical care population, we prefer a
low-dose UFH infusion targeting a PTT of 30–41 seconds.
With this protocol, we are able to provide a verifiable pro­
phylactic effect regardless of the physiological state of the
patient, although this comes at the cost of greater nursing
utilization. UFH also has the benefit of a short half-life, and,
in the setting of hemorrhage, it is reversible with protamine.
There is a risk of development of HIT with this medication,
and platelet levels must be monitored. Should thrombocy­
topenia develop in a burn patient, all heparin administra­
tion should be held until antibody titers can be returned.
Because there are a myriad of causes of thrombocytopenia
in burn patients, conversion to a secondary agent, such as a
DTI, ought to be considered carefully on a case-by-case basis
given the increased risk of bleeding associated with these
medications and their lack of reversal agents.177
LMWH exerts its principal effect by inactivating factor
X. Anticoagulant activity can be monitored with an anti-
factor Xa level target of 0.2–0.5 IU/mL for prophylaxis and
0.5–1.2 IU/mL for therapeutic anticoagulation. In a review
of practice at a large academic medical center, levels were
determined to be insufficiently monitored and frequently
outside the intended range in patients weighing less than
45 kg, more than 150 kg, or with impaired renal func­
tion.178 These medications are delivered by subcutaneous
injection and, as such, carry pharmacodynamic concerns
regarding inconsistent absorption. There are also oral
factor Xa inhibitors; however, there is not currently suf­
ficient data nor experience to advocate their prophylactic
with hemodynamically significant oozing from wound and
donor sites, the administration of platelets and recombinant
factor VIIa has been shown to improve hemostasis.161,162 Of
interest, recombinant factor VIIa seems most efficacious at
lower temperatures.163 Prothrombin complex concentrate
(PCC) is gaining utility in treating coagulopathies derived
from medications such as warfarin or argatroban and now
has an expanding role in treating trauma and perioperative
coagulopathies.164 PCC is also gaining use as an adjunct or
replacement for FFP to reverse factor-deficient coagulopa­
thies and expedite operative intervention.165,166
Venothromboembolic
Prophylaxis
Once burn patients recover from TIC they develop an ele­
vated risk of venous thrombosis and thromboembolism. A
recent study indicated that platelet-derived microparticles
(PMPs) are responsible for the hypercoagulability seen
immediately post-burn, particularly the decline in platelets,
and that an ADP-induced platelet activation was crucial to
the enhanced clotting seen a week post-burn.94 Addition­
ally, Levin et al. showed that thermal trauma incites an
increase in the number of erythrocyte-derived microvesi­
cles. These, in turn, increase the procoagulant activity
while reducing the antithrombin and fibrinolytic activity of
erythrocytes, thereby contributing to post-burn hyperco­
agulability.167 Furthermore, the typically defined criteria for
hypercoagulability described in Virchow’s triad exist in all
major burn patients: venous stasis from reduced activity
such as bed-rest, endothelial activation or injury from shock
state and inflammation, and hypercoagulability from acute-
phase reactants.168,169 Meizoso recently characterized the
detailed pathophysiology of hypercoagulability in burn
patients, concluding that larger-scale studies are needed to
protocolize safe and effective thromboprophylaxis.170 A
typical burn ICU patient will be high or highest risk based
on the American College of Chest Physician guidelines and
Caprini score, indicating both mechanical and chemical
prophylaxis.168 In a 2005 survey of 84 U.S. burn centers,
76.1% routinely provided VTE prophylaxis, 31 utilizing
subcutaneous unfractionated heparin (UFH), 16 low-
molecular-weight heparin (LMWH), and 1 a heparin infu­
sion.171 In a 2013 review of their institution’s patients in a
single year, Mullins et al. reported an incidence of 113
DVTs in 86 patients for an incidence of 5.92%.172
The modalities that underlie VTE prophylaxis are
mechanical and pharmacological prophylaxis. Mechanical
treatments, such as intermittent pneumatic compression,
aim to prevent venous pooling and mechanically pump
blood from the extremities. These devices also stimulate
fibrinolytic pathways, which further decreases the risk of
venous thrombosis.173,174 Chemical prophylaxis, such as
heparin, is intended to reduce thrombosis by interfering
with the coagulation cascade. Prophylaxis is often compli­
cated in the burn population. For instance, mechanical pro­
phylaxis is often impractical or impossible due to donor sites
or wounds on the legs. Pharmacoprophylaxis agents can
have inconsistent effects due to altered pharmacokinetics
and pharmacodynamics leading to either venous thrombo­
sis or hemorrhage.

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
243
of HSCs, long-term (LT) and short-term (ST), are distin­
guishable by more than their divergent self-renewal and dif­
ferentiation capacities.193–195 Aptly named, LT-HSCs remain
permanently self-renewing cells with minimal response to
physiologic stress and exhibit a total dearth of lineage-
specific surface markers.182 ST-HSCs derive from LT-HSCs
and affect their production and differentiation depending
on the existing pathologic state in their niches. ST-HSCs
give rise to multipotent progenitor cells (MPPs),196 which
lack self-renewal potential but remain able to differentiate
use in the acute burn patient for VTE prophylaxis. The half-
lives of these agents are longer than UFH, and they only
require dosing every 12–24 hours, which reduces nursing
workload but increases the duration of bleeding, should it
occur. In particular, Fondaparinux has a 17- to 21-hour
half-life and thus is particularly prone to cause bleeding in
our experience with burn patients; the use of fondaparinux
is ill-advised. When these medications are chosen for burn
patients, factor Xa levels should be monitored due to
unpredictable subcutaneous absorption and large changes
in creatinine clearance from hypermetabolism or renal
impairment, although these pharmacologic issues are most
often studied related to antibiotic dosing.179 There are cur­
rently no reversal agents for this class, although scant data
suggest that PCC may limit bleeding.180
There are circumstances in which VTE prophylaxis may
need to be held in a major burn patient, such as bleeding.
In these instances, an inferior vena cava (IVC) filter should
be considered to reduce the risk of fatal pulmonary embo­
lism. Furthermore, several centers routinely monitor
patients for DVT formation with a weekly Doppler exam.
Hematopoiesis
Given the myriad of risks incurred to glean the benefits of
transfusion, it is preferable for patients to generate their
own replacement blood. Hematopoiesis is the production
of the more than 10 distinct mature peripheral blood cell
types.181 Well-regulated hematopoietic differentiation is
vital to generate all blood cells necessary for defense against
invasive pathogens, gas exchange, and wound healing.182
This process begins in the yolk sac, continues in the pla­
centa and the aorta-gonad-mesonephros region, progresses
to the fetal liver until finally occurring throughout postna­
tal life in the bone marrow.183,184 Table 22.1 details the roles
of growth factors and cytokines in directing hematopoi­
esis. Unfortunately, production is often insufficient to meet
a burn patient’s RBC requirements in the setting of large
excisions and grafting procedures combined with critical
care. This stems from the large volume of blood loss seen
in burn surgeries as well as the fact that thermal trauma
directs hematopoiesis away from erythropoiesis and toward
immune cell production.
Two pathways exist for hematopoiesis: myeloid and lym­
phoid. The myeloid lineage ultimately produces RBCs and
the cells comprising the innate immune system (e.g., plate­
lets,185 macrophages, neutrophils, eosinophils, and baso­
phils). The lymphoid lineage forms the cornerstone of the
adaptive immune system by generating B and T cells. Den­
dritic cells (DCs) and natural killer (NK) cells develop from
either lineage. While only half the bone marrow is hemato­
poietically active,186 an estimated 200 billion erythrocytes
(0.5–2% of total RBCs),187,188 100 billion leukocytes, and
100 billion platelets (~7% of total platelets) are nonetheless
produced daily in a healthy adult.
Accounting for one in every 105 nucleated cells in the
bone marrow of a healthy adult, hematopoietic stem cells
(HSCs) are the fountainhead of the hematopoietic hierar­
chy. Significantly they are the only cells in this system able
to be both self-renewing and multipotent (able to differenti­
ate into all potential blood cells).181,189–192 The two variants
Table 22.1  The Roles of Growth Factors and Cytokines
in Hematopoiesis
Growth Factor
or Cytokine
Role in Hematopoiesis
Stem cell factor
Essential for hematopoietic stem cell
proliferation and differentiation
Activates the c-kit receptor
Flt-3 ligand
Enhances multipotent progenitor, early
lymphoid, myeloid, natural killer, and
dendritic cell proliferation
Activates the Flt-3/flk-2/CD135 receptor
IL-3
Plays a role in hematopoietic stem cell, myeloid,
and erythroid cell line expansion
IL-6
Increased production following burn injury and
infection
Essential for expansion of hematopoietic stem
and progenitor cells
G-CSF
Stimulates granulocyte proliferation in the bone
marrow and augments immune activity of
cells in blood
Increased immediately following burn injury
and in response to infection
RhG-CSF use is not indicated for use in burn
patients
CSF-1 or M-CSF
Essential for monocyte and macrophage
differentiation
Increases the survival of monocytes and
macrophages
GM-CSF
Regulates the proliferation and differentiation of
hematopoietic progenitors
Enhances antigen presentation by DCs and
macrophages
Prophylactic administration accelerates bacterial
clearance and killing
IL-7
Necessary for both engagement into lymphoid
lineage and maintenance and expansion of
lymphoid cells
Erythropoietin
Stimulates erythroid proliferation and prevents
apoptosis to increase erythrocyte production
May have a role in tissue protection via a related
receptor
rhEPO has not been shown to benefit burn
patients
Thrombopoietin
Enhances megakaryocyte proliferation and
reduces apoptosis to increase platelet
production
May increase following burn injury and
contribute to thrombocytosis
Evolving role in stem and progenitor cell
proliferation
G-CSF, Granulocyte colony-stimulating factor; GM-CSF, granulocyte-
monocyte colony-stimulating factor; IL, interleukin.

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
244
EPO response to anemia, there is limited increase in EPO
following burn. Earlier studies had small sample sizes, used
unreliable urine bioassays, and could not overwhelmingly
support an appropriate EPO response, leading to contra­
dictory results.217,218 Later comparison of serum bioassays
and radioimmunoassays showed no correlation between
the two methods, and their results suggested significant dif­
ferences between the sensitivity of these tests.219,220 More
recent larger studies using serum radioimmunoassays dem­
onstrated an increase in EPO in response to decreased Hb
concentrations but inconsistent erythropoietic response to
this EPO increase.130,221
While only erythroid-committed cells in the bone marrow
possess the EPO receptor, a related EPO receptor and
response to EPO have been identified in nonhematopoietic
tissues, including neurons, glial cells, retina, heart, skel­
etal muscle, kidney, ovary, uterus, testis, and endothelial
cells.222–225 Consequently the ability of EPO to reduce apop­
tosis and prevent damage to these tissues has been explored.
RhEPO in particular can reduce apoptosis after cerebral
ischemia226; protect the myocardium and promote remodel­
ing following myocardial ischemia, allowing for restoration
of cardiac function;227,228 and protect against renal injury
from ischemia, improving renal function.229 Despite these
findings and the expected erythropoietic response to rhEPO,
its use in burn patients has not been substantiated.
Recombinant human erythropoietin (rhEPO) helps
augment erythropoiesis in patients with chronic anemias
(e.g., end-stage renal disease and HIV with antiretroviral
use), decreasing transfusion rates and improving quality of
life. To decrease transfusion rates and correct the anemia
of critical illness, multiple trials have explored rhEPO use
in the critically ill, including burn patients. Unfortunately
both large clinical trials and meta-analyses of critically ill
medical, surgical, and trauma patients show no significant
reduction in transfusion rates with rhEPO use.230,231 JM Still
and others performed a study of rhEPO in burn patients
resulting in no significant increase in hematocrit percentage
or decrease in transfusion rates.232–234 Critically ill patients
may possess a resistance to EPO,235 which may be a function
of antierythropoietin antibodies236 or a relative reduction
in erythropoietic response due to less EPO-responsive ery­
throid precursors after burn-induced hematopoietic hierar­
chy shift.237 As such, rhEPO is not indicated for use in burn
patients. However a recent study showed that rhEPO sig­
nificantly reduced the markers of multisystem organ failure
and, in the lung, specifically reduced apoptosis and histo­
logical signs of tissue injury in mice with second-degree
scald burns.238 While the use of rhEPO has been shown to
increase the rate of reepithelialization in scald injury and
decrease time to close the wound when injected directly
into the injury site,239 we still cannot recommend the use of
rhEPO in burn patients to decrease transfusion rates. These
new data highlight the potential use for other burn-induced
complications beyond the purview of this chapter.
MYELOID GROWTH FACTORS
Granulocyte Colony-Stimulating Factor
Granulocyte colony-stimulating factor (G-CSF) is the
primary growth factor responsible for the proliferation and
into every hematopoietic lineage.183,197,198 The progression
of hematopoiesis, from stem cells to progenitor groups to
terminally differentiated cells (Fig. 22.3), allows for the
rapid amplification of cell production by the upstream pro­
liferation of stem cells.199 The hematopoietic hierarchy is
not without controversy; other suggested hematopoietic
progressions200,201 differ in the branch points at which
certain progenitor populations lose lineage potential202
or advocate that select cell groups have the potential to
dedifferentiate and enter a different lineage.203 MicroRNAs
(miRNAs), growth factors, and cytokines present in the
bone marrow influence the commitment patterns of these
progenitor cells, yielding mature, fully differentiated bone
marrow cells that later populate the bloodstream.
Up-regulation of fetal liver kinase-2 (Flk2) is a shared
feature of all lineages of HSC differentiation203 as is the
epigenetic regulation exerted by microRNAs on every stage
of hematopoiesis.204 The expression of a limited set of tran­
scription factors, controlled by growth factors, cytokines,
and miRNAs present in the bone marrow milieu, control
lineage commitment, cell fate,205–207 and, ultimately, the
composition of cells in the bloodstream. As patients age,
there is an HSC shift toward myeloid potential.208
Bone marrow hematopoiesis demonstrated an overall
increase in the HSC population (identified as LSKs [Lineage­
negative, Sca-1+ cKit+] in mice) as early as 48 hours following
burn injury,209 and the expansion of LSKs persisted for at
least 21 days post-burn.210 Despite their multilineage poten­
tial (Fig. 22.3), LSKs do not differentiate evenly across all lin­
eages. Only ST-HSCs and MPPs increase, with no significant
change in LT-HSCs.211 In the progenitor compartment, there
is a significant increase in granulocyte-monocyte progeni­
tors (GMPs) with a concomitant decrease in megakaryocyte-
erythroid progenitor (MEP) production. Given the hierarchical
nature of hematopoiesis, changes in ST-HSC and MPP pro­
duction, and the lineage shift toward greater GMP and lesser
MEP production may herald the overall problems present
after burn injury: erythropoietic production (anemia) and
myeloid function (immune dysfunction).209,210 In a recent
work, myelo-erythroid commitment following thermal insult
was shown to be under β-adrenergic control via MafB regula­
tion, indicating that burn injury perturbs the hematopoietic
paradigm.212 For more details please refer to Chapter 23 on
the significance of the hormonal, adrenal, and sympathetic
responses to burn injury. Further work on HSCs and progeni­
tor cell responses may provide avenues for early therapeutic
intervention, which may ameliorate the negative hematopoi­
etic consequences of burn injury.
HSCs have considerable potential in treating blood
disorders.213–215 The utilization of these cells as a possible
therapy for the anemia or immune dysfunction present in
severely burned patients is currently not in progress. Rea
and colleagues assayed the cells present in the healing
burn wound, finding that hematopoietic cells were merely
transient and predominantly present only in the acute
inflammatory phase, with a small number persisting in the
healing dermis.216 Ascertaining the long-term hematopoi­
etic response to various degrees of burn wounds will be
crucial in developing HSC-based therapies for burn injuries.
Due to burn-associated anemia, erythropoietin (EPO)
levels should be increased during treatment and recovery
from the burn injury. However, contrary to the expected

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
245
LT-HSC
ST-HSC
HSC
Compartment
MPP
CLP
CMP
MCP
Progenitors
GMP
MEP
Monocytes
Macrophages
Neutrophils
Megakaryocytes
Red Blood
cells
B-cells
T-cells
Differentiated
Cells
Dendritic
Cells
Mast
Cells
Fig. 22.3  A Hierarchical Model of Hematopoiesis The model here shows the three compartments of hematopoietic cells: stem cells, lineage-commited progenitors, and terminally differentiated cells.
The first step in lineage commitment occurs at the branch point from multipotent progenitors (MPPs) to myeloid (CMP, common myeloid progenitor) or lymphoid lineages (CLP, common lymphoid
progenitor) or MCP, mast cell progenitors). CLPs differentiate into T and B cells. The CMP population can branch in to GMPs (granulocyte-monocyte progenitors) or MEPs (megakaryocyte-erythroid
progenitors), which then lead to their respective terminally differentiated populations.

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
246
Similar hyporesponsiveness in monocytes has been dem­
onstrated in trauma patients.264 These findings provide a
plausible mechanism and a role for CSF-1 and its cognate
receptor interactions in monocyte/macrophage biology fol­
lowing burn injury.
GM-CSF
Granulocyte-monocyte colony-stimulating factor (GM-CSF)
regulates proliferation and differentiation of hematopoietic
progenitor cells, as well as modulating the function of
mature leukocytes.265 GM-CSF enhances the antigen-
presenting capacity of macrophages and DCs, increases
complement-mediated phagocytosis, and augments bacte­
rial killing by both innate immune cells266,267 and chemo­
taxis of leukocytes.268,269 GM-CSF is produced by a variety
of cells, including macrophages, B lymphocytes, pulmo­
nary epithelial cells, neutrophils, and stromal cells.270,271 In
response to burn injury, bone marrow GM progenitors
respond by producing more GM-CFU colonies .261 Adminis­
tration of GM-CSF prior to burn injury and E. coli sepsis
enhanced bacterial clearance and survival of experimental
animals.272 Similarly, GM-CSF improved the survival of neo­
natal rats when administered prophylactically prior to S.
aureus infection.273 However, GM-CSF administration after
the onset of infection did not provide a survival benefit.274
While the inactivation of GM-CSF or GM-CSF receptor
genes in mice did not alter the number of granulocytes and
monocytes, these animals exhibited significant alveolar
macrophage dysfunction. Furthermore GM-CSF-deficient
mice are very susceptible to pulmonary group B streptococ­
cal infection.271 Cioffi et al. studied the effects of GM-CSF in
burned adults. They found a 50% increase in mean leuko­
cyte counts after the first week post-burn in treated patients.
Application of GM-CSF did increase myeloperoxidase activ­
ity (cytosolic oxidative function) 1 week post-burn, but
these levels returned to unburned control levels during
weeks 2 and 3 of treatment, while remaining elevated in
the untreated patients. Extracellular oxidative function,
measured by superoxide production, was initially depressed
in both burned groups compared to nonburned controls,
although GM-CSF-treated patients demonstrated a return
to nonburned control levels after week 1, while these levels
remained below control levels in the untreated burn
patients.275 In a multicenter clinical trial, administration of
rhGM-CSF in hydrogel to deep second-degree burn wounds
has been shown to be both safe and to accelerate wound
healing.276,277 A subsequent study found topical application
of GM-CSF reduced healing time of partial-thickness burn
wounds by 5.1 days compared to standard treatment with
no significant increase in adverse effects. The same study
examined two other growth factors, fibroblast and epider­
mal, and found a decrease in healing time by 5.02 and 3.12
days, respectively, as well as improvement in scar color,
height, pliability, and vascularity.278 Further research exam­
ining the efficacy of topical administration of rhGM-CSF on
deep partial-thickness burn wounds similarly found accel­
erated wound healing with no difference in adverse reac­
tions.279 These data corroborated other studies that likewise
found accelerated wound healing with application of topical
rhGM-CSF and no difference in adverse reactions in adult280
and pediatric burn patients.281 Given the promising data,
differentiation of bone marrow granulocyte progenitors
into mature granulocytes.240,241 G-CSF is produced by
monocytes, fibroblasts, and endothelial cells stimulated to
produce G-CSF in response to inflammatory cytokines
(tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6],
IL-1).222 Although it stimulates the production of neutro­
phils in the bone marrow, in the periphery G-CSF augments
the bactericidal activity of neutrophils by priming the oxi­
dative burst, increases neutrophil half-life by preventing
apoptosis, and down-regulates the overall inflammatory
response by decreasing the cytokine production of mono­
cytes and macrophages.242 In various animal models of
burn and burn sepsis, the benefits of G-CSF were shown to
be the killing of translocated bacteria,243 regulating the pro­
inflammatory response to injury,244 enhancing neutrophil
chemotaxis,245 and improving survival in combination with
antibiotic therapy.246,247
At baseline, there are very low levels of G-CSF present in
the blood. However following an inflammatory or infectious
process, G-CSF levels dramatically increase. Following a
burn injury, G-CSF levels in the blood are initially increased
and then gradually decline to baseline 3–4 weeks following
injury.248–250 The initial increase in G-CSF may prime the
neutrophilic component of the immune response for future
bacterial insult. However, the immune dysfunction seen fol­
lowing burn injury or burn sepsis may be related to hypo­
responsiveness of bone marrow progenitors and peripheral
neutrophils to G-CSF.251 Recent studies suggest that the
increase in serum G-CSF post-burn corresponds to an
increase in the resistance to infection, activation of innate
immune responses, and prioritization of bone marrow
responses, indicating that it plays a central role for burn
patient survival, especially in the setting of infection.252
Administration of recombinant human G-CSF (rhG-CSF)
to burn septic animals prior to the initiation of septic insult
has been shown to improve the survival rate of burn septic
mice.245,246,253 However administration of G-CSF 24 hours
after the onset of septic insult had little effect on sur­
vival.254,255 Despite the potential benefit of exogenous G-CSF
administration on the inflammatory and infectious response
during burn injury, the use of rhG-CSF (Filgrastim)256 is not
indicated in the treatment of burn patients.
CSF-1
CSF-1 (M-CSF) is a preeminent growth factor for the dif­
ferentiation, proliferation, and survival of monocytes and
macrophages.257 It also stimulates chemotaxis, cytokine,
and superoxide production in macrophages.258,259 Hume
et al. first demonstrated that administration of CSF-1 to
mice resulted in monocytosis and an increase in peritoneal
and tissue macrophages.260 In response to burn injury, CSF-
1-responsive GM-CFU are increased in the bone marrow and
this results in enhanced monocytopoiesis.261 The under­
pinning of this monocytopoiesis post-burn arises from
increased expression of CSF-1 receptors in ERMP-20+ bone
marrow compartment, which comprises monoblasts and
promonocytes,261 which begins to be initiated much earlier
at progenitor level in GMPs209 and CMPs.210 Additionally
burn injury and sepsis also alter the inflammatory cytokine
phenotype of CFU-GM-derived macrophages in that they
predominately result in hyporesponsive macrophages.262,263

22  •  Hematology, Hemostasis, Thromboprophylaxis, and Transfusion Medicine in Burn Patients
247
transcription factors to specific regions on a gene.294 Tran­
scription factors are nuclear proteins that act as control
points in the conversion of a gene to a functional protein.294
Since many key proteins are turned over rapidly to meet
the changing needs of the tissues, a complex system of cell
signaling architecture, with the final common pathway of
gene transcription, must exist to produce bioactive proteins
on demand. Since cells respond to several signals simultane­
ously, and many ligand–cell interactions stimulate similar
proximal signals, tight control of transcriptional initiation
must exist for the proper orchestration of cellular responses.
The role of transcription factors in hematopoietic cell
fate is an evolving topic of study. The lineage-restricted
proliferation and differentiation program of hematopoiesis
is achieved through switching on and off specific sets of
genes in response to cell signals. Since thermal injury and
sepsis are accompanied by hematologic and hematopoi­
etic changes that determine the overall pathophysiological
response of burn patients, it is reasonable to assume that
transcriptional regulation of hematopoietic developmental
genes play a significant role. It is known that GATA-1, sct/
tal1, and Klf1 form the transcriptional core of the erythroid
lineage and are all expressed by the earliest hematopoietic
progenitors.295 The relationship between transcription
factors is complex because they are not independent of one
another but demonstrate antagonism. In fact, the inability
of one transcription factor to suppress the other has been
linked to the development of hematologic malignancies.
However little is known about hematopoietic transcription
factor changes following pathologic injury, even though
they may control the dramatic hematopoietic shifts follow­
ing severe trauma and burn injury. Given the importance
of these transcription factors to cell fate and the significant
shifts in lineage commitment patterns, knowledge of these
transcription factors and their roles in hematopoiesis may
help in providing a foundation for future reference. Fur­
thermore recent studies indicating the poor correlation of
animal models to humans with regards to transcriptional
response after burn/trauma/endotoxemia highlight the
need for medical research to shift from a reliance on animal
models,296 especially mouse models,297 although the clinical
translation efficacy is debated.298
Conclusion
Hematology plays a major role in burn care. Patients suffer
from anemia due to RBC losses in surgery as well as the
anemia of critical illness. Operative hemostasis is important
both to limit RBC loss and prevent shock. Coagulopathies
develop due to factor consumption and insufficient produc­
tion as well as hypothermia. Transfusion of various blood
products is critical to the management of patients. Hema­
topoiesis is directed away from erythropoiesis to the produc­
tion of the immune cells vital to fight off invading microbes
and heal wounds. Venous thrombosis becomes a major risk
in these critically ill patients, adding another mortality risk.
Hematologic management is a central component of burn
critical care and ought to be carefully considered.
Complete references available online at

cautious increasing use as a topical treatment to promote
wound healing is warranted, but further examination of
rhGM-CSF, along with fibroblast and epidermal growth
factors, is also recommended.
LYMPHOID GROWTH FACTORS
Several growth factors/cytokines contribute to the forma­
tion of lymphoid cells; the most prominent and well studied
is IL-7. The IL-7 receptor is unique to lymphoid cells. Thus
IL-7 is the cytokine/growth factor that influences the expan­
sion of this cell line. IL-7 receptor engagement is essential
not only for lymphoid cell proliferation and survival but
also for HSC differentiation into the lymphoid lineage. The
IL-7 receptor enhances lymphoid cell survival through
maintenance of Bcl-2.282 Bone marrow stromal cells and
the thymus predominantly produce IL-7. T cells are unique
since their maturation takes places in the thymus as opposed
to the bone marrow, and they undergo a process of positive
and negative selection dependent on both IL-7 activation
and expression of the transcription factor Notch1.283 Alter­
ations in IL-7 production, in addition to other cytokines,
can negatively impact survival after inhalation injury.284
Additional growth factors/cytokines contributing to lym­
phopoiesis include IL-2, IL-15, and IL-23.
MEGAKARYOCYTE GROWTH FACTORS
Megakaryocyte and platelet production are regulated by
thrombopoietin. Similar to EPO, thrombopoietin enhances
megakaryocyte progenitor proliferation by amplifying cell-
cycle regulators and preventing apoptosis.222 It is the only
growth factor necessary for proliferating megakaryocytes
and their progenitors.285 Unlike erythropoietin, thrombo­
poietin has a synergistic role with other growth factors
and cytokines in the maintenance and proliferation of
HSCs286 and can be used in their expansion.287 Thrombo­
poietin stimulates platelet release from the bone marrow
and in the periphery, thereby up-regulating platelet func­
tion and aggregation.288 Produced in the liver, kidney, skel­
etal muscle, and stromal cells of the bone marrow,222,289
thrombopoietin production may be increased in response
to increased IL-6 production.290 Given the elevated IL-6
levels present following burn injury, IL-6-induced throm­
bopoietin release may be responsible for the thrombocyto­
sis often seen immediately post-burn.291 Elevated levels of
thrombopoietin, and subsequently platelet activation, may
be present following burn injury.292 The evidence from a
recent study would support the notion that thrombopoietin
blockade could help prevent organ damage in burn patients
with sepsis.293
TRANSCRIPTION FACTORS
While growth factors control hematopoietic cell fate, the
development of terminally differentiated cells is under the
control and coordination of a limited set of transcription
factors. Ultimately specific sequential and temporal gene
expression patterns dictate hematopoietic commitment.
These genetic processes are governed though modula­
tions in the rate of gene transcription, which are accom­
plished through the binding of DNA-binding proteins or

247.e1
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248
Significance of the Hormonal,
Adrenal, and Sympathetic
Responses to Burn Injury
DEREK CULNAN, CHARLES VOIGT, KAREL D. CAPEK, KUZHALI MUTHUMALAIAPPAN,
and DAVID HERNDON
23 
corticosteroids and the medulla that secretes catechol­
amines. Both are critical to orchestrating the systemic
“storms” required to survive a massive injury.
The cellular and biochemical pathways through which
catecholamines work these organism-level alterations are
an area of active study. We will discuss the pathologi­
cal alterations in these systems and how they relate to
modern critical care and the remainder of the endocrine
response.
Strong Sympathetic Activation
Following Burn Trauma
The catecholamine surge following burn trauma was
delineated in landmark papers in 1957 demonstrating
marked elevations in 24-h urine levels of norepinephrine
and epinephrine proportional to burn size, highest in the
first 3 days and remaining elevated for weeks.1,2 Herndon
et al. repeated these studies, finding sustained elevation
in urinary epinephrine and norepinephrine levels past
35 weeks in pediatric burn patients.3,4 Jeschke et al. sub­
sequently demonstrated that cortisol, catecholamines,
and hypermetabolism are significantly elevated up to 3
years after severe burn injury.5 In light of the decades of
evidence for sympathetic activation following thermal
injury, it is critical to understand the resultant physiologic
effects.
CARDIOVASCULAR RESPONSE
The chapters on multisystem organ failure and shock
describe the physiology of the “ebb” phase from distribu­
tive shock and myocardial depression in which cardiac
function is depressed. By 48 h post-burn the myocardium
becomes hyperdynamic in a β-adrenergic–mediated manner
transitioning to the “flow phase.”4,6 Even small burns are
associated with significant changes in cardiac function and
long-term pathologic changes.7 One sympathetic reflex arc
begins when hypotension stimulates baroreceptor (carotid
sinus and aortic arch) afferent nerve activity, with resul­
tant increases in efferent sympathetic outflow. This sympa­
thetic signal for peripheral vasoconstriction and consequent
increase in peripheral vascular resistance is mediated in part
by the nerve-stimulated release of norepinephrine. Angio­
tensin II (AII) and arginine vasopressin (AVP) also act to
Introduction
The endocrine system is central to coordinating the sys­
temic response to burn trauma (Table 23.1). Pathological
and compensatory changes are seen in the hypothalamic-
pituitary-adrenal (HPA) axis, thyroid, pancreatic, and
gonadal hormonal secretions. These changes act in concert
with the humoral effects of cytokines and immunological
mediators discussed in the chapters on burn edema (Chapter
8) and multisystem organ failure (Chapter 31). They mediate
the innate adaptive (stress) response critical to survival in
patients, particularly those who recover sans medical treat­
ment. However in patients receiving medical treatment, they
often prove maladaptive. Understanding these fundamental
responses is critical to the appropriate application of critical
care to burned and traumatized patients.
Normal Hypothalamic-
Pituitary-Adrenal Axis
The physiologic response of the HPA axis begins with the
hypothalamic release of corticotrophin-releasing hormone
(CRH) into the hypophyseal portal system, which mediates
the release of adrenocorticotrophic hormone (ACTH) from
the anterior pituitary. This, in turn, stimulates the synthesis
and release of cortisol from the adrenal cortex. The situ­
ation is more complex because the hypothalamus’s affer­
ent and efferent connections are numerous and diverse in
physiological effect. The hypothalamus is the fountainhead
of the autonomic nervous system, being its most rostral
component. Hypothalamic nuclei originate central outflow,
primarily via the dorsal longitudinal fasciculus, to numer­
ous caudal central autonomic centers (pain modulation,
heart rate, respiration, blood pressure, salivation, and the
dorsal motor nucleus of the vagus) and to the intermedio­
lateral cell column of the thoracic cord, which includes
sympathetic nervous system (SNS) afferents to the adrenal
glands. Hypothalamic stimulation thus initiates the release
of epinephrine and norepinephrine from the chromaffin
cells of the adrenal medulla, which essentially are modi­
fied postsynaptic neurons. The action of these hormones
and neurotransmitters is traditionally thought to facilitate
adaptation to changing conditions. As the terminal signal
transducer of the global stress response, the adrenal glands
function as two distinct parts: the cortex that produces

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
249
and Finnerty reviewed the menagerie of animal studies
demonstrating the centrality of β-receptor dysfunction
in mediating this cardiac pathophysiology and have given
mechanistic insight into the efficacy of modern burn therapy
with β-blockade.6
The sympathetic surge continues long after volume
status is restored and baroreceptor signaling ends. Despite
elevated levels of circulating norepinephrine and epineph­
rine, there is a paradoxical decreased peripheral vascular
resistance during the hyperdynamic “flow” phase. Accom­
panying reduced cardiac afterload is increased cardiac
preload and thus increased cardiac output. There is abun­
dant evidence that mediators of neural, humoral, and
metabolic origins are involved in driving the decrease in
vascular resistance following thermal injury. The signifi­
cance of β2-adrenergic receptors in vasodilation has been
demonstrated using knockout mice,14 thus pointing to the
significance of epinephrine. The situation is complicated in
the burn patient by the increase in nerve-stimulated release
of norepinephrine, which can potentially mediate vasocon­
striction. However evidence exists that the local distribu­
tion of adrenergic receptors mediating either vasodilation
or vasoconstriction will determine the effect of circulating
epinephrine and nerve-stimulated norepinephrine release
on peripheral vascular resistance.15 Blood flow regulation
to the burned extremity remains intact: even in legs with
85% surface burned, increasing the surface temperature
causes increases in blood flow comparable to unburned
legs.16 In addition, increased tissue metabolism has been
recognized to produce metabolites that mediate increased
blood flow by reducing vascular resistance.17 With markedly
increased metabolism in major burns, these metabolites,
along with catecholamines, nitric oxide (NO),18 and atrial
natriuretic peptide,9 may contribute to decreased vascular
resistance.19
When decreases in peripheral vascular resistance compro­
mise tissue perfusion and lead to end-organ damage (e.g., the
urinary granular casts of tubular necrosis), pressor agents
may be required to maintain adequate tissue perfusion in the
setting of adequate volume status. Epinephrine is the drug of
choice, providing optimal vasoconstrictor and inotropic
effects. In cases of resuscitated burn shock, the additional
inotropic support of epinephrine is essential to maintain
tissue perfusion without overly constricting the cutaneous
vasculature needed to heal burn injuries. For example dobu­
tamine, a β-adrenergic inodilator, is an important inotrope
in select burn patients, and the novel non-adrenergic inodila­
tor, levosimendan, may find utility in treating cardiac failure
in burn patients.20
CATECHOLAMINE RESISTANCE
Acidosis is the most common cause of catecholamine
resistance. Macarthur et al.21 described inactivation of
catecholamines by superoxide anions contributing to the
observed hypotension of septic shock in rat models. They
found treatment with superoxide dismutase not only abro­
gated endotoxin-induced hypotension in anesthetized rats,
but also elevated circulating levels of catecholamines. These
findings suggest that compensatory sympathetic activa­
tion, which counteracts hypotension during conditions of
sepsis, may be blunted by inactivation of catecholamines
Table 23.1  Influence of Catecholamines on
Cardiovascular, Metabolic, and Immune Response to
Thermal Injury
Physiologic Variable
Sympathetic-Mediated Change
Following Burn Injury
Resting metabolic rate
Increase238
Increase29
Increase25
Increase (in vitro)171
Proteolysis
No change (urea production)30
No change (protein oxidation)238
Decrease39
Glucose production and
oxidation
Decrease secondary to increase in
lipid catabolism29,239
No change238
Glycogenolysis
Increase (indirect evidence via
cAMP)240
Gluconeogenesis
Increase (indirect evidence via
cAMP)240
Lipolysis
Increase30
Increase238
Increase29
Increase32
Cardiac output
Increase29
Increase30
Peripheral vascular
resistance
Unknown
Heart rate
Increase39
Increase30
T-cell number and function
Unknown
B-cell number and function
Unknown
Neutrophil number and
function
Decrease71
Monocyte number and
function
Increase (indirect; clonogenic
potential)241
Increase (indirect; clonogenic
potential)242
Increase71,243
Citation of studies from the current literature suggesting that sympathetic
activation is involved in changing the listed physiologic variables
following thermal injury.
increase vascular tone.8,9 Additionally a complex interplay of
AII and catecholamines further modulates vascular tone.10
Concurrently AVP has been shown to reversibly depress myo­
cardial function in the isolated heart. AVP and catecholamine
overstimulation may thus contribute to myocardial depres­
sion following burn injury early in the compensation of the
“ebb phase.”11,12
As the heart transitions to the “flow phase” within 48 h
after insult, sympathetic outflow is likely an important driver
in maintaining supranormal cardiac function during recov­
ery from thermal injury. In a group of burned patients under­
going visceral blood flow and metabolic measurements, the
average cardiac index was 8.2 +/−0.5 L/m2 min.13 In the
same study, liver and kidney metabolic and blood flow mea­
surements were also conducted, and all were found to be
elevated. These data allude to a supraphysiologic circulatory
need requisite for recovery from severe burn injury. Guillory

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
250
with resultant heat production. Elijah et al. further eluci­
dated the effects of peroxisome proliferator activated recep­
tor (PPAR) on lipolysis and hyperglycemia in the severely
burned.34
Wilmore developed experimental paradigms suggesting
the role of catecholamines in mediating the hypermetabolic
response to thermal injury.25 Findings included a positive
correlation of increased plasma catecholamines and whole-
body oxygen consumption following thermal injury,25 as
well as demonstrating that adrenergic blockade lowers the
burn-induced increase in metabolic rate and cardiac output
to control levels in animal models.25,29
Experimental findings in rats suggested that the adrenal
medulla, while essential for high rates of heat production
following thermal injury, is not the primary driver of the
hypermetabolic response.35,36 Animals with hypothalamic
lesions did not increase metabolism following thermal
injury and were chronically hypothermic,37 not unlike
experiments in which the adrenal medulla was removed
prior to thermal injury.35 These results are consistent with
clinical observations of burn patients in whom reductions
in heat loss were achieved with occlusive dressings and for
whom elevated environmental temperatures demonstrate
partial reductions in metabolic rate and catecholamine
secretion.38
β-BLOCKADE
Building on findings that catecholamines drive post-burn
hypermetabolism, Herndon et al.39,40 demonstrated that
pediatric patients could be treated with the β-adrenergic
blocker propranolol to successfully reduce metabolic
rate without compromising cardiovascular function. In
a more recent study by this group,41 β-adrenergic block­
ade in pediatric patients for 4 weeks during recovery
from severe burns reduced the elevation in resting energy
expenditure and reversed the reduction in net muscle–
protein balance by 82%. Such treatment also prevented
fatty liver and loss in fat-free whole-body mass and pro­
vided for a more efficacious recovery in these children.42,43
Subsequent studies built on these findings demonstrated
improvements when dosing was continued for 1 year post-
burn.44 Recent animal studies have further established a
cyclooxygenase-2 role in inflammatory proliferation in the
liver.45 Downregulation of fructose-1,6-bisphosphatase-2
mRNA has been observed in muscle tissue following treat­
ment with propranolol; this enzyme may play a role in
gluconeogenesis, although the metabolic significance of
this tissue-specific transcriptional alteration remains to
be determined.46 Propranolol leaves α-adrenergic recep­
tors unopposed, resulting in peripheral vasoconstriction
and increasing vascular resistance. Reduced blood loss has
been observed, with postoperative hematocrit 5–7% higher
with propranolol.47 The exercise-induced enhancements in
muscle mass, strength, and VO2 peak were not impaired
by propranolol; instead, aerobic response to exercise was
improved in massively burned children.48 β-Blockade in
nonburned septic patients has become an area of active
research and, based on these findings in burned patients,
demonstrates value for some patients, although the overall
indications and patient selection have yet to be fully
elucidated.49,50
by superoxides in the extracellular milieu. In a conscious
rat model of sepsis, superoxide inhibition enhanced plasma
levels of catecholamines, increased blood pressure, and
improved survival.22 They also found that NO reduces the
biologic activity of norepinephrine without altering nerve-
stimulated release.23 Case et al. showed increased superoxide
release for T cells in a norepinephrine-stimulated manner.24
These findings may provide insight into the clinical observa­
tions involving critically ill patients in which pharmacologic
norepinephrine administration is ineffective in correcting
hypotension.
CATECHOLAMINES AND HYPERMETABOLISM
Despite myriad factors reported to promote or inhibit the
development of the post-burn hypermetabolic state, many
investigators have demonstrated sympathetic catechol­
amines (norepinephrine more so than epinephrine) to be
the effector limb of the transition to and maintenance of
this hypermetabolic state.25 Herndon et al. clearly showed
this using a 50% full-thickness scald burn rodent model,
with groups pretreated with thyroidectomy, adrenalectomy
(+/− dexamethasone replacement), and reserpine depletion
of catecholamines.26 Adrenalectomy or reserpine blunted
more than half of the hypermetabolic response. Wilmore
et al. demonstrated catecholamines to be the mediator of the
human hypermetabolic response to thermal injury.25 Several
key findings were generated by that study: the β-adrenergic
(but not α-adrenergic) blockade reduced metabolic rate,
pulse, blood pressure, and free fatty acids. Additionally
the investigators documented the “nonliving” response
to thermal injury: poikilothermia. They noted that when
burned patients were placed in cooler environments (21°C),
their metabolic rates generally increased, with urinary
catecholamine excretions increasing in parallel, except­
ing four nonsurvivors who showed less catecholamine
elaboration, became hypothermic, and did not elevate
their metabolic rates. The reason these patients failed to
develop sufficient hypermetabolic responses to permit sur­
vival remains only partially understood. Burned patients
consistently selected a higher room temperature (~30°C)
and also had skin and core temperature increases of 1.7°C
–2°C above controls.27 Elevations in energy requirements
could be partially modulated through adjustments in envi­
ronmental temperature. Burn patients treated in warm
environments of 32°C exhibited reduced metabolic rates
compared to those treated at 25°C, although both groups
remained hypermetabolic. After injury, and concurrent with
an elevated hypothalamic temperature set-point and cardiac
index, qualitative and quantitative changes occur in the
flow of biological energy and mass (substrate) through the
patient.28
Experimental studies of Wolfe and Durkot29 suggest that
the adrenergic drive following burn facilitates lipolysis, influ­
encing fatty acid oxidation. The importance of adrenergic
drive on lipid metabolism in burn was shown in human
patients through the use of stable isotopic studies as well
as adrenergic antagonists.30–32 The profile of the plasma
lipids is dramatically changed as well.33 These results indi­
cate that not only is lipolysis following thermal injury medi­
ated by β2-adrenergic receptors, but also suggest increased
intracellular and extracellular triglyceride–fatty acid cycling,

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
251
isolated atria,80,81 myenteric plexus,82 and brain tissue83
have proved that TNF-α can negatively affect the release
of norepinephrine.
Although the precise mechanisms of the negative modu­
lation of proinflammatory cytokines by catecholamines are
poorly understood, it may be achieved through the ability
of catecholamines to induce the antiinflammatory cytokine
IL-10.84–87 Whole-animal studies involving assessment of
circulating levels of IL-1087 as well as studies of human
whole blood and mononuclear cells stimulated with LPS
in the presence of adrenergic agonists84,86,88 support this
premise. Immunomodulatory effects were further elu­
cidated by Takenaka et al. demonstrating the effects on
T-cell differentiation to CD4+ via a dendritic cell-mediated
pathway.89 Additionally experimental neurotrauma resulted
in increased IL-10 consequent to endogenous adrenergic
stimulation in the absence of LPS or other evidence of infec­
tious challenge.90
SYMPATHETIC RESPONSE TO SEPSIS
Burn injury is commonly complicated by transient bactere­
mia, infection, and sepsis (see chapters on Infection [Chapter
12] and Multisystem Organ Failure [Chapter 31]). Infec­
tion causes a marked sympathetic response proportional
to the degree of insult91 in which there are simultaneous
and opposing forces of hyperinflammation versus immu­
nosuppression. Sepsis is accompanied by an enormous
catecholamine surge leading to changes in cardiovascular
output, immunomodulatory effects, and catabolism. Pro­
pranolol has been shown to attenuate those changes.92 The
use of an adrenergic blockade as an immunomodulator has
found further utility in other traumatic injuries.93 Further­
more animal models of septic peritonitis suggest that initial
sympathetic activation, as measured by elevated levels of
plasma norepinephrine and greater norepinephrine turn­
over, persists for many hours.94,95
Collectively these data clearly support a complex trophic
interconnection between the SNS and immune system.
Burn- and sepsis-induced sympathetic responses exert sig­
nificant influence on bone marrow cellular events. Evidence
for norepinephrine regulation of myelopoiesis in experi­
mental thermal injury with sepsis is detailed in Chapter 22
on hematology.212
Role of Thyroid Function
An early rat study showed that thyroidectomy did not alter
the post-burn increase in metabolism, although adrenal­
ectomy or catecholamine depletion with reserpine did
reduce post-burn metabolic rates.26 Subsequent human
studies demonstrated generally normal total triiodothyro­
nine (T3) and thyroxine (T4), free T3 and T4, and thyroid-
stimulating hormone (TSH) levels in uncomplicated burn
patients. However in those patients with infection or sepsis,
decreased amounts of free T4 and T3 were observed.96 T3
replacement did not alter metabolic rate or mortality post
burn97 but may have decreased circulating levels of norepi­
nephrine and epinephrine. These and other studies suggest
that the hypermetabolic response to burn is independent
of thyroid hormones.98 More importantly, these data, in
SYMPATHETIC INFLUENCES ON
IMMUNE FUNCTION
New data have clarified the interconnections between the
immune and sympathetic nervous systems and are well
reviewed by Pedro et al.51 Understanding these interactions
may be important to comprehending the implications of
our pharmacologic treatments with β-adrenergic antago­
nists and agonists on immune function.
Immunohistochemical staining demonstrates substan­
tial sympathetic innervation of all primary (thymus and
bone marrow) and secondary (spleen and lymph nodes)
lymphoid organs.52–55 Innervation has been shown to
reach immune cell compartments of the spleen (the white
pulp), periarterial lymphoid sheath, marginal zone, and
marginal sinus areas, as well as the splenic capsule and
trabeculae.56–59 Sympathetic nerve terminals have been
described in direct apposition to T cells, interdigitating den­
dritic cells, and B cells.60
Immune modulation by adrenergic signaling was
recently reviewed by Sanders.61 Lymphocytes (including
activated and resting B cells, naïve CD4+ T cells, T-helper
[TH1] cell clones, and newly generated TH1 cells) express
β-adrenergic receptors, but they are not expressed in newly
generated TH2 cells.62–64 Furthermore there is significant
evidence that norepinephrine can modulate the function
of CD4+ T cells, which in turn can modulate antibody pro­
duction of B cells.65 Sympathetic neurons suppress CD8+
T-cell receptor response and cytotoxic activity.66 In addi­
tion, norepinephrine can directly influence B-cell antibody
production depending on the time of exposure following
activation.67 The physiologic importance of these in vitro
findings is supported by a series of in vivo experiments
involving severe combined immunodeficient (scid) mice
depleted of norepinephrine prior to reconstitution with
antigen-specific TH2 and B cells. These experiments dem­
onstrate that norepinephrine is necessary to maintain a
normal level of antibody production in vivo.62 Furthermore
other whole-animal experiments also involving scid mice
provide evidence that the immune response itself stimulates
the release of norepinephrine from adrenergic nerve ter­
minals in bone marrow and the spleen, which in turn can
influence antibody production by B cells.68 β-Blockade in 20
pediatric burn patients significantly reduced serum tumor
necrosis factor-α (TNF-α) and interleukin-1β (IL-1β).69 The
parasympathetic system further conditions the immuno­
modulatory role of the SNS. Recently it was shown that the
vagal synapses trigger acetylcholine release from memory
T cells, in turn reducing TNF-α through α-7-nicotinic ace­
tylcholine receptor.70 These findings suggest the potential
of sympathetic/parasympathetic activation in mediating
immune responses.
In animal models, blocking β-adrenergic receptors soon
after injury partially restored the lipopolysaccharide (LPS)-
stimulated TNF-α secretory potential of circulating mono­
cytes lost during the course of burn injury and sepsis.71
Apart from adrenergic inhibition of LPS-stimulated TNF-α
release in isolated macrophages,72–75 similar inhibition
of LPS-stimulated TNF-α production has also been dem­
onstrated in human mast cells,76 microglial cells,77 astro­
cytes,78 and cytotoxic T lymphocytes.79 In contrast to
adrenergic stimulation of TNF-α release, experiments with

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
252
and Pruitt wrote a masterful review of the coordinated
hypothalamic response to injury in 1976: “Stress in Surgi­
cal Patients as a Neurophysiological Reflex Response.”104
Burned men exhibit hypogonadism and Leydig cell failure
following thermal injury, resulting in depressed testoster­
one levels. Plymate et al. measured levels of sex hormones
(e.g., sex hormone-binding globulin [SHBG] and luteinizing
hormone [LH]) and thyroid hormones in the weeks follow­
ing burn injury. They showed an increase in estradiol levels
and a concomitant decrease in the secretion of bioactive
LH following burn injury, suggestive of an alteration in
hypothalamic control of the gonadal axis leading to sup­
pression of testosterone release. SHBG also exhibited sig­
nificant changes, with an initial decrease and subsequent
rise in concentration as compared to controls. This increase
in SHBG results in a further suppression of testosterone by
reducing the amounts of the unbound hormone. The levels
of SHBG strongly correlated with levels of T3 and free T3 as
well. This study helped elucidate the complex relationships
of alterations in hypothalamic, thalamic, and gonadal regu­
lation in the burned male.105 Taken together, these studies
allude to a pervasive shift from normal hypothalamic func­
tion to a post-injury “mobilization” that remains but partly
understood.
It appears that synthesis of C19 steroids by the adrenals
and testes is compromised as a result of enhanced produc­
tion of C21 steroids, such as cortisol. Aldosterone levels
are also subnormal, despite elevated plasma renin activ­
ity. This suggests a shift in pregnenolone metabolism away
from mineralocorticoid and adrenal androgen pathways
toward the glucocorticoid pathway.100 DHEAS also has a
profound influence on the immune response, and a role for
DHEAS as a modulator of the immune response is now well
established.106–109 Given that immunostimulatory proper­
ties of TH1 cells are low during severe illness,100 DHEAS
deficiency may be a contributing factor to the immune
suppression in burn patients. In vitro treatment of human
T cells with DHEAS increases IL-2 production (which is
required for clonal expansion) and IL-2 mRNA synthe­
sis.109 Interestingly this effect was seen only in CD4+CD8−
and not in CD4−CD8+ cells. DHEAS-treated cells were also
able to mediate a more potent cytotoxic effect than were
untreated cells.
Under conditions of severe physical stress and chronic
illness, dopamine levels have been shown to be elevated;110,111
consequently dopamine may also influence immune status
and adrenal steroid secretion in burn patients. Exogenous
dopamine is often used in the treatment of critically ill
patients because of its vasopressor, renal vasodilator, and
cardiac inotropic properties. Povoa et al. reviewed vaso­
pressor use in septic shock and found a need for a multi­
modal selection of these agents.112 However several other
studies indicate that dopamine treatment may undermine
an already depressed immune system. This effect appears
to act via the suppression of prolactin release from the
anterior pituitary. Dopamine suppresses serum prolactin
and DHEAS levels but not cortisol levels.113,114 In vitro,
prolactin has a synergistic effect on ACTH-induced DHEAS
secretion by human adrenal cells.115 Thus it is possible that
the dopamine-induced suppression of prolactin is respon­
sible for lowering DHEAS levels and hence suppression of
the T-cell proliferative response. The in vitro proliferative
conjunction with more recent work by Senel et al., allude
to a post-burn shift in metabolic control away from thyroid
signaling in favor of other mediators.99
SEX STEROIDS FOLLOWING BURN TRAUMA
Androgens
Release of C19 Steroids.  In the normal physiologic state,
dehydroepiandrosterone sulfate (DHEAS), a weak andro­
gen, is the major secretory product of the adrenal cortex.
In burn patients, there is an increase in cortisol secretion
and a distinct decrease in serum DHEAS levels100 owing to
a reduction in synthesis.101 Testosterone and androstene­
dione levels decrease abruptly. In burn patients, subnor­
mal testosterone levels persist for 3–18 months post burn,
whereas cortisol levels normalize earlier.101 The decrease in
testosterone secretion may be the direct effect of excessive
cortisol levels on the testes.102,103 Wilmore, Long, Mason,
Table 23.2  Influence of Glucocorticoids on Metabolic
and Immune Response to Thermal Injury
Physiologic Variable
Glucocorticoid-Mediated
Change Following Burn Injury
Resting energy
expenditure
Increased152,176,179
Oxygen consumption
Increased244,245
Primary fuel
Lipids, glucose190
Proteolysis
Increased in skeletal
muscle160,161,163,164,246
Acute-phase protein
synthesis
Increased133,247,248
Nitrogen excretion
Increased244
Glycogenolysis
Increased via effect on
glucagon157,158
Gluconeogenesis
Increased153,154,247
Lipolysis
Increased191
Ketone body formation
Normal193
Triglyceride level
Increased193,247
Thymic changes
T-cell population
T-cell proliferation
B-cell population
Involution218
Decreased217,249
Inhibited219,220,248
Not conclusive from current data
Neutrophil population
—chemotaxis
—demargination
—bactericidal activity
Increased223,249,250
Suppressed223
Increased223,226
Suppressed228
Monocyte population
Increased transiently with
corticosteroids but decreased
in burn patients250–252
  —chemotaxis
Suppressed224
  —bactericidal activity
Suppressed224,227
Bone formation
Decreased200
Citation of studies from the current literature suggesting that glucocorticoid
release is involved in changing the listed physiologic variables following
thermal injury.

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
253
Danner and colleagues carefully mapped the HPA axis
response to a massive septic insult in their lethal canine
pneumonia model as they attempted to define the “critical
illness-related corticosteroid insufficiency” (CIRCI). They
found a massive surge in total, bound, and free serum cor­
tisol and in ACTH. Additionally they determined that ACTH
failed to promote a further increase in cortisol and that
dexamethasone did not suppress cortisol, possibly because
the adrenals were already maximally stimulated. Signifi­
cantly in sepsis-surviving animals, the HPA axis recov­
ered to normal levels whereas ACTH and dexamethasone
responsiveness recovered by 10 h compared to nonsur­
vivors. In contrast, the mineralocorticoid response with
hyperaldosteronism remained past 72 h and did not regain
dexamethasone suppression. Thus mineralocorticoids are
ACTH-independent in the setting of sepsis. These data
support the adrenal exhaustion hypothesis.119
In a postmortem study of adrenal glands of ICU patients,
it was found that the adrenocortical structure was dis­
rupted following critical illness. These patients tended to
have adrenal glands that weighed less than controls, with
significantly less protein content and greater fluid content.
There was also considerable downregulation of ACTH-
regulated genes.120
Elevated plasma-cortisol levels have been shown during
critical illness, especially during an episode of systemic
inflammatory response syndrome (SIRS). However cortisol
production during the day in patients with SIRS, although
elevated, is less than doubled. ACTH is suppressed in these
patients, implying a non-ACTH-driven response. It has
been demonstrated that during critical illness clearance of
plasma cortisol is significantly reduced, playing a signifi­
cant role in the hypercortisolism of the critically ill stress
response.120 Other investigators determined in the setting
of septic shock that only serial hormonal measurements
and provocative testing were useful for HPA axis function
assessment. They further identified high aldosterone levels
in a population with poor outcomes from sepsis.119
Norbury et al. followed urinary cortisol levels in 212
severely burned children, finding three- to fivefold increases
in cortisol excretion up to 100 days post-burn. Urinary
norepinephrine levels were significantly increased up to 20
days,4 as shown in Fig. 23.1. Hypercortisolemia has been
suggested as a driver of whole-body catabolism following
severe burn. To test this hypothesis, Jeschke et al. blocked
cortisol production with ketoconazole in 55 severely burned
children. They found normalization of the eightfold elevation
in urine cortisol in the treatment group. Counterintuitively,
no change was seen in inflammatory response, acute-phase
proteins, body composition, muscle protein breakdown or
synthesis, or organ function. Their data suggest that post-
burn hypercortisolemia does not play a central role in the
catabolic response.121
Jeschke and Herndon characterized the long-term inflam­
matory and acute-phase responses in 977 pediatric burn
patients with greater than 30% TBSA with 24-h urinary
excretion. They found significant elevations of cortisol, cat­
echolamines, cytokines, and acute-phase proteins for up to 3
years, as seen in Fig. 23.2. They also observed insulin resis­
tance, increased fracture risk, hepatomegaly, increased
cardiac output and cardiac dysfunction, and impaired
strength over the same period.4,5
response of T cells from patients on dopamine therapy is
diminished,113 and cells treated with DHEAS mediate a
more potent T-cell cytotoxic effect.109
Extensive studies and clinical experiences were under­
taken over the past decade with androgen supplementation
using oxandrolone. Reeves and Finnerty detailed the 5-year
outcomes of long-term oxandrolone treatments following a
24-month administration in severely burned children. They
found significantly increased bone mineral content, greater
height velocity, reduced cardiac work, and augmented
muscle strength.116 This is described in greater detail in the
chapter on hypermetabolism (Chapter 30). Overall there is
a hypoandrogeneric state post burn, and supplementation
with the anabolic steroid oxandrolone is effective at both
ameliorating hypermetabolism as well as shifting the patient
toward anabolism.
Estrogens
The impact of xenoestrogens on mortality in burned patients
has been investigated. Found in insecticides used from the
1950s to the 1970s, xenoestrogens are compounds that
can act as estradiol receptor agonists or antagonists and
that are stored in fat. During the hypermetabolic state fol­
lowing thermal injury, the xenoestrogens are released along
with mobilized lipids from these fat stores. In older burn
patients who were more likely to have higher concentra­
tions of these compounds in their bodies, it was discovered
that nonsurvivors had significantly increased levels of two
xenoestrogens, heptachlor epoxide and oxychlordane. It
was suggested that these compounds may induce the inac­
tivation of estradiol, progesterone, testosterone, and gluco­
corticoids via the induction of steroid hydroxylases, as well
as antagonizing estradiol receptors, which may result in
decreased inflammation and cytokine release.117
ADRENAL CORTICAL STEROIDS FOLLOWING
BURN TRAUMA
Adrenocortical response is critical to coordinating the
systemic response to thermal injury. The glucocorticoid
surge following burn injury has long been measured by
both serum and urinary excretion markers. Regulation of
glucocorticoid secretion is complex, with multiple determi­
nants of the adrenal cortex secretion of cortisol, including
pituitary ACTH, but also afferent neural control and hyper­
thermia, which blunts the adrenal response to ACTH. Fur­
thermore the usual circadian rhythm of cortisol secretion is
dampened after burn injury. In 1982, Vaughn et al. showed
elevated circulating and urinary cortisol, with a weak cor­
relation to the level of ACTH. Superior correlations were
noted between cortisol and total body surface area (TBSA),
metabolic rate, and average body temperature. These obser­
vations in burned patients indicate that adrenal hypersecre­
tion of cortisol is in response to temperature, circulating
mediators of hypermetabolism, direct adrenal innervation,
and a decrease in adrenal cortex responsiveness to ACTH.
As a result, the authors concluded that cortisol may play a
secondary role in permitting and promoting the changes
seen in post-injury hypermetabolism.118 On this basis, they
attributed post-injury metabolic and thermal changes pri­
marily to sympathetic tone and circulating catecholamines
(norepinephrine and epinephrine).

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
254
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Urine cortisol (g/24 h)
0
Time post burn (days)
Time post burn (days)
400
300
200
100
0–10
11–20
21–40
41–100
101–200
201–500
500
Urinary norepinephrine (g/24 h)
0
140
120
100
20
40
60
80
0–10
11–20
21–40
41–100
101–200
201–500
500
Time post burn (days)
Urinary norepinephrine (g/24 h)
0
30
25
20
5
10
15
0–10
11–20
21–40
41–100
101–200
201–500
500
Average male urine cortisol
Average female urine cortisol
Fig. 23.1  Urinary cortisol and catecholamine excretion after burn injury in children. (From Norbury WB, Herndon DN, Branski LK, Chinkes DL, Jeschke MG.
Urinary cortisol and catecholamine excretion after burn injury in children. J Clin Endocrinol Metab. Apr 2008;93(4):1270–1275.)
*
*
*
*
Days post-burn
A
Urinary norepinephrine (g/day)
0
130
120
110
100
10
20
30
40
50
60
70
80
90
Non–burned
0–7
8–10
11–16
17–22
23–28
29–34
35–40
41–60
61–90
91–180
181–270
271–365
366–540
541–730
731–1100
Days post-burn
B
Urinary epinephrine (g/day)
0
60
10
20
30
40
50
Non–burned
0–7
8–10
11–16
17–22
23–28
29–34
35–40
41–60
61–90
91–180
181–270
271–365
366–540
541–730
731–1100
Days post-burn
C
Urinary cortisol (g/day)
0
20
40
60
80
100
120
140
160
180
200
220
Non–burned
0–7
8–10
11–16
17–22
23–28
29–34
35–40
41–60
61–90
91–180
181–270
271–365
366–540
541–730
731–1100
Days post-burn
D
sCOL (g/dl)
0
60
10
20
30
40
50
Non–burned
0–7
8–10
11–16
17–22
23–28
29–34
35–40
41–60
61–90
91–180
181–270
271–365
366–540
541–730
731–1100
Fig. 23.2  Long-term persistence of the pathophysiologic response to severe burn injury. (From Jeschke MG, Gauglitz GG, Kulp GA, et al. Long-term
persistence of the pathophysiologic response to severe burn injury. PLoS One 2011;6(7):e21245.)

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
255
SUBSTRATE CYCLING
Influence on Metabolic Pathways
Elevated energy expenditure and hyperglycemia are hall­
marks of thermal injury. The heavy demand for energy
stems from the increase in essential functions, such as the
synthesis of proteins required for wound healing, the syn­
thesis of acute-phase proteins, and inflammatory mediators.
The increase in substrate cycling is partly responsible for the
elevation in resting energy expenditure in burn patients. This
occurs when enzymes catalyzing opposing reactions of the
same pathway are simultaneously active. For example, in
the conversion of glucose to glucose-6-phosphate and back
to glucose, the demand for energy increases to resynthesize
adenosine triphosphate (ATP) used in this and similar reac­
tions. In burn patients, the rate of glucose production and
glycolysis, as well as of lipolysis and re-esterification of tri­
glycerides, is elevated.31 This cycling of substrates generates
heat through the hydrolysis of high-energy phosphate bonds
in ATP, thereby contributing to thermogenesis as well as
increased energy requirements in burn patients.142 Concur­
rently muscle mitochondrial decoupling and fat browning
adaptions occur to increase thermogenic capacity.
Hormonal Determinants of Glucose Utilization
In 1986, glucose and alanine fluxes were studied in adult
burn patients with stable isotope tracer infusions, soma­
tostatin infusion (suppressing insulin and glucagon), and
insulin + glucose replacement (isolated glucagon suppres­
sion). Insulin and glucagon levels were both significantly
elevated above those in unburned individuals. Somatosta­
tin infusion reduced both insulin and glucagon levels and
induced a stable decrease in glucose production at 30 min
with a progressive decrease in glucose uptake over the
course of 30–180 min. When glucagon was selectively
reduced via the reinfusion of insulin to restore basal levels
in conjunction with glucose infusions to maintain euglyce­
mia, glucose production was suppressed significantly below
levels when somatostatin was infused alone, and glucose
clearance was restored to pre-infusion levels. This study
provided evidence for glucagon control of hepatic glucose
production (HGP) in the post-burn state, with basal levels
of insulin further suppressing HGP while exerting greater
influence to increase (peripheral) glucose uptake. Glucagon
reduction (via somatostatin + insulin infusion) did not alter
the alanine clearance or flux rates; however suppression of
insulin and glucagon (from somatostatin infusion alone)
increased the alanine flux rate, consistent with increased
peripheral protein catabolism when the insulin signal is
diminished. The authors noted prior observations indicat­
ing tachyphylactic hepatic gluconeogenesis in response
to glucagon. However in the setting of hypercortisolemia
(observed in these patients), prolonged HGP in response to
glucagon signaling manifests.143
A concurrent study of unburned adults differentiated the
response to endogenous insulin infusions from the response
to a proximate glucose infusion using somatostatin sup­
pression of endogenous insulin and glucagon + insulin
replacement to basal levels during the glucose infusion.
This study established that glucose infusion (1 and 4 mg/kg
per minute), independent of endogenous insulin effect, sup­
presses endogenous glucose production, stimulates alanine
Free versus Total Cortisol
Glucocorticoids circulate in the body bound to cortisol-
binding globulin (CBG), such as transcortin, as an inactive
complex. Only 1–10% of total plasma cortisol circulates
unbound and is responsible for the biological activity of
glucocorticoids. Free plasma cortisol is a surrogate for the
difficult-to-measure tissue cortisol.122,123 Burn injury shifts
the equilibrium between unbound and total cortisol toward
an elevation in the unbound fraction.124 Serum CBG and CBG-
binding capacity are low in burn injury, severe infection, and
septic shock.124–126 In burn patients, CBG levels have been
shown to decrease markedly, with the lowest values occur­
ring 48 h after injury.127 Even a minor burn, such as 3%
TBSA, results in a reduction of serum CBG levels by 30%,128
which return to normal levels 1–2 weeks later. The net effect
of the decrease in CBG levels following thermal injury may
not only result in increased levels of free cortisol but also in
the amount of excreted cortisol, which is reflected in high
urinary corticosteroid levels. The urinary cortisol concentra­
tion was observed to increase progressively with burn size,
with the highest levels in the 60–99% TBSA burn groups.129
Additional explanations for increased levels of corticoster­
oids in burn patients may be due to the direct inhibitory effect
of corticosteroids on the biosynthesis of CBG.130–132 Further­
more IL-6 elevation associated with massive burns has also
been implicated in reducing CBG synthesis.133
Evidence exists suggesting that cortisol elevation with cor­
responding decreased ACTH may be driven by endothelin or
atrial natriuretic peptide/hormone (ANP/H). Vermes et al.134
demonstrated significant elevation in both plasma endothe­
lin and ANP levels for 8 days following hospitalization in
severely ill patients with sepsis or trauma. Fittingly endothe­
lin has been shown to be a modulator of the sympathetic
response.135 In addition, infusion of ANP in humans has been
demonstrated to block CRH-stimulated secretion of ACTH
and cortisol,136 while endothelin-1 and endothelin-3 enhance
secretion of steroid hormones from the adrenal cortex.137
However endothelin-3 has been reported to elevate ACTH
and corticosterone levels in rats,138 whereas endothelin-1
results in elevated ACTH in humans.139 Based on this, Vermes
et al.134 suggest that endothelin may be responsible for stimu­
lating steroid secretion, whereas ANP’s action on the HPA
axis may suppress ACTH secretion, thereby explaining the
paradoxical increase in cortisol with concomitant low ACTH
levels in severely stressed patients.
By precisely measuring cortisol, Cohen et al. found no sig­
nificant correlation between total plasma, free plasma, and
tissue microdialysis cortisol levels. Tissue microdialysis cor­
tisol levels were significantly increased in burned patients
compared with healthy controls. Furthermore via subcu­
taneous microdialysis of cortisol levels in burned and non-
burned tissue of severely burned patients, they discerned no
significant difference in local cortisol concentrations. This
indicates that local microenvironmental changes in burned
tissue, such as more cortisol cleaved from CBG by the neutro­
phil elastase, failed to significantly affect local cortisol levels.
They concluded that free cortisol demonstrated a better cor­
relation with TBSA than total cortisol.140 Given the sensitiv­
ity of cortisol to pain and stress as well as diurnal variations,
Brown et al. advocate the utilization of salivary α-amylase
as a surrogate in the setting of outpatient investigations.141

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
256
can drive the new synthesis of gluconeogenic enzymes and
acute-phase proteins in response to burn injury.
The complete details of the mechanisms involved in burn-
mediated alterations in protein metabolism are unknown.
However some information can be gleaned from studies on
other states of excessive catabolism. In conditions such as
metabolic acidosis, adrenalectomy halts muscle proteoly­
sis and does not increase expression of components of the
ubiquitin–proteasome pathway.163,164 These effects can be
reversed by dexamethasone administration. Further support
for this premise is provided by in vitro studies, which show
that dexamethasone-induced increases in proteolytic degra­
dation in myocytes can be abolished by the glucocorticoid
inhibitor RU486.165 Ding and coworkers166 suggest that
partial inhibition of the ubiquitin–proteasome pathway may
be beneficial in enhanced catabolic states. Taken together,
these data suggest that interaction of glucocorticoids and
the ATP-requiring ubiquitin–proteosome system may play
an important role in burn-induced proteolysis.167–171
Another aspect of protein catabolism following burn is the
generation of gluconeogenic amino acids. Plasma levels of
alanine are increased following burn.172 Nitrogen produced
as a result of transaminating alanine to the gluconeogenic
intermediate, pyruvate, is subsequently converted into glu­
tamine and then to urea for excretion by the liver. In muscle
tissue, alanine aminotransferase (ALT/SGPT) transfers an
amino group from glutamine to pyruvate, forming alanine
and α-ketoglutarate. Alanine is then dumped into the blood­
stream, taken to the liver, and returns to the muscle as glucose
(the glucose–alanine cycle). This is one reason why plasma
alanine increases after burn. By contrast, in the liver, glu­
tamine enters the mitochondria, and eventually nitrogen is
processed via the urea cycle.173 Glutamine is one of the major
participants in the translocation of amino acids from periph­
eral tissues to the liver for nitrogen excretion. Expression of
glutamine synthase is increased to compensate for glutamine
depletion in peripheral tissues. Following burn injury, gluta­
mine synthase mRNA is increased first in the lung and later
in muscle.174 Adrenalectomy partially reduces burn-induced
glutamine synthase mRNA174 in a tissue-specific manner,
with no such effect in the kidney or liver. There is evidence
suggesting that glucocorticoids may augment glutamine syn­
thesis in lung and muscle tissues.175 Mobilization of protein
from peripheral tissues is also indicated by the increase in
phenylalanine in the blood of burn patients.172 Phenylala­
nine is the only amino acid not degraded by peripheral tissue;
hence it accumulates in the circulation when uptake by the
liver is compromised.
The hypermetabolic and catabolic states seen in thermal
injury remain long after the burn wound completely
heals:152,176–179 reduction in protein catabolism and enhance­
ment of lean body mass were seen only 9–12 months follow­
ing the initial injury.177 Therefore the post-burn treatment of
growth deficiency must be prolonged beyond wound healing.
Many treatment algorithms to modulate this growth
retardation and hypermetabolism have been examined and
subsequently reviewed by Diaz.180 Indirect effects of gluco­
corticoids on glucose levels in burn include modulation of
insulin-like growth factor-1 (IGF-1), an important mediator
of growth hormone (GH) action.181,182 Marked depression
of all components of the IGF-1 complex is seen following
burn.183–187 Elevated glucocorticoid levels in burn patients
production, and suppresses urea production.144 A further
analysis of data collected as part of the T3 replacement trial
described earlier showed that the metabolic rate increased
proportionally with and was independently predicted by
plasma glucagon.145
In the setting of an adequate, constant nitrogen intake,
increasing carbohydrate feeding spared protein catabo­
lism and mitigated negative nitrogen balance, whereas
intravenous fat emulsion did not affect nitrogen balance
independently.146,147 These studies indicated the primary
determinants for nitrogen excretion were carbohydrate
intake and metabolic rate. Nitrogen excretion was mini­
mized when the carbohydrate intake approximated the
metabolic rate. Insulin was additively anabolic to carbo­
hydrate intake in further decreasing nitrogen excretion
when patients were provided constant and sufficient protein
intake.148
GLUCOCORTICOIDS FOLLOWING BURN INJURY
In burn patients likely to recover, plasma glucocorticoid
levels are moderately elevated or in the upper normal range,
can persist beyond a month,124,149 and return to normal
as healing progresses.150 In contrast, patients with severe
thermal injury (90% TBSA) have markedly lower levels of
glucocorticoids, suggesting that they are unable to mount
an adequate response.124
Glucocorticoids and Carbohydrate Metabolism
Glucocorticoids contribute to hyperglycemia by enhancing
endogenous production of glucose in the liver.151–154 Fol­
lowing burn, elevated glucose levels are sustained through
gluconeogenesis and impaired glucose utilization. The
increased plasma lactate produced by peripheral tissues fol­
lowing burn, as documented by Wolfe et al.,155 is an essen­
tial substrate for gluconeogenesis by the liver. Burn injury
causes intrinsic alterations in the liver, which increase the
conversion of pyruvate to oxaloacetate at the expense of
nontricarboxylic acid cycle sources.156 Efficient mobiliza­
tion of glucose from glycogen and skeletal muscle amino
acids for gluconeogenesis requires glucagon secretion,145,157
which is stimulated by glucocorticoids.145,157,158 Glucocorti­
coids sustain the action of glucagon and prevent the usual
development of tachyphylaxis from high levels of glucagon.
In addition to gluconeogenesis, impaired glucose utilization
and insulin resistance can also play a role in sustaining
high circulating levels of glucose in burn patients.152
Glucocorticoids and Protein Metabolism
Protein catabolism is a part of burn hypermetabolism,
resulting in negative nitrogen balance. Cuthbertson’s159
landmark studies were the first to suggest the important
concept that nitrogen loss is a whole-body rather than a
local burn wound response. The increase in proteolysis seen
in burn injury is at least partly mediated by glucocorticoids.
In humans160 and in animal models,161 administration of
glucocorticoids enhances muscle proteolysis. Furthermore
burn injury-induced muscle proteolysis can be inhibited by a
glucocorticoid receptor antagonist.162 Amino acids mobilized
from peripheral tissues are transported to the liver where,
unlike in other tissues, cortisol stimulates protein synthesis.
The increased hepatic protein synthesis in response to cortisol

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
257
donor sites as well as reduction of hospital stay without
increasing mortality or scarring.205 IGF-I supplementation
was also examined and had an even greater anabolic effect
but with less resultant hypoglycemia or hyperglycemia.206
However Takala et al.207 ascertained increased morbidity
and mortality in trauma patients, and the use and further
study of these hormones has since been restricted.208 In a
subsequent study, Herndon and Voigt employed a combina­
tion treatment of oxandrolone and propranolol that signifi­
cantly ameliorated growth arrest in pediatric burn patients
without the risks associated with IGF-1 treatment.209 Rojas
et al. reviewed the current pharmacotherapy for hyperme­
tabolism in burn patients and cover these issues in detail.210
Glucocorticoids on Immune Suppression
Severely burned patients are susceptible to opportunistic
infections, and sepsis is a major cause of death associated
with burns. Burn injury leaves the patient vulnerable to
opportunistic infections via skin, GI, respiratory, and
urinary tracts.211 The glucocorticoid response to thermal
injury appears to play an important role in immune dys­
function, with impairment of both specific and nonspecific
defenses. Corticosteroids reduce lymphocyte, eosinophil,
and basophil numbers; alter lymphocyte subpopulations;
depress immunoglobulin production by B cells; and sup­
press neutrophil and monocyte/macrophage activity.
Acute thymic involution212,213 and a reduction of the
total T-cell population occur soon after burn injury.212–215
During initial thymic involution in an animal model, there
is marked depression of CD4+/CD8+ lymphocytes. Thymic
involution is a common response to various types of stress
and trauma.216 In humans, the depression of T lymphocytes
is reflected by the reduction of both CD4+ and CD8+ cell
numbers.214 In an animal model,212 CD4+CD8− cells are
reported to be more sensitive to the effects of thermal injury
than are CD4−CD8+ cells. Unsurprisingly CD4+CD8− cell
numbers remain suppressed during the initial 2-week
period following burn injury.
Thymic changes following exogenous administration of
glucocorticoids are similar to those seen in burn,217,218 in
that both noninjury exogenous hypercortisolism states and
burn injury are associated with decreased CD4+CD8+ and
increased CD4+CD8− thymocytes.213 The reduction in
CD4+CD8+ cell numbers during the first 24 h after burn is
due to glucocorticoid-mediated apoptosis because burn-
induced thymocyte apoptosis is suppressed by adrenalec­
tomy or the administration of a glucocorticoid antagonist.213
Other factors contributing to lymphocyte dysfunction and
immunosuppression resulting from elevated corticosteroid
levels may include direct inhibition of T-cell proliferation,
IL-2 production,219,220 apoptosis,221 and altered lymphocyte
membrane fluidity.222
Apart from these effects on lymphocytes, glucocorticoids
also enhance susceptibility to infections by modifying
monocyte and neutrophil function. Movement of circulat­
ing inflammatory cells to the site of infection is suppressed
by the ability of glucocorticoids to reduce the cellular
response to chemotactic stimuli,223–225 diminish neutrophil
adherence,226 and induce a shift from marginal to circulat­
ing cells.223 Glucocorticoids also suppress the bactericidal
activity of monocytes227 and neutrophils,228 perhaps
through impairment of lysosomal function.229
may contribute to the suppression of the acid labile subunit
(ALS) of the IGF-1 complex. Treatment of rats with dexa­
methasone results in low levels of serum ALS as well as liver
ALS mRNA.188,189
In addition to amino acids released from peripheral
tissue,190 free fatty acids are released from adipose tissue by
cortisol.191 In burned children and adults, increased lipoly­
sis is reflected in the elevated plasma levels of palmitic and
oleic acids.32,192,193 Collectively these effects lead to hepato­
megaly and a cushingoid phenotype.
Glucocorticoids on Bone Metabolism
Aside from combating the increased demand for energy,
glucocorticoids also affect bone development. Abnormal
bone metabolism in burn injury has been demonstrated in
animals and humans.194,195 In children, the reduction in
bone mineral density persists for at least 5 years after severe
burn injury (>40% TBSA) and results in permanent retar­
dation of linear growth.196,197 The reasons for loss of bone
mineral density include increased production of endog­
enous glucocorticoids, the inflammatory response, immo­
bilization, aluminum loading, and production of cytokines
(e.g., IL-1 and IL-6) that facilitate bone resorption.198 In an
animal study, Hoscheit et al. found increased markers of
bone resorption, particularly RANKL, in the first 2 weeks
after burn, suggesting that the decreased bone mass after
burn injury results from increased resorption and decreased
bone formation.199
Glucocorticoids have potent effects on bone formation
and resorption, resulting in loss of bone mass. Weinstein
and coworkers200 investigated the long-term (equivalent to
3–4 human years) effects of glucocorticoids on bone metab­
olism in an animal model and reported a reduction in osteo­
clastogenesis and osteoblastogenesis leading to reduced
bone turnover and reduced bone formation, respectively.
Enhanced osteoclast and osteoblast apoptosis was observed
in mice subjected to long-term glucocorticoid administra­
tion, as well as in patients with glucocorticoid-induced
osteoporosis.200 In addition, glucocorticoids directly down­
regulate expression of type I collagen and upregulate
expression of collagenase-3 in chondrocytes.201 On the
other hand, IGF-1 enhances expression of type I collagen
and suppresses the expression of collagenase-3.202 Thus the
massive increase in glucocorticoids and the corresponding
decrease in IGF-1 in burn injury have the ability to pro­
foundly alter bone and cartilage formation.
The mechanisms by which glucocorticoids mediate bone
resorption are unclear. Glucocorticoids may mediate bone
resorption by their dual capacity to initially inhibit osteo­
clast synthesis and later stimulate osteoclast synthesis,
coupled with an increase in bone resorption.203 Another
mechanism by which cortisol may influence bone resorp­
tion is by suppression of IGF-1 or GH-induced chondrocyte
proliferation.204 The antiproliferative effect of glucocorti­
coids may be mediated through downregulation of the GH
receptor and binding affinity, as well as suppression of the
local production of IGF-1 by these cells.
Supplementation with exogenous recombinant human
GH (rhGH) was studied by Herndon et al.180,205,206 and was
found to have a profound anabolic effect on the muscle and
skin. Breederveld et al. reviewed trials of GH in burn
patients, noting more rapid healing of burn wounds and

23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
258
Although severe burns are associated with alterations in
B-cell production and function, there is considerable incon­
sistency in the literature.230–235 For example, in rats subjected
to 30% burn injury, splenic lymphocytes respond poorly to
LPS, and immunoglobulin synthesis is reduced in compari­
son to control animals.236 Others have found an increase in
circulating B cells early after burn injury.232 Administration
of methylprednisolone to normal volunteers for 2–4 weeks
also reduces serum immunoglobulin levels.237
This review provides a glimpse of how the catecholamine
and hormonal responses to thermal injury support com­
pensatory cardiovascular, metabolic, and immunologic
changes. Although adrenergic mechanisms are important
for their ability to influence intracellular signaling path­
ways, their roles as modulators of gene expression are still
being explored. While alteration of gene expressions by
glucocorticoids is well described, less is known about the
interplay of glucocorticoids with the complex post-injury
signaling milieu seen with severe thermal injury or other
forms of trauma.
Complete references available online at

Further Reading
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Wilmore DW, Aulick LH, Mason AD, et al. Influence of the burn wound on
local and systemic responses to injury. Ann Surg. 1977;186(4):444-458.

258.e1
23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
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246. Batstone GF, Levick PL, Spurr E, et al. Changes in acute phase reac­
tants and disturbances in metabolism after burn injury. Burns Incl
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247. Batstone GF, Alberti KGMM, Hinks L, Smythe P. Metabolic studies in
subects following thermal injury. Burns. 1976;2(4):207-225.
196. Klein GL, Herndon DN, Langman CB, et al. Long-term reduc­
tion in bone mass after severe burn injury in children. J Pediatr.
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197. Rutan RL, Herndon DN. Growth delay in postburn pediatric patients.
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198. Klein GL, Wolf SE, Goodman WG, Phillips WA, Herndon DN. The
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199. Hoscheit M, Conner G, Roemer J, et al. Burn injury has skeletal site-
specific effects on bone integrity and markers of bone remodeling.
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200. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of
osteoblastogenesis and promotion of apoptosis of osteoblasts and
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201. Canalis E. Clinical review 83: mechanisms of glucocorticoid action
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203. Manelli I, Giustina I. Glucocorticoid-induced osteoporosis. Trends
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208. Jeschke MG. Postburn hypermetabolism: past, present, and future. J
Burn Care Res. 2016;37(2):86-96.
209. Herndon DN, Voigt CD, Capek KD, et al. Reversal of growth arrest
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212. Colic M, Mitrovic S, Dujic A. Thymic response to thermal injury in
mice: I. Alterations of thymocyte subsets studied by flow cytometry
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214. Maldonado MD, Venturoli A, Franco A, Nunez-Roldan A. Specific
changes in peripheral blood lymphocyte phenotype from burn
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215. Organ BC, Antonacci AC, Chiao J, et al. Changes in lymphocyte
number and phenotype in seven lymphoid compartments after
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216. Selye H. Thymus and adrenals in the response of organism to injuries
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219. Gillis S, Crabtree GR, Smith KA. Glucocorticoid-induced inhibition
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220. Taniguchi T. Regulation of cytokine gene expression. Annu Rev
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258.e6 23  •  Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
248. Sevaljevic L, Petrovic M, Bogojevic D, Savic J, Pantelic D. Acute-phase
response to scalding: changes in serum properties and acute-phase
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249. Calvano SE, Albert JD, Legaspi A, et al. Comparison of numerical
and phenotypic leukocyte changes during constant hydrocortisone
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251. Volenec FJ, Wood GW, Mani MM, Robinson DW, Humphrey LJ.
Mononuclear cell analysis of peripheral blood from burn patients.
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252. Wallner S, Vautrin R, Murphy J, Anderson S, Peterson V. The haema­
topoietic response to burning: studies in an animal model. Burns Incl
Therm Inj. 1984;10(4):236-251.

259
The Hepatic Response to
Thermal Injury
MARC G. JESCHKE, OMAR NUNEZ LOPEZ, and CELESTE C. FINNERTY
24 
under normal conditions and following a severe insult such
as a burn injury.
Anatomy and Physiology of
the Liver
ANATOMY
In an average-sized adult, the liver weighs approximately
1500 g, making up almost 2% of the total body weight.
Following a severe burn injury, the liver size can increase
significantly to meet additional demands. The Couinaud’s
segmental system, the preferred anatomy classification
system, divides the liver into eight independent functional
units (termed segments) rather than relying on the tradi­
tional morphological description based on the external
appearance of the liver. Roman numerals (I–VIII) delineate
the segments based on the dual vascular inflow, biliary
drainage, and lymphatic drainage within each segment.17
PHYSIOLOGY
A broad spectrum of biological functions is orchestrated by
the liver. The interrelated physiologic-anatomic units of the
liver direct the following processes:
a. Energy homeostasis and nutrient metabolism: the syn­
thesis, degradation, and coupled interconversion of
amino acids, carbohydrates, and lipids are closely
linked to hepatic energy metabolism.
b. Protein synthesis and amino acid metabolism: The liver
uses amino acids directly for protein synthesis and as
a source of organic nitrogen for nonessential amino
acid synthesis. The overall balance of amino acid syn­
thesis, degradation, dietary supply, and body distribu­
tion is reflected by plasma amino acid levels.
c. Carbohydrate metabolism: The liver plays an impor­
tant role in maintaining carbohydrate homeostasis,
principally through glucose catabolism, production,
and storage. The ability to use, store, synthesize,
and release glucose gives the liver a central role in
maintaining stable serum glucose levels. Compro­
mise of this function can result in hypoglycemia or
hyperglycemia.18
d. Lipid metabolism: Hepatic metabolic energy require­
ments are met principally through β-oxidation of free
fatty acids (FFA). Fatty acids synthesized in the liver
or derived from peripheral fat depots combine with
glycerol in the liver to form triglycerides (TG). Through
Introduction
The extreme hypermetabolic and hypercatabolic stress
responses induced by a severe burn injury are characterized
by increased proteolysis, lipolysis, and production of endog­
enous glucose via glycogenolysis and gluconeogenesis. The
critical organ controlling these processes is the liver. With
major roles in metabolism, inflammation, immunity, and
the acute-phase response, the liver orchestrates the basic
functions that modulate survival and recovery in severely
burned patients. The function of the liver following a severe
burn injury has been elucidated, demonstrating that the
preservation of liver function is associated with survival.
The strong correlation between postburn survival and the
expression of cytokines and acute-phase proteins (APPs)
produced by the liver further supports this contention.
Worldwide, the World Health Organization (WHO) attri­
butes approximately 265,000 deaths each year to burn
injuries and their sequelae, with the vast majority of these
injuries occurring in low- and middle-income countries.1
In the United States alone, burns result in approximately
4000 deaths, 24,500 hospitalizations, and more than
745,000 nonhospitalized injuries per year, with an inci­
dence rate of 280 burns (per 100,000 people).2,3 The effects
induced by burns are not limited to the injured area alone.
A severe burn injury has devastating effects on the injured
patient by affecting almost every organ system, resulting in
greater morbidity and mortality.4 Amplified glucose avail­
ability leads to increased protein catabolism and lipolysis,
initiating the postburn hypermetabolic stress response.4–6
Systemic inflammation, including pathophysiologic regula­
tion of cytokines, hormones, and APPs, drives the hyper­
metabolic response.7–9 Prolongation or amplification of
the hypermetabolic or inflammatory responses may result
in dysregulation of counterregulatory stress hormones
(catecholamines, cortisol, glucagon), thereby exacerbat­
ing postburn hypercatabolism, multiorgan failure, and
death.10,11
For more than 20 years, reductions in morbidity and
mortality have resulted from research efforts focused on
improving postburn resuscitation, hypermetabolism, infec­
tion control, ventilation, and wound healing.5 Greater
advances in clinical care, however, are needed to reduce
morbidity and mortality even further. With a series of
studies, we have concluded that the liver plays a fundamen­
tal role in the systemic response to burn.12–16 Through the
modulation of immune, inflammatory, metabolic, and
acute-phase response signal transduction pathways, the
liver contributes greatly to survival and recovery following
a severe burn injury.11 This chapter discusses liver function

24  •  The Hepatic Response to Thermal Injury
260
The Hepatic Response to a Severe
Thermal Injury
LIVER DAMAGE AND MORPHOLOGICAL
CHANGES
Burn-induced liver injury is variable and is typically propor­
tional to the severity of the burn injury. Hepatomegaly, or
a fatty liver, is a common postburn finding (Fig. 24.1).
These changes can be reversed; however the significance of
these alterations is related to the extent of fat deposition and
its etiology.29 Autopsies of deceased pediatric burn victims
revealed that fatty infiltration of the liver is associated with
hepatic failure and endotoxemia.30 Increased hepatic
edema, typically observed within 12 hours after burn
injury, is associated with damage to the liver. Both liver and
body weight significantly increase at 2–7 days postburn, as
compared to nonburned liver/body weight.13 In burned
rats, total hepatic protein concentrations are reduced sig­
nificantly, suggesting that the increase in liver weight is due
to edema and not to increased protein levels or hepatocyte
numbers. Hepatic edema may induce release of hepatic
enzymes into the circulation as a result of cellular damage
or by altering membrane permeability. Aspartate amino­
transferase (AST) and alanine aminotransferase (ALT) are
typically detected only at low levels in plasma. Therefore,
detection of elevated levels in the circulation indicates pos­
sible hepatocyte injury. Severe hepatic damage can also be
detected by elevations in serum glutamate dehydrogenase
or alkaline phosphatase (ALKP). Elevations in ALKP provide
insight into the function of the extrahepatic biliary tract
and are frequently elevated in hepatobiliary disease. The
liver damage induced by thermal injury is secondary to
edema formation, hypoperfusion, and inflammation. Fol­
lowing a severe burn, elevations between 50% and 200%
of AST, ALT, and ALKP are observed (Fig. 24.2). These
serum markers peak early during the first 24 hours after
the burn injury, indicating that burn-induced liver damage
is a rapid phenomenon.14,31
Increased hepatocyte death, both by apoptosis and necro­
sis, is associated with liver damage.13 Two distinctly differ­
ent pathways result in cell death: programmed cell death
(apoptosis) and necrosis.32 Cell shrinkage, uniform frag­
mentation of DNA, and membrane blebbing characterize
apoptotic cells. Necrosis, on the other hand, is characterized
by cellular swelling, fragmentation of the DNA in a random
manner, activation of lysosomes, and complete breakdown
of the cellular membrane enabling cellular contents to be
extruded into the interstitium. These final steps induce an
inflammatory response by attracting inflammatory cells,
causing the release of free radicals and proinflammatory
cytokines, leading to additional tissue breakdown. The mor­
phological hallmarks unique to each process are used to
differentiate between apoptotic and necrotic cells. At the
time of autopsy, 10–15% of severely burned decedents had
signs of liver necrosis, as determined by pathological
examination.33
Apoptosis also occurs in the liver following a cutaneous
thermal injury (Fig. 24.2).13 The liver tries to maintain
homeostasis when hepatocyte apoptosis increases by a
compensatory increase in hepatocyte proliferation. Despite
the production of very-low-density lipoproteins
(VLDL), the liver provides peripheral tissues with indi­
rect access to the convergent metabolic processes in
the hepatocyte that lead to triglyceride synthesis. Fol­
lowing synthesis by the liver, high-density lipopro­
teins (HDL) circulate in the plasma, where they
scavenge free cholesterol released from aging cell
membranes. The liver also produces apoprotein CII,
which is required for the peripheral activation of lipo­
protein lipase, and cholesterol.19,20
e. Biotransformation: Many environmental compounds
(including drugs) and endogenous metabolic prod­
ucts are lipid soluble and nonvolatile, precluding
their efficient excretion in urine or feces. Through
biotransformation reactions, the liver transforms
these substances into more water-soluble analogs
and enhances their excretion via urine or bile.21
f. Excretion: The biliary tract is the principal excretory
route for numerous exogenous and endogenous sub­
stances. Six hundred to eight hundred milliliters of
bile are secreted daily, using a canalicular surface
area of approximately 10 m2. Inorganic ions account
for most of the osmotic activity in bile, keeping it
approximately isotonic with plasma. Organic solutes
present in bile include conjugated bile acids, phos­
pholipids (lecithin), cholesterol, bile pigments, hor­
mones, and small amounts of protein.22,23
g. Immunologic functions: A major portion of the mono­
nuclear phagocyte system is centered in hepatic sinu­
soids. Kupffer’s cells use phagocytosis and pinocytosis
to clear bacteria, particulate matter, and old erythro­
cytes from sinusoidal blood. Kupffer’s cells are also
the major site of lipopolysaccharide (endotoxin)
detoxification. The liver also contributes to the
humoral arm of body defense through uptake and
secretion of IgA.24
h. Vitamin metabolism: Vitamin uptake, storage, and
mobilization are additional important functions of
the liver. The absorption of fat-soluble vitamins (A, D,
E, and K) is dependent on bile salts. Because vitamin
A is stored exclusively in the liver, excess ingestion
may be associated with significant hepatic injury.
Hepatic stellate cells play a role in vitamin A storage
as well. The initial vitamin D activation step, conver­
sion of vitamin D3 to 25-hydroxycholecalciferol,
occurs in the liver. Coagulation factors II, VII, IX, and
X are dependent on vitamin K, which is essential for
the γ-carboxylation and activation of these factors.
Vitamin E has recently garnered much attention due
to its potent antioxidative properties. Following a
severe thermal or traumatic injury, vitamin E might
reduce oxidative stress and subsequent damage.25–27
i. Hormonal system: The liver is an important site of
hormonal synthesis, secretion, or interaction. Growth
factors that are important for growth and develop­
ment such as insulin-like growth factor-I (IGF-I) and
the IGF binding proteins (IGFBPs) are made and
secreted by the liver. Production and secretion into
the bloodstream of angiotensinogen occurs within
the liver. Synthesis of hepatocyte growth factor
(HGF), a major hepatic regenerative growth factor,
occurs in the liver.28

24  •  The Hepatic Response to Thermal Injury
261
Time postburn
* Significant difference
burn vs. normal, P < .05
*
*
*
*
Week 1
Normal Range
D/C
Week 3
Week 2
Liver size
% to Predicted
260
140
120
160
100
220
240
200
180
Ai
B
Aii
Fig. 24.1  A, Massive hepatomegaly (i) and hepatic fatty infiltration (ii) of a burn victim at autopsy. B, Liver size increased throughout acute hospitaliza­
tion by over 200% in 242 surviving burn patients. (From Jeschke MG. The hepatic response to thermal injury: is the liver important for postburn outcomes?
Mol Med. 2009;15:337–351.)
*
*
AST (U/L)
100
200
300
400
500
600
0
C
B
24
C
B
48
*
*
ALT (U/L)
20
40
60
80
100
120
140
160
180
200
Control
Burn
0
C
B
24
C
B
48
*
*
Albumin (g/dL)
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
0.0
C
B
24
C
B
48
*
*
Caspase-3
(OD/OD actin)
0.1
0.2
0.3
0.4
0.0
C
B
24
C
B
48
*
*
TUNEL-positive cells (%)
1
2
3
4
0
C
B
24
C
B
48
A
D
Ei
Eii
F
B
C
Fig. 24.2  Hepatic dysfunction of the rat burn model mimics the postburn human disease state. A, Serum aspartate amino transferase (AST) 24 and 48
hours after thermal injury. B, Serum alanine amino transferase (ALT) 24 and 48 hours after thermal injury. C, Serum albumin 24 and 48 hours after
thermal injury. D, Caspase-3 activity in liver lysates as determined by successive Western blotting with active caspase-3 and actin antibodies. The data
are expressed as a ratio of the two band intensities. E, TUNEL staining of a liver section before (i) and 24 hours after (ii) thermal injury. F, Quantified
TUNEL-positive cells 24 and 48 hours after thermal injury. Time after injury in hours is indicated. C, Control; B, burn. Data presented are mean ± SEM.
*P < 0.05 (Burned animals n = 8 and controls n = 4 per time point). *Significant difference between burn and control, P < 0.05. (From Jeschke MG. The
hepatic response to thermal injury: is the liver important for postburn outcomes? Mol Med. 2009;15:337–351.)

24  •  The Hepatic Response to Thermal Injury
262
increases in cytosolic calcium.46 Mitochondrial damage
occurs as a result of increased cytosolic calcium, leading to
the release of cytochrome c, which then binds to the inositol
triphosphate receptor (IP3R), causing a reduction in the
amount of calcium stored in the ER. In addition, ER stress
triggers apoptosis by activating c-Jun N-terminal-kinases
(JNK). The serine on the insulin receptor substrate 1 (IRS-1)
protein is then phosphorylated, blocking the tyrosine on the
same protein from being activated by phosphorylation. At
the same time, the prosurvival phosphoinositide 3-kinase
(PI3K)/serine-threonine protein kinase (Akt) signaling
pathway is blocked, amplifying the ER stress response by
further activating the inositol triphosphate receptor (IP3R).
If the unfolded protein burden can be limited through the
use of chemical chaperones, this discovery may be of thera­
peutic significance as a method to promote hepatocyte sur­
vival.47 Alternative pharmacologic agents are being
developed to block proapoptotic ER stress signaling path­
ways, and, looking ahead, these alternatives may prove
beneficial by improving clinical outcomes.48,49
EFFECTS ON THE BILIARY SYSTEM
Intrahepatic cholestasis frequently occurs following trauma
or sepsis without demonstrable extrahepatic obstruction.
Drug toxicity, total parenteral nutrition, and hypoxia are
also associated with this phenomenon.50 The occurrence of
intrahepatic cholestasis is associated with impaired bile acid
and organic anion transport in basolateral and canalicular
hepatocytes.51,52 Intrahepatic cholestasis occurs in approxi­
mately 26% of patients.33
MONONUCLEAR PHAGOCYTE SYSTEM (MPS)
The immune system is severely compromised following a
major thermal injury, resulting in heightened susceptibility
to infections and sepsis.51,53,54 The phagocytic functions of
the mononuclear phagocyte system (MPS) are depressed
postburn,55 although the mechanism by which this occurs
is unknown. Investigations have demonstrated that MPS
dysfunction may be related to hemolysis. By regulating the
production of APPs and proinflammatory cytokines, the
liver modulates the immune response.43,56,57
Glucose, Protein, and Lipid Metabolism
Hypermetabolic stress is induced by large burns covering in
excess of 40% of the total body surface area (TBSA), and
this response is accompanied by inflammation, the develop­
ment of hyperdynamic circulation, temperature elevation,
and increased glycolysis, gluconeogenesis, glycogenolysis,
proteolysis, and lipolysis.58–60 These massive alterations
affecting major physiologic processes occur following
traumatic injury and critical illness as well, although the
duration, severity, and the magnitude of these responses
are far greater in severely burned patients.5 Exaggerated
elevations in catecholamines, glucocorticoids, glucagon,
and dopamine trigger the hypermetabolic response via a
highly complex cascade of events.4,31,61 Additional factors
in this response, however, have been identified, including
proinflammatory cytokines (IL-1 and IL-6, TNF), platelet-
activating factor, endotoxin, neutrophil-adherence com­
plexes, free radicals (reactive oxygen species and nitric oxide),
the attempt to maintain homeostasis in overall hepatocyte
number, the liver is unable to immediately regain mass or
maintain protein concentration. The molecular mecha­
nisms that initiate and propagate hepatocyte apoptosis fol­
lowing a cutaneous burn are not known.34–37 Blood flow to
the bowel is decreased by approximately 60% for up to 4
hours following a thermal injury.38 Hepatic blood flow is
likely decreased as well, and this may be one of the early
events inducing programmed cell death. Apoptotic signals,
including interleukin-1 (IL-1) and tumor necrosis factor-α
(TNF-α), increase systemically during this same time
frame.39–42 Additional studies have revealed that the eleva­
tions of proinflammatory cytokines are not limited to the
serum. Local elevations also occur after a thermal injury, as
seen with increased concentrations of hepatic IL-1α, IL-1β,
IL-6, and TNF-α.43–45 Taken together, these events are prob­
ably early events in the induction of hepatocyte apoptotic
signaling.
Underlying Molecular Mechanisms
The induction of hepatocyte apoptosis and dysfunction fol­
lowing a severe burn (Fig. 24.3), involves specific reduc­
tions in endoplasmic reticulum (ER) calcium that lead to
Hepatocyte
Burn
ER Ca2+ ↓
Apoptosis
Cytosolic Ca2+ ↑
ER stress ↑
Cytochrome C
release ↑
Mitochondrial
damage ↑
IP3R ↑
IP3R ↑
PI3K/Akt ↓
JNK
IRS-1
Insulin resistance
Metabolic dysfunction
Tyrosinep
Serinep
Fig. 24.3  Schematic of suggested pathways involved in the hepatic
response postburn. Thermal injury leads to gross alterations in endo­
plasmic reticulum (ER) calcium with increased cytosolic calcium con­
centration. Increased cytosolic calcium induces mitochondrial damage,
which releases cytochrome c. Cytochrome c increases the existing ER
stress/Unfolded protein response (UPR) but also binds to the IP3R, aug­
menting the depletion of ER calcium stores. ER stress/UPR leads to cell
apoptosis and activation of JNK, which phosphorylates the 612 serine
of IRS-1, blocking phosphorylation of tyrosine IRS-1. ER stress/UPR also
impairs the prosurvival PI3K/Akt signaling, resulting in increased acti­
vation of the IP3R, increasing ER stress/UPR. (From Jeschke MG. The
hepatic response to thermal injury: is the liver important for postburn
outcomes? Mol Med. 2009;15:337–351.)

24  •  The Hepatic Response to Thermal Injury
263
catecholamine-induced enhancement of glycogenolysis in
the liver and direct sympathetic stimulation of glycogen
breakdown.72 Peripheral insulin resistance occurs in the
muscle and adipose tissue when glucose disposal is impaired
by catecholamines following alterations in insulin signaling
and glucose transporter type 4 (GLUT-4) translocation.71,77
At 7 days postinjury, IRS-1 activation is impaired at the
tyrosine binding site, leading to Akt inhibition in muscle
from severely burned children.67 Protein farnesylation (a
posttranslational lipid modification of cysteine residues)
has been identified as an additional pathophysiologic mech­
anism involved in the metabolic dysfunction observed after
burn injury.78 Interference with the insulin signaling path­
ways in liver and muscle has also been linked to a reduc­
tion in mitochondrial oxidation in both tissues and altered
lipolytic rates, resulting in attenuation of insulin’s action
on glucose production in the liver and glucose uptake in
the liver.76,79 Glucose production via gluconeogenesis and
glycogenolysis is increased by glucagon and epinephrine,
which, in concert with cortisol and growth hormone (GH),
act to sustain this response.69,80 Release of the aforemen­
tioned stress hormones is initiated by the action of proin­
flammatory cytokines, resulting in an indirect effect of these
inflammatory mediators on postburn hyperglycemia.81–84
These same proinflammatory cytokines, including IL-6,
monocyte chemotactic protein-1 (MCP-1), and TNF, have
been found to directly modify the insulin signal transduc­
tion pathway, further exacerbating postburn insulin resis­
tance in the liver and skeletal muscle.85,86 Throughout the
acute and convalescent periods following the burn injury,
breakdown of lean muscle protein is prolonged by the sup­
raphysiological expression of proinflammatory cytokines
and perturbations in the metabolic pathways.8,87,88 Thermal
injury impairs the body’s ability to use fat as an energy
source. Significant variation in the expression of the coun­
terregulatory hormones glucagon and cortisone occurs
postburn. While burn injury decreases glucagon, there is a
and factors involved in the coagulation and complement
cascades.62 Following activation of the biological processes,
these mediators and the resulting byproducts contribute to
the increased metabolic rate and altered glucose metabo­
lism that occurs following thermal injuries.63
The precise temporal occurrence of the modulation of
these postinjury metabolic events has led to the classifica­
tion of two events: the “ebb phase” and the “flow phase.”64
The first 12–14 hours following a severe burn injury are
called the “ebb phase.”65,66 Events characterizing this period
include decreased cardiac output, reduced oxygen con­
sumption, attenuated metabolic rate, and hyperglycemia
with impaired glucose tolerance. These metabolic processes
slowly increase to a plateau over the next 5-day period,
termed the “flow phase.”64 During this time, insulin release
in response to glucose challenge is twice that seen in non­
burned volunteers. Insulin resistance characteristically
develops concurrent with elevation in plasma glucose levels
during this period67 (Fig. 24.4). Although these metabolic
alterations were assumed to resolve as soon as wound
closure was complete, impaired glucose metabolism has
been demonstrated in approximately 12% of pediatric burn
injury survivors 24–36 months after severe thermal inju­
ries; burn size, age, lean mass, and adiposity are predictors
of insulin resistance in burned children.68
Because the metabolic alterations that accompany criti­
cal illness have the potential to modify energy substrate
utilization, glucose availability must be maintained. Stress
mediator release acts in opposition to the anabolic actions
of insulin by augmenting hepatic glucose production69 to
increase gluconeogenic substrates such as glycerol, alanine,
and lactate by increasing lipolysis of adipose tissue and
proteolysis of skeletal muscle.70–74 The release of hepatic
glucose is not suppressed by hyperglycemia, and the physi­
ologic inhibitor property of insulin on glycogenolysis is
impaired, inducing posttrauma hyperglycemia.75,76 The
hyperglycemic response to stress is further aggravated by
Lactate
Wound
6 carbon 3 carbon flow
Heat

± Insulin
++++ Catecholamines
++++ Glucagon
++++ Glucocorticoids

± Insulin
++++ Catecholamines
Glycogen
Protein
3-C
3-C
Heat
Glycogen
Protein
Urea
Fat
Fatty
acids
Triglycerides
Glucose
Anaerobic metabolism
Skeletal muscle
Liver
Fig. 24.4  Metabolic changes postburn with the liver playing an essential role. (From Jeschke MG. The hepatic response to thermal injury: is the liver
important for postburn outcomes? Mol Med. 2009;15:337–351.)

24  •  The Hepatic Response to Thermal Injury
264
there is a reduction in secretion of VLDL-TGs, which is not
responsive to the increased synthesis of liver TGs.104 It
would therefore be expected that reducing FFA availability
could minimize accumulation of TGs in the liver.
The liver is clearly a key player in the orchestration and
modulation of burn-responsive metabolic processes post­
burn. Alterations in the metabolism of glucose, fat, and
protein can result in poor outcomes, and these processes are
controlled by the liver. Therefore, we propose that the liver
is an essential organ in the response to severe burn injury
and that liver function may determine outcomes of severely
burned patients.
Acute-Phase Response
There is a shift in hepatic protein synthesis following a major
trauma such as a severe burn injury. Hepatic constitutive
protein production is downregulated while production is
shifted to increase APPs.11,31,57 This shift in production of
APPs represents a reprioritization of liver function to meet
new metabolic demands, heighten the immune and inflam­
matory responses, and support coagulation and wound
healing.57 Traditionally APPs have been divided into two
subcategories based on whether they were mediated by
IL-1-like cytokines such as IL-1 or TNF (type I APPs, e.g.,
haptoglobin or α1-acidglycoprotein) or IL-6-like cytokines,
including IL-6 or IL-11 (type II APPs, e.g., α2-macroglobulin
and fibrinogen).11 As more evidence supports frequent com­
munication between the type I and type II APPs, this strict
division appears to be an artificial categorization that is no
longer representative of function or response. While acute-
phase protein synthesis is upregulated, constitutive hepatic
proteins, including albumin, transthyretin, transferrin,
and retinol binding protein, are downregulated.108–111 Rela­
tive to normal levels, albumin and transferrin expression
decrease by 50–70% following a severe burn. Two mech­
anisms downregulate the production of these proteins:
the liver shifts from synthesizing constitutive proteins to
APPs, coupled with extensive loss of constitutive proteins
due to capillary leakage. These proteins are lost into the
massive extravascular space and burn wound. The loss of
these proteins following trauma, however, may negatively
impact clinical outcomes. Albumin and transferrin are
important transporter proteins and contribute to regula­
tion of both osmotic pressure and plasma pH. Due to the
exclusive roles that these proteins play, reduction in their
synthesis has been used to monitor recovery and predict
mortality.111–113
As noted earlier, cytokines also mediate the acute-phase
response. The temporal, biphasic modulation of proinflam­
matory cytokine expression is highly regulated and predict­
able. Immediately following a burn, there is an increase in
IL-1, IL-6, IL-8, and TNF expression that peaks between
2- and 10-fold above normal levels. After approximately 12
hours, there is a slight decrease in expression, followed by
another increase before the overall levels begin to decline. As
a testament to the extreme nature of a burn compared with
other traumatic injuries, both animal and human studies
have revealed that, following a traumatic injury, cytokines
return to normal levels within 2 days, whereas the elevation
can last for more than 2 weeks after thermal injury.114,115
The signaling cascade modulating this response includes a
multitude of pro- and antiinflammatory signal transcription
marked increase in cortisone levels that lasts for at least 3
years postinjury.61,89 Although the likelihood that perturba­
tions of the hormonal system drive postburn hyperglyce­
mia is low, impairment of insulin receptor signaling at the
molecular level is the more probable instigator.90
Soon after injury, marked lean body mass wasting is
driven by the increase in energy requirements, which are
mainly satisfied by degradation of proteins in skeletal
muscle in severely burned individuals.5,91 Stable isotope
infusion studies have confirmed that this muscle break­
down is associated with pronounced negative nitrogen bal­
ances that persist for up to 9 months postinjury.58 Significant
reductions in muscle mass probably contribute to whole-
body postburn insulin resistance, as the majority of insulin-
stimulated glucose uptake occurs in the skeletal muscle.92
Stable isotope studies using leucine to monitor whole-body
protein flux confirmed the relationship between hyperglyce­
mia and muscle protein catabolism and even showed that
hyperglycemia increases proteolysis.93 Significantly elevated
rates of infection and delayed wound healing are associated
with reductions in lean body mass of 10–15%.94 The growth
delay in severely burned pediatric patients that lasts for up
to 2 years may be accounted for by this persistent protein
catabolism.58,95–97
During the acute response to burn, there are significant
changes in the metabolism of fat, which lead to elevations
in serum TGs and FFA, along with changes in body fat
content and distribution.98 This massive mobilization of fat
tissue results in fatty deposits in the liver and other organs,
most likely due to decreased expression of fat-transporting
proteins coupled with elevations of serum TGs and FFA.
Hepatomegaly with hepatic steatosis is associated with
increases in septic episodes and ultimately with greater
mortality,30 further supporting the notion that impaired
liver function in the severely burned patient is closely linked
to survival. The hepatic accumulation of TGs occurs both
in critically ill patients and in severely burned patients.99–101
In fact, liver size is increased by more than fourfold in
severely burned patients.30,102 Despite the similar deposition
of TGs in the liver following critical illness, the rate of TG
accumulation in the postburn liver is far greater than that
of any other pathological condition with hepatic steatosis
as a sequelae. Hepatic TGs accumulate following a severe
burn, resulting from lipolysis induced by β-adrenergic stim­
ulation that releases excessive amounts of fatty acids into
the circulation.103,104 Although insulin typically suppresses
lipolysis, the burn-induced insulin resistance is apparent by
the diminished effectiveness of insulin in this capacity.100
Uptake of fatty acids from the circulation by the liver is
proportionate to the amount of FFAs available,20,105 as lipol­
ysis increases FFA delivery, hepatic uptake is increased, and
the fatty acids are either oxidized or synthesized into TGs.
Because oxidation is a rate-limited step, there is a marked
acceleration in the rate of TG synthesis and deposition
when large amounts of fat are available either due to lipoly­
sis or diet.106 Synthesis of hepatic TGs is considered to be a
direct metabolic response to a severe burn injury. Excessive
intake of glucose and consequent hyperglycemia also lead
to postburn hepatic steatosis.107 Under normal conditions,
increases in VLDL-TG secretion accompany accelerated
synthesis of hepatic TGs, which reduces the accumulation
of TGs in the liver. However, in severely burned patients,

24  •  The Hepatic Response to Thermal Injury
265
scavenging properties of vitamin C are crucial following
a burn injury. As part of the hypermetabolic response,
an elevation in free radicals including superoxide, per­
oxide, and hydroxyl is thought to increase burn-induced
vascular permeability. Administration of vitamin C may
reduce microvascular permeability, which would reduce
the need for fluid replacement, in turn improving patient
outcomes.125
Coagulation and Clotting Factors
A severe burn injury alters the coagulation cascade and
activates thrombotic and fibrinolytic responses. During the
early shock phase following the burn, there is a decrease in
most of the homeostatic markers due to dilutional effects
associated with fluid resuscitation and loss or degradation
of plasma proteins to the extravascular space or the wound.
Once resuscitation is achieved, clotting factors typically
return to normal levels. Thrombogenicity increases later
during the postburn course as a result of decreases in anti­
thrombin III, protein C, and protein S levels resulting in an
increase in the risk of thrombosis. The risk for developing
disseminated intravascular coagulation (DIC) is consider­
ably heightened by this hypercoagulable state. Postmortem
DIC has been discovered in 30% of all examined cases, indi­
cating another association between liver damage and poor
outcomes.126
Hormones
The liver is a major site for hormone synthesis and action.
In vitro and in vivo studies have demonstrated that HGF
accelerates hepatic regeneration, improves hepatic func­
tion, and modulates the acute-phase response.127–129 Eleva­
tion of plasma HGF occurs within 30–60 minutes following
injury, presumably signaling the hepatocytes to begin divid­
ing in order to meet the anticipated burden. The initiating
signal that stimulates plasma HGF upregulation, however,
is currently unknown, although it has been hypothesized
that there is either an increase in extrahepatic production
of HGF by the spleen, lung, gut, or kidney or a decrease in
excretion of hepatic HGF. Hepatocyte DNA synthesis is stim­
ulated by this rapid increase in HGF.28 HGF only has this
effect under specific conditions; when administered to non­
injured rats, only a small number of hepatocytes were
induced to initiate DNA synthesis. This study demonstrated
that priming events—such as those experienced following
a burn injury—are required to enable hepatocytes to
respond to mitogenic signals.28
IGF-I is also synthesized in the liver.130 In the body,
approximately 99% of IGF-I is bound to one of the six
binding proteins, IGFBP 1–6, for transport.131 These hor­
mones are synthesized in the liver following GH stimula­
tion.132 The effects mediated by IGF-I are similar in burn
and other pathological states—improvements in cell prolif­
eration, cell repair mechanisms, increased protein expres­
sion in the muscle, and restored normal functioning of
intestinal and immune cells.133–135 In the immediate post­
trauma and postburn periods, IGF-I is a key player in regen­
erating the liver and modulating the acute-phase response
to restore hepatic homeostasis and function.135,136 The
influence of hormones on hepatic recovery and regenera­
tion is an important consideration when trying to restore
hepatic function.
factors including nuclear factor-κ B (NF-κB), c-jun, tyro­
sine phosphorylation and activation of intracellular tyro­
sine kinases (JAKs), CCAAT/enhancer-binding proteins
(C/EBPs), signal transducer and activator of transcription
(STAT) 1, STAT3, STAT5, latent cytoplasmic transcrip­
tion factors, and mitogen-activated protein.56,108,109,116–119
Transcription, translation, and expression of APPs are
initiated by the action of these signaling molecules. IL-6
in particular is suspected of being a major—if not the
primary—mediating cytokine. Amplification of the IL-6
signal occurs by activation of glycoprotein 130 (gp 130)
and the JAK-kinases (JAK-1) and propagation of the signal
via translocation of STAT1 and STAT3 to the nucleus,
where transcription and translation of APPs occur. This
rapid initiation of the acute-phase response serves a single
purpose: to protect the body from further damage. When
the acute-phase response occurs in a balanced fashion, the
body is protected and returns to a homeostatic existence.
When there are prolonged amplifications of proinflamma­
tory cytokines and APPs, however, hypercatabolism results,
leading to increased incidence of sepsis, multiorgan failure,
morbidity, and mortality.8,10,112
Vitamin Metabolism
Vitamins are requisite components of many biological func­
tions including energy production and utilization, inflam­
mation, wound healing, metabolism, and antioxidation.
Vitamin deficiencies are caused by the burn-induced hyper­
metabolic response, so supplementation is required to main­
tain crucial biological functions.120,121 Vitamin A is reduced
in burn patients, perhaps related to reduced levels of its
transporter—retinol binding protein. Without vitamin A,
dermal wound repair is suboptimal, and supplementation
with this vitamin may enhance wound healing. Vitamin E is
a critical antioxidant that has profound effects in reducing
lung injury.27 Because this vitamin is also depleted in the
serum and in the tissue following a burn injury, supplemen­
tation is also recommended. Vitamin D, a necessary nutrient
to maintain bone health, is also reduced following a burn
injury, contributing to postburn osteopenia and increas­
ing the risk of bone fractures; vitamin D3 supplementation
after burn injury and beyond the acute period is advocated
to counteract the trajectory of low vitamin D levels and
associated morbidity.122–124 Riboflavin and thiamin, also
reduced by burn injury and trauma, are important par­
ticipants in energy generation, protein metabolism, and
wound repair. Thiamin is a key co-factor for energy gen­
eration in the Krebs cycle, for glucose oxidation, and for
the formation of collagen. Riboflavin decreases postburn;
due to its role as a coenzyme in oxidation-reduction reac­
tions, this vitamin should also be supplemented.120 Post­
burn reduction of folic acid negatively impacts DNA and
RNA synthesis. Folate utilization is also impaired by inad­
equate availability of vitamin B12 and methionine. Folate
deficiency therefore can also occur as a result of defi­
cient levels of these two nutrients. Energy-generating and
protein metabolic processes rely on the coenzymes vitamin
B6 and B12. Supplementation should be in the form of a
multivitamin in order to have adequate levels of these nec­
essary components. Additional functions of these vitamins
include fatty acid catabolism (vitamin B12) and metabolism
of amino acids (vitamin B6). The antioxidant/free radical

24  •  The Hepatic Response to Thermal Injury
266
(Fas/FasL).139 Through a series of RNA interference studies,
Song et al.140 elegantly demonstrated that reduction in the
expression of Fas is protective during fulminant hepatitis.
Silencing Fas prevented death, leading to the conclusion
that hepatic dysfunction contributes to mortality and res­
toration of hepatic function reduces mortality. Although
investigation of the role of Fas/FasL in burns is still in its
early stages, evidence supports the postburn induction of
Fas/FasL141 possibly hinting at the mechanism underlying
burn-induced hepatocyte apoptosis and dysfunction.
Because animal models do not fully recapitulate the
human clinical response, prospective clinical studies are
necessary to determine the relationship between liver func­
tion and postburn outcomes. In a study conducted as part
of the Inflammation and the Host Response to Injury Col­
laborative Research Program, we used discovery proteomics
to compare plasma protein expression in survivors and
nonsurvivors of severe burn injuries.142 A total of 32
patients, including 16 nonsurvivors and 16 survivors were
matched according to burn size and injury severity. Discov­
ery proteomics techniques were used to determine plasma
protein expression. In burn patients, 43 proteins were asso­
ciated with mortality. The main activity of the associated
proteins involve the complement cascade, coagulation
cascade, acute-phase response pathway, and cytokine sig­
naling suggest that the response of the liver may be crucial
to survival following a burn injury.142
Another study involving 330 burned children deter­
mined whether proteomics could be used to augment clini­
cal parameters as predictors of mortality in pediatric burn
patients. The study showed that the combination of both
clinical and proteomic variables improved the outcome pre­
diction accuracy from 52% to 81%. The panel of 38 poten­
tial biomarkers included hormones, proteins, and cytokines,
and most of these biomarkers are produced by the liver.
Taken together, the data in severely burned children and
adults indicate that the liver is crucial for determining sur­
vival and postburn outcomes.143
Conclusion
To summarize, the widespread effects of a burn injury
impact almost every organ system, resulting in significant
morbidity and mortality.5 This chapter has explored the
liver’s central role in the response to severe thermal injury.
Myriad functions of the liver are essential for survival (Fig.
24.5), and the burn injury alters all of these hepatic
responses. Available data provide strong evidence that the
concentrations of hepatic proteins in the circulation can
serve as biomarkers predictive of postburn morbidity and
mortality. We therefore interpret these findings as support­
ing the central role of the liver in determining patient
outcome and propose that attenuation of liver damage and
restoration of hepatic function will result in a reduction of
postburn morbidity and mortality.
Acknowledgments
This chapter was supported by grants from the American
Surgical Association Foundation, the Shriners Hospitals for
Children (71008 and 84080), the NIH (P50-GM060338,
T32-GM-008256, R01-GM56687, R01-GM087285, and
Importance of the Liver for
Postburn Outcomes
We have described liver function under normal and severe
stress conditions. In addition, it is important to emphasize
that it is not known whether liver function and integrity are
essential for favorable outcomes following a severe burn.
Price et al. found an association between impaired liver
function and integrity, and unfavorable postburn outcomes,
in a retrospective study.137 Our group and others have con­
ducted several studies to determine the relationship between
liver function and burn outcomes. In a review of autopsies
from severely burned children, Barret et al. reported the
incidence of hepatomegaly, fatty liver, and sepsis. Approxi­
mately 80% of the patients had hepatic fat infiltration,
whereas 100% of the patients had hepatomegaly.30 Addi­
tionally the incidence of sepsis was greater in patients with
severe fatty infiltration of the liver. In a study of 102 severely
burned children, burn injury was associated with liver
enlargement in all patients regardless of outcome.14 During
the first week following a burn injury, liver size was signifi­
cantly increased (+185 ± 5%), peaked during the second
postinjury week (+226 ± 19%), and remained significantly
enlarged (+189 ± 10%) at the time of discharge. Prolonged
alteration of the hepatic structure was indicated by the con­
tinued increase in predicted liver weight (+140–150%)
even 6, 9, and 12 months postburn. Synthesis of hepatic
proteins was impaired for at least 12 months following the
burn injury. Based on this study, it was concluded that a
severe burn injury induced significant enlargement of the
liver concurrent with impaired hepatic protein synthesis.
Mittendorfer et al. determined the contributions of hepa­
tomegaly and hepatic steatosis to outcomes following a
severe burn in the well-established rodent model.106 Follow­
ing a burn covering 60% TBSA, nutritional manipulation
was used to induce fatty liver in a subset of rats. Hepato­
megaly and hepatic steatosis were induced by consumption
of a high-fat diet. If both hepatomegaly and fatty liver were
present, postburn mortality increased to 40% (compared
with 0% in the control group). Based on these findings, we
concluded that the integrity and function of the liver were
crucial for survival after a severe burn injury because hepa­
tomegaly, hepatic steatosis, and liver dysfunction were asso­
ciated with increased postburn mortality. Other models
have been used to demonstrate the importance of liver func­
tion for survival after critical illness.138 In a murine sepsis
model, Deutschman et al. found that IL-6 knockout mice
were more likely to die as opposed to their littermates with
normal IL-6 expression. Hepatic alterations were apparent
in the IL-6 knockout animals following cecal ligation and
puncture. Cholestasis, steatosis, and hepatocellular injury
were not found in the normal mice but were apparent in the
IL-6 knockout animals; liver regeneration was absent in the
septic IL-6 knockout animals, while apparent in the control
group. The investigators demonstrated that IL-6 is a key
regulator of the pathological changes of the liver observed
after sepsis. The most interesting finding, however, was the
association of a three- to fourfold increase in mortality in
animals with hepatic damage or dysfunction.138 Hepatic
failure and concomitant hepatocyte apoptosis have been
linked to the signaling pathway involving Fas and Fas ligand

24  •  The Hepatic Response to Thermal Injury
267
Further Reading
Chondronikola M, Meyer WJ, Sidossis LS, et al. Predictors of insulin resis­
tance in pediatric burn injury survivors 24 to 36 months postburn. J
Burn Care Res. 2014;35(5):409-415.
Jeschke MG, Chinkes DL, Finnerty CC, et al. Pathophysiologic response to
severe burn injury. Ann Surg. 2008;248:387-401.
Jeschke MG, Micak RP, Finnerty CC, et al. Changes in liver function and
size after a severe thermal injury. Shock. 2007;28:172-177.
R01-GM112936), the NIH National Center for Advancing
Translational Sciences the NIDILRR (KL2 TR001441), and
the CFI Leaders Opportunity Fund (25407). The authors
have no conflicts of interest to disclose.
Complete references available online at

Coagulation
• Alterations in
clotting system
Hormonal system
• Alterations in
IGF-I, HGF, GH
Acute-phase response
• Increased acute-phase proteins
• Decreased constitutive proteins
• Increased cytokines
Biliary system
• Intrahepatic cholestasis
• Impaired intrahepatic
bile acid transporters
Metabolic response
• Hyperglycemia
• Insulin resistance
• Proteolysis
• Lipolysis
• Glycogenolysis
• Gluconeogenesis
Reticuloendothelial system
• Depressed RES response
• Immune compromise
Vitamin metabolism
• Decreased vitamin A,
B12, C, D, E
Fig. 24.5  Overview of hepatic functions and responses. (From Jeschke MG. The hepatic response to thermal injury: is the liver important for postburn
outcomes? Mol Med. 2009;15:337–351.)

267.e1
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268
Importance of Mineral and
Bone Metabolism after Burn
JEFFREY LISIECKI, BENJAMIN LEVI, and GORDON L. KLEIN
25 
hypercalcemia occurs followed by suppression of parathy­
roid hormone (PTH) secretion and PTH-stimulated renal
conversion of 25-hydroxyvitamin D to calcitriol (1,25-
dihydroxyvitamin D). With low Ca intake, the opposite
occurs.
These mechanisms are likely mediated by the parathyroid
chief cell Ca-sensing receptor (CaR). The CaR is a membrane-
bound G protein-coupled protein that may be up- or down­
regulated.3 In patients with CaR downregulation, higher
circulating Ca is required to suppress PTH production and
secretion, giving rise to primary hyperparathyroidism.4 In
patients with CaR upregulation, less circulating Ca is
needed, leading to hypoparathyroidism.5
Parathyroid hormone normally increases bone resorp­
tion and renal tubular Ca reabsorption to raise serum Ca
concentrations. Furthermore, it stimulates the renal enzyme
25-hydroxyvitamin D-1α hydroxylase to convert 25-
hydroxyvitamin D to 1,25-dihydroxyvitamin D or calcitriol.
Calcitriol then binds to intestinal epithelial cells and
increases transcellular Ca absorption.
Intravenous (IV) administration of Ca bypasses the intes­
tinal control mechanism and suppresses PTH and calcitriol
production.
PHOSPHATE
In contrast to Ca, the intestine plays no significant regulatory
role in the absorption of PO4. Approximately 80% of dietary
PO4 is absorbed, and the bone stores approximately 90% of
the body’s PO4. Homeostatic control appears to rest primar­
ily within the kidney.6,7 Thus, the renal excretory rate of PO4
primarily regulates serum PO4 concentrations and main­
tains them within a normal range. Fibroblast growth factor
(FGF)-23 is a key regulator of PO4 and vitamin D metabo­
lism in humans.8 FGF-23 gene mutations cause autosomal
dominant hypophosphatemic rickets, a phosphate-wasting
disorder. FGF-23-mediated renal phosphate wasting occurs
through downregulation of the type II sodium–phosphate
co-transporters NPT2a and NPT2c.8
MAGNESIUM
Approximately 60% of the body’s Mg is stored in the skel­
eton1 but not at sites where matrix is calcified. Mg absorp­
tion varies with dietary intake, with about 40% of an
average daily load being absorbed.1 The relationship
between Ca and Mg absorption is described as inverse, but
the mechanism of this is unclear. Renal excretion is the
main route of Mg elimination, and it may vary with Mg
Metabolic Actions of Calcium,
Phosphate, and Magnesium
As insoluble elements, minerals are major inorganic com­
ponents of bone tissue and confer weight-bearing proper­
ties to the skeleton. Soluble calcium (Ca), phosphate (PO4),
and magnesium (Mg) play important roles in metabolic
pathways, acting as cofactors and regulators of numerous
biochemical systems.
CALCIUM
Calcium functions in neurotransmission, cell depolariza­
tion, impulse propagation, and muscle contractility. In
intracellular pathways, after capture by Ca-binding protein
or protein kinase C, Ca serves as a second messenger. In
extracellular metabolism, Ca activates several factors in the
coagulation cascade.1
PHOSPHATE
Phosphate has an integral role in the storage and transfer
of energy. Inorganic phosphate groups are exchanged in
multiple metabolic reactions that allow energy-demanding
activities in the human body (e.g., adenosine triphosphate
[ATP] metabolism). Phosphorylation reactions represent
the mainstay of cellular respiration. In the form of phos­
pholipid, PO4 is a major structural component of cell
membranes.1
MAGNESIUM
Magnesium is essential to the cell and mitochondria. It is a
cofactor in the transfer of PO4 groups, and it is necessary in
reactions involving purine nucleotide metabolism.1 Mg also
functions in plasma membrane excitability, stabilizing con­
ditions characterized by abnormal nerve excitation or
vasospasm.
Homeostasis of Calcium,
Phosphate, and Magnesium
CALCIUM
Intestinal efficiency to absorb Ca is inversely related to Ca
intake, varying from 20% to 70%.2 The regulatory mecha­
nism is shown in Fig. 25.1. With high Ca intake, transient